Abstract:
The present invention relates to methods of regulating TNF receptor releasing enzyme (TRRE) activity. Composition altering TRRE activity, including a family of proteins and the genes encoding these proteins having TRRE activity, are provided. These proteins, RNA products, or DNA sequences can be administered to individuals suffering from a disease characterized by abnormal TRRE activity. In the case of diseases associated with elevated levels of TNF, such as rheumatoid arthritis, an inhibitor of TRRE is administered to the disease site to decrease the local levels of TNF. Methods of isolating other compositons which increase or decrease TRRE activity are also provided.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a continuation-in-part of patent application Ser. No. 08/964,747, filed Nov. 5, 1997, which is a continuation-in-part of Provisional Patent Application No. 60/030,761, filed Nov. 6, 1996. 
    
    
     FIELD OF THE INVENTION 
     This invention relates to the purification and characterization of factors that substantially alter tumor necrosis factor (TNF) receptor (TNF-R) releasing enzyme (TRRE) activity, and methods of use thereof. Modulation of TRRE levels indirectly modulates effective levels of TNF. The invention further relates to methods of treatment of pathological conditions caused or exacerbated by altered levels or activity of TNF such as inflammatory conditions including autoimmune diseases, infections, septic shock, obesity, cachexia, and conditions that are associated with decreased effective levels or activity of TNF such as cancer. 
     BACKGROUND OF THE INVENTION 
     Tumor necrosis factor (TNF or TNF-α) and lymphotoxin (LT or TNF-β) are related cytokines that share 40 percent amino acid (AA) sequence homology. Old (1987)  Nature  330:602-603. These cytokines are released mainly by macrophages, monocytes and natural killer (NK) cells in response to broad immune reactions. Gorton and Galli (1990)  Nature  346:274-276; and Dubravec et al. (1990)  Proc. Natl. Acad. Sci. USA  87:6758-6761. Although initially discovered as agents inducing hemorrhagic necrosis of tumors, these cytokines have been shown to have essential roles in both the inductive and effector phases of immune reactions and inflammation. The two cytokines cause a broad spectrum of effects on cells in vitro and tissues in vivo, including: (i) vascular thrombosis and tumor necrosis; (ii) inflammation; (iii) activation of macrophages and neutrophils; (iv) leukocytosis; (v) apoptosis; and (vi) shock. Beretz et al. (1990)  Biorheology  27:455-460; Driscoll (1994)  Exp. Lung Res.  20:473-490; Ferrante (1992)  Immunol. Ser.  57:417-436; Golstein et al. (1991)  Immunol. Rev.  121:29-65; and van der Poll and Lowry (1995)  Shock  3:1-12. For a review of the mechanism of action of TNF, see Massague (1996)  Cell  85:947-950. TNF has been associated with a variety of disease states including various forms of cancer, arthritis, psoriasis, endotoxic shock, sepsis, autoimmune diseases, infections, obesity, and cachexia. Attempts have been made to alter the course of a disease by treating the patient with TNF inhibitors. These attempts have met with varying degrees of success. For example, oxpentifylline did not alter the course of Crohn&#39;s disease, a chronic inflammatory bowel disease. Bauditz et al. (1997)  Gut  40:470-4. However, the TNF inhibitor dexanabinol provided protection against TNF following traumatic brain injury. Shohami et al. (1997)  J. Neuroimmun.  72:169-77. 
     Cachexia is pathological weight loss generally associated with anorexia, weakness, anemia, asthenia, and loss of body lipid stores and skeletal muscle protein. This state often accompanies burns, trauma, infection, and neoplastic diseases. Lawson et al. (1982)  Annu. Rev. Nutr.  2:277-301; Argiles et al. (1988)  Mol. Cell. Biochem.  81:3-17; and Ogiwara et al. (1994)  J. Surg. Oncol.  57:129-133. TNF concentrations are elevated in many patients with cachexia. Scuderi et al. (1986)  Lancet  2:1364-65; Grau et al. (1987)  Science  237:1210-1212; and Waage et al. (1986)  Scand. J Immunol.  24:739-743. TNF inhibits collagen αI gene expression and wound healing in a murine model of cachexia. Buck et al. (1996)  Am. J. Pathol.  149:195-204. In septicemia (the invasion of bacteria into the bloodstream), increased endotoxin concentrations may raise TNF levels, causing cachexia. Beutler et al. (1985)  Science  229:869-871; Tracey et al. (1987)  Nature  330:662-664; and Michie et al. (1988)  New Engl. J. Med  318:1481-1486. During cachexia, the loss of white adipose tissue is caused by the decreased activity of lipoprotein lipase (LPL); TNF lowers the activity of this enzyme. Price et al. (1986)  Arch. Biochem. Biophys.  251:738-746; Cornelius et al. (1988)  Biochem. J.  249:765-769; Fried et al. (1989)  J. Lipid. Res.  30:1917-1923; Semb et al. (1987)  J. Biol. Chem.  262:8390-8394; and Evans et al. (1988)  Biochem. J.  256:1055-1058. Fat tissue loss is also associated with an increase in lipase activity and inhibition of glucose transport; TNF is also linked to both of these changes. Kawakami et al. (1987)  J. Biochem.  331-338; Feingold et al. (1992)  Endocrinology  130:10-16; and Hauner et al. (1995)  Diabetologia  38:764-771. TNF mediates hypertriglyceridaemia associated with cachexia. Dessi et al. (1995)  Br. J Cancer  72:1138-43. TNF also participates in the protein wasting, loss of skeletal muscle and loss of nitrogen associated with cachexia. Costelli et al. (1993)  J. Clin. Invest.  92:2783-2789; Flores et al. (1989)  J. Clin. Invest.  83:1614-1622; Goodman (1991)  Am. J. Physiol.  260:E727-730; Zamir et al. (1992)  Arch. Surg.  127:170-174; Llovera et al. (1993)  J. Natl. Cancer Inst.  USA 85:1334-1339; and Garcia-Martinez et al. (1993)  FEBS Lett.  323:211-214. 
     Cachexia is also associated with TNF expression in cancer patients. TNF is linked to the three factors contributing to body weight control: intake, expenditure, and storage of energy. Administration of either TNF or IL-1, for example, induces a decrease in food intake. Rothwell (1993)  Int. J. Obesity  17:S98-S101; Arbos et al. (1992)  Mol. Cell. Biochem.  1 12:53-59; Fargeas et al. (1993)  Gastroenterology  104:377-383; Plata-Salaman et al. (1994)  Am. J. Physiol.  266:R1711-1715; Schwartz et al. (1995)  Am. J. Physiol.  269:R949-957; and Oliff et al. (1987)  Cell  50:555-563. Interestingly, TNF may have key roles in both extremes of weight problems. Abnormalities in its activity may lead to obesity; changes in its production result in the opposite effect, cachexia. Argilés et al. (1997)  FASEB J.  11:743-751. 
     TNF has additional, related roles. It is involved in thermogenesis, particularly nonshivering thermogenesis in brown adipose tissue (BAT), a tissue with an elevated level in cachexia. Nicholls (1983)  Biosci. Rep.  3:431-441; Rothwell (1993)  Int. J. Obesity  17:S98-S101; Bianchi et al. (1989)  Horm. Metab. Res.  21:1 1; and Oudart et al. (1995)  Can. J. Physiol. Pharmacol.  73:1625-1631. TNF has also been implicated in non-insulin-dependent (type II) diabetes. Hotamisligil et al. (1995)  J. Clin. Invest.  95:2409-2415; Arner (1996)  Diabetes Metab.  13:S85-S86; Spiegelman et al. (1993)  Cell  73:625-627; Saghizadeh et al. (1996)  J. Clin. Invest.  97:1111-16; and Hofmann et al. (1994)  Endocrinology  134:264-270. 
     These data help explain how TNF mediates the opposite effects of obesity and cachexia. TNF has functional similarities to leptin, which has been proposed to be an “adipostat.” Zhang et al. (1994)  Nature  372:425-432; Phillips et al. (1996)  Nature Genet.  13:18-19; and Madej et al. (1995)  FEBS Lett.  373:13-18. Like leptin, TNF is expressed and secreted by adipocytes and can travel to the brain. TNF administration also results in an increase in circulating leptin concentrations. Grunfeld et al. (1996)  J. Clin. Invest.  97:2152-57. It is possible to reconcile the participation of TNF in obesity and cachexia. TNF can be considered one of many signals coming from adipose tissue that participate in the feedback mechanism that informs the hypothalamic center about the state of the adipocyte energy depot. TNF probably counteracts excessive energy intake and is able to stimulate thermogenesis either directly or by increasing sympathetic activity. TNF released by adipose tissue will also stimulate lipolysis, decrease LPL activity, decrease the expression of the glucose transporter GLUT4, and inhibit lipogenesis in the adipocyte, thus contributing to the maintenance (but not increased fat deposition) of the adipose tissue mass. In cachexia, however, the situation is different. A high production of TNF by activated macrophages (as a result of a tumor or an infection) contributes to anorexia, increased thermogenesis, and adipose tissue dissolution. However, a pathological state can be created where there is an excess of TNF informing the brain that adipose tissue needs dissolution. The two situations can thus be reconciled: in cachexia there is a pathological overproduction of TNF; in obesity, the physiological action of TNF as a signal to control food intake and energy expenditure is impaired. Argilés et al. (1997).  FASEB J.  11:743-751. 
     Attempts have been made to ameliorate the untoward effects of TNF by treatment with monoclonal antibodies to TNF or with other proteins that bind TNF, such as modified TNF receptors. Patients with sepsis or septic shock have been treated with anti-TNF antibodies. Neither coagulation nor the fibrinolytic system was affected by an anti-TNF antibody in a study of patients with sepsis or septic shock. Satal et al. (1996)  Shock  6:233-7. Some improvement in the clinical and histopathologic signs of Crohn&#39;s disease were afforded by treatment with anti-TNF antibodies. Neurath et al. (1997)  Eur. J. Immun.  27:1743-50; van Deventer et al. (1997)  Pharm. World Sci.  19:55-9; van Hogezand et al. (1997)  Scand. J. Gastro.  223:105-7; and Stack et al. (1997)  Lancet  349:521-4. In the treatment of experimental autoimmune encephalitis (EAE), an animal model of the human disease multiple sclerosis (MS), treatment with TNF-R fusion protein prevents the disease and the accompanying demyelination, suggesting the possible use of this treatment in MS patients. Klinkert et al. (1997)  J. Neuroimmun.  72:163-8. 
     Regulation of TNF expression is being tested in treatment of endotoxic shock. Mohler et al. (1994)  Nature  370:218-220. Modulation of TNF-R activity is also being approached by the use of peptides that bind intracellularly to the receptor or other component in the process to prevent receptor shedding. PCT patent publications: WO 95/31544, WO 95/33051; and WO 96/01642. Modulation of TNF-R activity is also postulated to be possible by binding of peptides to the TNF-R and interfering with signal transduction induced by TNF. European Patent Application EP 568 925. 
     Human TNF and LT mediate their biological activities, both on cells and tissues, by binding specifically to two distinct, although related, glycoprotein plasma membrane receptors of 55 kDa and 75 kDa (p55 and p75 TNF-R, respectively). Holtmann and Wallach (1987)  J. Immunol.  139:151-153. The two receptors share 28 percent amino acid (AA) sequence homology in their extracellular domains, which are composed of four repeating cysteine-rich regions. Tartaglia and Goeddel (1992)  Immunol. Today  13:151-153. However, the receptors lack significant AA sequence homology in their intracellular domains. Dembic et al. (1990)  Cytokine  2:231-237. Due to this dissimilarity, they may transduce different signals and, in turn, exercise diverse functions. 
     Recent studies have shown that most of the known cellular TNF responses, including cytotoxicity and induction of several genes, may be attributed to p55 TNF-R activation. Engelmann et al. (1990)  J. Biol. Chem.  265:1531-1536; Shalaby et al. (1990)  J. Exp. Med.  172:1517-1520; and Tartaglia et al. (1991)  Proc. Natl. Acad. Sci. USA  88:9292-9296. In addition, the p55 receptor controls early acute graft-versus-host disease. Speiser et al. (1997)  J. Immun.  158:5185-90. In contrast, information regarding the biological activities of p75 TNF-R is limited. This receptor shares some activities with p55 TNF-R and specifically participates in regulating proliferation of and secretion of cytokines by T cells. Shalaby et al. (1990); and Gehr et al. (1992)  J. Immunol.  149:911-917. Both belong to an ever-increasing family of membrane receptors including low-affinity nerve growth factor receptor (LNGF-R), FAS antigen, CD27, CD30 (Ki-1), CD40 (gp50) and OX 40. Cosman (1994)  Stem Cells  (Dayt.) 12:440-455; Meakin and Shooter (1992)  Trends Neurosci.  15:323-331; Grell et al. (1994)  Euro. J. Immunol.  24:2563-2566; Moller et al. (1994)  Int. J. Cancer  57:371-377; Hintzen et al. (1994)  J. Immunol.  152:1762-1773; Smith et al. (1993)  Cell  73:1349-1360; Corcoran et al. (1994)  Eur. J. Biochem.  223:831-840; and Baum et al. (1994)  EMBO J.  13:3992-4001. 
     All of these receptors share a repetitive pattern of cysteine-rich domains in their extracellular regions. In accord with the pleiotropic activities of TNF and LT, most human cells express low levels (2,000 to 10,000 receptors/cell) of both TNF-Rs simultaneously. Brockhaus et al. (1990)  Proc. Natl. Acad. Sci.  USA 87:3127-3131. Expression of TNF-R on both lymphoid and non-lymphoid cells may be up and down-regulated by many different agents, such as bacterial lipopolysaccharide (LPS), phorbol myristate acetate (PMA; a protein kinase C activator), interleukin-1 (IL-1), interferon-gamma (IFN-γ) and IL-2. Gatanaga et al. (1991)  Cell Immunol.  138:1-10; Yui et al. (1994)  Placenta  15:819-835; and Dett et al. (1991)  J. Immunol.  146:1522-1526. Although expressed in different proportions, each receptor binds TNF and LT with equally high affinity. Brockhaus et al. (1990); and Loetscher et al. (1990)  J. Biol. Chem.  265:20131-20138. Initial studies showed that the complexes of human TNF and TNF-R are formed on the cell membrane, internalized wholly, and then either degraded or recycled. Armitage (1994)  Curr. Opin. Immunol.  6:407-413; and Fiers (1991)  FEBS Lett.  285:199-212. 
     TNF binding proteins (TNF-BP) were originally identified in the serum and urine of febrile patients, individuals with renal failure, cancer patients, and even certain healthy individuals. Seckinger et al. (1988)  J. Exp. Med.  167:1511-1516; Engelmann et al. (1989)  J. Biol. Chem.  264:11974-11980; Seckinger et al. (1989)  J. Biol. Chem.  264:11966-11973; Peetre et al. (1988)  Eur. J. Haematol.  41:414-419; Olsson et al. (1989)  Eur. J. Haematol.  42:270-275; Gatanaga et al. (1990a)  Lymphokine Res.  9:225-229; and Gatanaga et al. (1990b)  Proc. Natl. Acad. Sci USA  87:8781-8784. In fact, human brain and ovarian tumors produced high serum levels of TNF-BP. Gatanaga et al. (1990a); and Gatanaga et al. (1990b). These molecules were subsequently purified, characterized, and cloned by different laboratories. Gatanaga et al. (1990b); Olsson et al. (1989); Schall et al. (1990)  Cell  61:361-370; Nophar et al. (1990)  EMBO J.  9:3269-3278; Himmler et al. (1990)  DNA Cell Biol.  9:705-715; Loetscher et al. (1990)  Cell  61:351-359; and Smith et al. (1990)  Science  248:1019-1023. These proteins have been suggested for use in treating endotoxic shock. Mohler et al. (1993)  J. Immunol.  151:1548-1561; Porat et al. (1995)  Crit. Care Med.  23:1080-1089; Fisher et al. (1996)  N. Engl. J. Med.  334:1697-1702; Fenner (1995)  Z. Rheumatol.  54:158-164; and Jin et al. (1994)  J. Infect. Dis.  170:1323-1326. 
     Human TNF-BP consist of 30 kDa and 40 kDa proteins found to be identical to the N-terminal extracellular domains of p55 and p75 TNF-R, respectively. The 30 kDa and 40 kDa TNF-BP are thus also termed p55 and p75 sTNF-R, respectively. Studies of these proteins have been facilitated by the availability of human recombinant 30 kDa and 40 kDa TNF-BP and antibodies which specifically recognize each form and allow quantitation by immunoassay. Heller et al. (1990)  Proc. Natl. Acad. Sci. USA  87:6151-6155; U.S. Pat. No. 5,395,760; EP 418,014; and Grosen et al. (1993)  Gynecol. Oncol.  50:68-77. X-ray structural studies have demonstrated that a TNF trimer binds with three soluble TNF-R (sTNF-R) molecules and the complex can no longer interact with TNF-R. Banner et al. (1993)  Cell  73:431-445. The binding of the trimer and sTNF-R, however, is reversible and these reactants are not altered as a result of complex formation. At high molar ratios of sTNF-R to TNF, both recombinant and native human sTNF-R are potent inhibitors of TNF/LT biological activity in vitro as well as in vivo. Gatanaga et al. (1990b); Ashkenazi et al. (1991)  Proc. Natl. Acad. Sci. USA  88:10535-10539; Lesslaur et al. (1991)  Eur. J. Immunol.  21:2883-2886; Olsson et al. (1992)  Eur. J. Haematol.  48:1-9; and Kohno et al. (1990)  Proc. Natl. Acad Sci. USA  87:8331-8335. 
     Increased levels of TNF-R are also associated with clinical sepsis (septic peritonitis), HIV-1 infection, and other inflammatory conditions. Kalinkovich et al. (1995)  J. Interferon and Cyto. Res.  15:749-757; Calvano et al. (1996)  Arch. Surg.  131:434-437; and Ertel et al. (1994) Arch. Surg. 129:1330-1337. Sepsis, and septic shock affect thousands of patients every year and there is essentially no cure. This lethal syndrome is caused primarily by lipopolysaccharides (LPS) of Gram-negative bacteria and superantigens of Gram-positive bacteria. Clinical symptoms are initiated primarily by the release of endogenous mediators, such as TNF, from activated lymphoid cells into the bloodstream. TNF induces production of a cascade of other cytokines, including IL-1, IFN-γ, IL-8, and IL-6. These cytokines, along with other factors, promote the clinical symptoms of shock. Recombinant human sTNF-R is currently being tested in clinical trials to block TNF/LT activity in patients with septic shock and other conditions in which TNF and LT are thought to be pathogenic. Van Zee et al. (1992)  Proc. Natl. Acad. Sci. USA  89:4845-4849. Balb/c mice, the primary animal model, and multiple techniques have been used to test the effects of TNF modulators and other treatments on septic peritonitis. Jin et al. (1994)  J. Infect. Dis.  170:1323-1326; Mohler et al. (1993)  J. Immunol.  151:1548-1561; Porat et al. (1995)  Crit. Care Med  23:1080-1089; and Echtenacher et al. (1996)  Nature  381:75-77. LPS-induced shock has been shown to be ameliorated by FR167653, a dual inhibitor of IL-1 and TNF production. Yamamoto et al. (1997)  Eur. J. Pharmacol.  327:169-174. 
     While low levels of sTNF-R have been identified in the sera of normal individuals, high levels have been found in the sera of patients with chronic inflammation, infection, renal failure and various forms of cancer. Aderka et al. (1992)  Lymphokine Cytokine Res.  11:157-159; Olsson et al. (1993)  Eur. Cytokine Netw.  4:169-180; Diez-Ruiz et al. (1995)  Eur. J. Haematol.  54:1-8; van Deuren (1994)  Eur. J. Clin. Microbiol. Infect. Dis.  13 Suppl. 1:S12-6; Lambert et al. (1994)  Nephrol. Dial. Transplant.  9:1791-1796; Halwachs et al. (1994)  Clin. Investig.  72:473-476; Gatanaga et al. (1990a); and Gatanaga et al. (1990b). Serum levels of sTNF-R rise within minutes and remain high for 7 to 8 hours after the intravenous injection of human recombinant TNF or IL-2 into human cancer patients. Aderka et al. (1991)  Cancer Res.  51:5602-5607; and Miles et al. (1992)  Br. J. Cancer  66:1195-1199. It has also been observed that serum sTNF-R levels are chronically elevated in cancer patients and may remain at high levels for years. Grosen et al. (1993). It is clear that sTNF-R are natural inhibitors of these cytokines and regulate their biological activity post secretion. Fusion proteins consisting of a sTNF-R linked to a portion of the human IgG1 have also been developed for treating rheumatoid arthritis and septic shock. Moreland et al. (1997)  N. Eng. J. Med.  337:141-7; Abraham et al. (1997)  JAMA  277:1531-8. 
     New evidence has yielded information on cellular regulation of secreted cytokines. The evidence indicates that cells release molecules which resemble or contain the binding site of the specific membrane receptors. Massague and Pandiella (1993)  Annu. Rev. Biochem.  62:515-541; and Rose-John and Heinrich (1994)  Biochem. J.  300:281-290. These soluble forms specifically bind and, in the appropriate molar ratios, inactivate the cytokine by steric inhibition. Therefore, this may be a general phenomenon responsible for the regulation of cytokines and membrane antigens. 
     In addition to TNF-R, various types of membrane molecules have both soluble and membrane forms, including (i) cytokine receptors, e.g., IL-1R, IL-2R, IL-4R, IL-5R, IL-6R, IL-7R, IL-9R, granulocyte-colony stimulating factor-R (G-CSF-R), granulocyte-macrophage-colony stimulating factor-R (GM-CSF-R), transforming growth factor-β-R (TGFβ-R), platelet-derived growth factor-R (PDGF-R), and epidermal growth factor-R (EGF-R); (ii) growth factors, e.g., TNF-(pro-TNF-α), TGF-α, and CSF-1; (iii) adhesion molecules, e.g., intracellular adhesion molecule-1 (ICAM-1/CD54) and vascular cell membrane adhesion molecule (VCAM-1/CD106); (iv) TNF-R/NGF-R superfamily, e.g., LNGF-R, CD27, CD30, and CD40; and (v) other membrane proteins, e.g. transferrin receptor, CD14 (receptor for LPS and LPS binding protein), CD16 (FcγRIII), and CD23 (low-affinity receptor for IgE). Colotta et al. (1993)  Science  261:472-475; Baran et al. (1988)  J. Immunol.  141:539-546; Mosley et al. (1989)  Cell  59:335-348; Takaki et al. (1990)  EMBO J.  9:4367-4374; Novick et al. (1989)  J. Exp. Med.  170:1409-1414; Goodwin et al. (1990)  Cell  60:941-95 1; Renauld et al. (1992)  Proc. Natl. Acad. Sci. USA  89:5690-5694; Fukunaga et al. (1990)  Proc. Natl. Acad. Sci. USA  87:8702-8706; Raines et al. (1991)  Proc. Natl. Acad Sci. USA  88:8203-8207; Lopez-Casillas et al. (1991)  Cell  67:785-795; Tiesman and Hart (1993)  J. Biol. Chem.  268:9621-9628; Khire et al. (1990)  Febs. Lett.  272:69-72; Kriegler et al. (1988)  Cell  53:45-53; Pandiella and Massague (1991)  Proc. Natl. Acad Sci. USA  88:1726-1730; Stein et al. (1991) Oncogene 6:601-605; Seth et al. (1991)  Lancet  338:83-84; Hahne et al. (1994)  Eur. J. Immunol.  24:421-428; Zupan et al. (1989)  J. Biol. Chem.  264:11714-11720; Loenen et al. (1992)  Eur. J. Immunol.  22:447-455; Latza et al. (1995)  Am. J. Pathol.  146:463-471; Chitambar (1991)  Blood  78:2444-2450; Landmann et al. (1992)  J. Leukoc. Biol.  52:323-330; Huizinga et al. (1988)  Nature  333:667-669; and Alderson et al. (1992)  J. Immunol.  149:1252-1257. 
     In vitro studies with various types of cells have revealed that there are two mechanisms involved in the production of soluble receptors and cell surface antigens. One involves translation from alternatively spliced mRNAs lacking transmembrane and cytoplasmic regions, which is responsible for the production of soluble IL-4R, IL-5R, IL-7R, IL-9R, G-CSF-R, and GM-CSF-R. Rose-John and Heinrich (1994); and Colotta et al. (1993). The other mechanism involves proteolytic cleavage of the intact membrane receptors and antigens, known as shedding. Proteolysis appears to be involved in the production of soluble LNGF-R, TNF-R, CD27, CD30, IL-1R, IL-6R, TGFβ-R, PDGF-R, and CD14 (Id.). 
     Both soluble p55 and p75 TNF-R do not appear to be generated from processed mRNA, since only full length receptor mRNA has been detected in human cells in vitro. Gatanaga et al. (1991). Carboxyl-terminal sequencing of the human soluble p55 TNF-R indicates that a cleavage site may exist between Asn 172 and Val 173. Gullberg et al. (1992)  Eur. J. Cell. Biol.  58:307-312. This evidence is supported by the finding that human TNF-R with the mutation at Asn 172 and Val 173 was not released as effectively as native TNF-R on COS-1 cells transduced with cDNA of human TNF-R. Gullberg et al. (1992). The cytoplasmic portion of TNF-R does not appear to play an important role in releasing the soluble receptor forms from transduced COS-1 cells. COS-1 cells release sTNF-R even when transduced with cDNA of human p55 TNF-R which expresses only the extracellular domain but not the cytoplasmic domain. (Id.) sTNF-R shedding is not affected by dexamethasone, gold sodium thiomalate, or prostaglandin E2. Seitz et al. (1997)  J. Rheumatology  24:1471-6. Collectively, these data support the concept that human sTNF-R are produced by proteolytic cleavage of membrane TNF-R protein. 
     PMA is an extremely strong and rapid inducer of TRRE and, indirectly, TNF-R. Basically, PMA is a powerful stimulator of protein kinase C which is anchored inside the cell membrane once activated. Data suggest that (i) TRRE is stored in the cytoplasm very close to the cell membrane ready to be secreted through the protein kinase C cascade by PMA stimulation; (ii) TRRE is a peripheral (or extrinsic) membrane protein which is dissociated from the membrane through the change of interactions with other proteins or with any phospholipid by stimulated protein kinase C; or (iii) TRRE is an integral (or intrinsic) membrane protein which is cleaved and secreted to be an active form after its cytoplasmic portion interacts directly or indirectly with protein kinase C. 
     TRRE induction by PMA does not require de novo protein synthesis, RNA synthesis and transmission inside the cytoplasm, but only membrane internalization and movement. This is compatible with the data that TRRE was released very quickly by PMA stimulation and halted once PMA was removed. With PMA stimulation, however, TRRE synthesis begins at the same time as TRRE release. After the initial release, TRRE accumulates inside the cell or on the cell surface within 2 hours ready to be secreted by the next stimulation. Evidence for direct cleavage of TNF-R is that the shedding of sTNF-R occurs very quickly (5 minutes), with maximal shedding within 30 minutes. 
     In addition to PMA, shedding of sTNF-R has been known to be enhanced by several cytokines including TNF, IL-1, IL-6, IL-10 and IFN, leukocyte migration enhancement factors including formyl-methionyl-leucyl-phenylalanine (fMLP) and C5a, and calcium ionophore. Gatanaga (1993)  Lymphokine Res.  12:249-253; Porteu (1994)  J. Biol. Chem.  269:2834-2840; van der Poll (1995)  J. Immunol.  155:5397-5401; Porteu et al. (1991); and Porteu and Natah (1990)  J. Exp. Med.  172:599-607. IL-10 and epinephrine induce TRRE in the human monocyte cell line THP-1. 
     IL-10 is a potent inhibitor of monocyte- and macrophage-functions. Moore (1993)  Annu. Rev. Immunol.  11:165-190. IL-10 has anti-inflammatory activity on monocytes and inhibits the release of pro-inflammatory cytokines including TNF and IL-1. Bogdan et al. (1991)  J. Exp. Med.  174:1549-1555; Fiorentino et al. (1991)  J. Immunol.  147:3815-3822; de Waal Malefyt et al. (1991)  J. Exp. Med.  174:1209-1220; Katsikis et al. (1994)  J. Exp. Med.  179:1517-1527; Joyce et al. (1994)  Eur. J. Immunol.  24:2699-2705; and Simon et al. (1994)  Proc. Natl. Acad Sci. USA  91:8562-8566. Elevated levels of IL-10 have been detected in plasma of patients with sepsis, and after administration of LPS to animals. Marchant et al. (1994)  Lancet  343:707-708; Derkx et al. (1995)  J. Infect. Dis.  171:229-232; Durez et al. (1993)  J. Exp. Med  177:551-555; and Marchant et al. (1994)  Eur. J. Immunol.  24:1167-1171. In vivo, IL-10 has also been shown to protect mice against endotoxin shock. Gerard et al. (1993)  J. Exp. Med.  177:547-550; and Howard et al. (1993)  J. Exp. Med.  177:1205-1208. IL-10 leads to increased levels of mRNA for p75 TNF-R, increased release of soluble p75 TNF-R and a concomitant reduction of surface expression of p75 TNF-R on monocytes. Joyce et al. (1994). Thus, IL-10 may be considered to reduce the pro-inflammatory potential of TNF by (i) inhibiting the release of TNF itself, and (ii) down-regulating surface TNF-R expression while (iii) increasing production of sTNF-R capable of neutralizing TNF cytotoxicity. Joyce et al. (1994); and Leeuwenberg et al. (1994)  J. Immunol.  152:4036-4043. The data presented herein that IL-10 may induce TRRE activity are consistent with these findings and indicate a newly revealed function of IL-10 as an anti-inflammatory cytokine. 
     In stressful situations, including endotoxic shock, serum levels of catecholamines and glucocorticoids are elevated chiefly from adrenal medulla and adrenal cortex, respectively, in response to high serum level of adrenocorticotropic hormone (ACTH) throughout the whole body system. TNF also has been implicated in the early metabolic events following stressful situations, and infusion of recombinant TNF in dogs was associated with increase of serum levels of catecholamines, glucocorticoids and glucagon. Tracey et al. (1987)  Surg. Gynecol. Obstet.  164:415-422. As a local phenomenon, epinephrine and norepinephrine are found in macrophages which express β-adrenergic receptors and these endogenous catecholamines seem to regulate LPS-induced TNF production in an autocrine fashion in vitro. Hjemdahl et al. (1990)  Br. J. Clin. Pharmacol.  30:673-682; Hjemdahl et al. (1990)  Br. J. Clin. Pharmacol.  30:673-682; Talmadge et al. (1993)  Int. J. Immunopharmacol.  15:219-228; and Spengler et al. (1994)  J. Immunol.  152:3024-3031. Exogenous epinephrine and isoproterenol, a specific adrenergic agonist, inhibit the production of TNF from human blood and THP-1 cells stimulated by LPS. Hu et al. (1991)  J. Neuroimmunol.  31:35-42; and Severn (1992)  J. Immunol.  148:3441-3445. 
     While epinephrine may be an important endogenous inhibitor of TNF production, especially in sepsis, epinephrine also decreases the number of TNF-R on macrophages. Bermudez et al. (1990)  Lymphokine Res.  9:137-145. It has been shown that in trauma patients both p55 and p75 TNF-R levels were significantly elevated along with high serum level of epinephrine within 1 hour of injury. Tan et al. (1993)  J. Trauma  34:634-638. These findings are in agreement with the data that epinephrine induced TRRE activity and may lead to the increase of sTNF-R. 
     In addition to epinephrine, insulin and glucagon have the function to down-regulate TNF-R. Bermudez et al. (1990). Many inflammatory cytokines besides IL-10 may influence the shedding of sTNF-R including TNF, IL-1, IL-6, and IFN for up-regulation and IL-4 for down-regulation. van der Poll et al. (1995); Gatanaga et al. (1993); and Joyce et al. (1994). 
     Two reports describe the involvement of a metalloprotease in the production of sTNF-R by utilizing a specific metalloprotease inhibitor, TNF-α protease inhibitor (TAPI). TAPI blocks the shedding of soluble p75 and p55 TNF-R, respectively. Crowe et al. (1995); and Mullberg et al. (1995). Moreover, the processing of pro-TNF on the cell membrane was reported to be dependent on a matrix metalloprotease (MMP)-like enzyme. Gearing et al. (1994); and Gearing et al. (1995). MMPs are a family of structurally related matrix-degrading enzymes that play a major role in tissue remodeling and repair associated with development and inflammation. Matrisian (1990)  Trends Genet.  6:121-125; Woessner (1991)  FASEB J.  5:2145-2154; and Birkedal-Hansen et al. (1993)  Crit. Rev. Oral Biol. Med.  4:197-250. Pathological expression of MMPs is associated with tumor invasiveness, osteoarthritis, atherosclerosis, and pulmonary emphysema. Mignatti et al. (1986)  Cell  47:487-498; Khokha (1989)  Science  243:947-950; Dean et al. (1989)  J. Clin. Invest.  84:678-685; Henney et al. (1991)  Proc. Natl. Acad. Sci. USA  88:8154-8158; and Senior et al. (1989)  Am. Rev. Respir. Dis.  139:1251-1256. MMPs are Zn 2+ -dependent enzymes which have Zn 2+  in their catalytic domains. Ca 2+  stabilizes their tertiary structure significantly. Lowry et al. (1992)  Proteins  12:42-48; and Lovejoy et al. (1994)  Science  263:375-377. Thus, according to the similar metal dependency, at least one TRRE may be a part of the MMPs family of which 11 MMPs have been cloned. 
     The substrate-specificity of TRRE has been investigated using membrane receptors and antigens other than the two TNF-Rs. These receptors and antigens are expressed at sufficient levels on THP-1 cells to be detected by FACS analysis including (i) IL-1R, whose soluble form is known to be produced by proteolytic cleavage, (ii) CD30 (ki-1), which belongs to the same receptor family as TNF-R (TNF-R/NGF-R superfamily) and whose soluble form is produced presumably by a Zn 2+ -dependent metalloprotease, (iii) CD54 (ICAM1), which belongs to immunoglobulin superfamily of adhesion molecules including VCAM-1 and is known to have a soluble form, and (iv) CD11b, which belongs to the integrin family of adhesion molecules and which has not been shown to have a soluble form. TRRE is apparently very specific to only the cleavage of both TNF-Rs and did not affect any other membrane receptors and antigens which have soluble forms. 
     Given the involvement of TNF in a variety of pathological conditions, it would be desirable to identify and characterize factors that modulate expression of sequences encoding TRREs and/or which modulate activity of TRREs. The present invention relates to identification and characterization of such factors, as well as to methods of modulating TRRE activity. 
     SUMMARY OF THE INVENTION 
     The invention encompasses a composition which modulates TRRE activity. In one embodiment, the composition increases TRRE activity. In another embodiment, the composition decreases TRRE activity. In one embodiment, the composition further comprises a physiologically acceptable buffer. 
     In one embodiment of the present invention, the composition is encoded by a nucleic acid of at least 15 contiguous nucleotides of clones 2-8, 2-9, 2-14, 2-15, P2-2, P2-10, P2-13, P2-14, and P2-15, which are represented by SEQ ID NOs:1 to 10, or a complementary strand thereof. In another embodiment, the composition is an RNA encoded by at least 15 contiguous nucleotides of a sequence presented in any of SEQ ID NOs. 1 to 10, or a complementary strand thereof. The invention also encompasses nucleic acids encoding the amino acid sequences of at least 5 contiguous amino acids of any of SEQ ID NOs:147 to 154. In another embodiment, the composition is a protein encoded by at least 10 contiguous codons of a nucleic acid sequence presented in any of SEQ ID NOs. 1 to 10, or a complementary strand thereof 
     In another embodiment, the composition is an antisense nucleic acid that binds to a nucleic acid comprising at least 15 contiguous nucleotides of a nucleic acid sequence presented in any of SEQ ID NOs. 1 to 10, or a complementary strand thereof. In another embodiment, the composition is an antibody that binds to a protein encoded by at least 10 contiguous codons of any of SEQ ID NOs. 1 to 10, or a complementary strand thereof. In one embodiment, the composition further comprises a physiologically acceptable buffer. 
     In another embodiment, the invention encompasses a method of obtaining a composition which alters TRRE activity, comprising the steps of: introducing into a first cell with known TRRE activity clones from a library of a second cell with a different TRRE activity; selecting a first cell with altered TRRE activity; and isolating the clone from the first cell, wherein the clone encodes the composition. In one embodiment the method identifies clones which enhance TRRE activity, and in this case the TRRE activity of the first cell is higher than that of the second cell. In a variant of this method, the first and second cells are of the same cell type, and the change in TRRE activity can be caused by a change in the gene copy number; e.g., TRRE activity can increase if more copies of a gene encoding a factor that enhances expression of the TRRE are present, or TRRE activity can decrease if more copies of a gene encoding a factor which inhibits TRRE expression are present. In one embodiment the method identifies clones which decrease TRRE activity, and in this case the TRRE activity of the first cell is lower than that of the second cell. The invention further comprises a clone identified by this method. 
     In another embodiment, the invention encompasses a method of treating an individual having a disease associated with altered levels or activity of TNF comprising administering an amount of the composition which alters TRRE activity sufficient to indirectly or directly normalize said levels of TNF. In one embodiment, the disease is cancer. In various embodiments, the cancer is selected from the group consisting of astrocytoma, oligodendroglioma, ependymoma, medulloblastoma, primitive neural ectodermal tumor, pancreatic ductal adenocarcinoma, small and large cell lung adenocarcinomas, squamous cell carcinoma, bronchoalveolarcarcinoma, epithelial adenocarcinoma and liver metastases thereof, hepatoma, cholangiocarcinoma, ductal and lobular adenocarcinoma, squamous and adenocarcinomas of the uterine cervix, uterine and ovarian epithelial carcinomas, prostatic adenocarcinomas, transitional squamous cell bladder carcinoma, B and T cell lymphomas (nodular and diffuse), plasmacytoma, acute and chronic leukemias, malignant melanoma, soft tissue sarcomas, and leiomyosarcomas. In one embodiment the disease is cachexia. In another embodiment the disease is an inflammatory disorder. In one embodiment the disease is selected from the group consisting of autoimmune diseases, endotoxin shock, rheumatoid arthritis, trauma, infection and multiple sclerosis. In one embodiment the method of administration is selected from the group consisting of locally, parenterally, subcutaneously, intramuscularly, intraperitoneally, intracavity, intrathecally, and intravenously. 
     In another embodiment, the invention encompasses a method of measuring the TNF-receptor releasing (TRRE) activity of a test protein, comprising the steps of: obtaining cells that do not express significant amounts of TNF-R (TNF-R −  cells); manipulating the cells to express recombinant TNF-R (TNF-R +  cells); incubating the TNF-R +  cells in a suitable medium in the absence and presence of the protein; and measuring the level of soluble TNF-R in the cell supernatant, where the ratio of soluble TNF-R in the absence and presence of the protein is indicative of the TRRE activity of the protein. In another embodiment, the invention encompasses a protein with TRRE activity identified by this method. 
     In another embodiment, the invention encompasses a method of diagnosing a disease associated with altered levels or activity of the protein affecting TRRE activity, comprising the steps of: obtaining a biological sample from a patient; measuring activity of the protein in the sample; and comparing the activity to the activity of a control biological sample. In one embodiment the disease is cancer. In one embodiment the cancer is selected from the group consisting of glioblastoma, melanoma, neuroblastoma, adenocarcinoma, soft tissue sarcoma, leukemias, lymphomas and carcinoma. In one embodiment the cancer is carcinoma and is selected from the group consisting of astrocytoma, oligodendroglioma, ependymoma, medulloblastoma, primitive neural ectodermal tumor, pancreatic ductal adenocarcinoma, small and large cell lung adenocarcinomas, squamous cell carcinoma, bronchoalveolarcarcinoma, epithelial adenocarcinoma and liver metastases thereof, hepatoma, cholangiocarcinoma, ductal and lobular adenocarcinoma, squamous and adenocarcinomas of the uterine cervix, uterine and ovarian epithelial carcinomas, prostatic adenocarcinomas, transitional squamous cell bladder carcinoma, B and T cell lymphomas (nodular and diffuse), plasmacytoma, acute and chronic leukemias, malignant melanoma, soft tissue sarcomas, and leiomyosarcomas. 
     In another embodiment, the invention encompasses a method of treating a disease associated with elevated levels of soluble TNF receptor comprising administering an amount of an inhibitor of TNF receptor releasing enzyme effective to decrease the levels of soluble TNF receptor. In another embodiment, the disease is cancer. In another embodiment, the cancer is selected from the group consisting of astrocytoma, oligodendroglioma, ependymoma, medulloblastoma, primitive neural ectodermal tumor, pancreatic ductal adenocarcinoma, small and large cell lung adenocarcinomas, squamous cell carcinoma, bronchoalveolarcarcinoma, epithelial adenocarcinoma and liver metastases thereof, hepatoma, cholangiocarcinoma, ductal and lobular adenocarcinoma, squamous and adenocarcinomas of the uterine cervix, uterine and ovarian epithelial carcinomas, prostatic adenocarcinomas, transitional squamous cell bladder carcinoma, B and T cell lymphomas (nodular and diffuse), plasmacytoma, acute and chronic leukemias, malignant melanoma, soft tissue sarcomas, and leiomyosarcomas. In another embodiment, the inhibitor is selected from the group consisting of a metalloprotease inhibitor, an antibody that blocks the effective interaction between TNF receptor and TNF receptor releasing enzyme, a polynucleotide encoding said antibody, an antisense oligonucleotide specific for the gene encoding tumor necrosis receptor releasing enzyme, and a ribozyme specific for the gene encoding TNF receptor releasing enzyme. In another embodiment, the method further comprises the step of administering an amount of at least one cytokine effective to enhance an immune response against the cancer. In another embodiment, the cytokine is selected from the group consisting of interleukin 2, interleukin 4, granulocyte macrophage colony stimulating factor, and granulocyte colony stimulating factor. In another embodiment, the method further comprises the step of administering a chemotherapeutic agent. In another embodiment, the chemotherapeutic agent is selected from the group consisting of radioisotopes, vinca alkaloids, adriamycin, bleomycin sulfate, Carboplatin, cisplatin, cyclophosphamide, Cytarabine, Dacarbazine, Dactinomycin, Duanorubicin hydrochloride, Doxorubicin hydrochloride, Etoposide, fluorouracil, lomustine, mechlororethamine hydrochloride, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane, pentostatin, pipobroman, procarbaze hydrochloride, streptozotocin, taxol, thioguanine, and uracil mustard. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     FIG. 1 is a schematic representation of plasmid pCDTR2 which expresses p75 TNF-R. PCMV stands for cytomegalovirus; BGHpA stands for bovine growth hormone polyadenylation signal. 
     FIG. 2 is a graph depicting the results of measurement of p75 TNF-R on transfected COS-1 cells (C75R) by the method described herein. The results obtained with the C75R cells () is compared to that obtained with that from the parental COS-1 cells (▪). The receptor number was calculated from a Scatchard plot (inset). 
     FIG. 3 depicts the results of Western Blot analysis of soluble receptors released from C75R cells by TRRE. 
     FIG. 4 is a graph depicting the results of a modified in vitro TNF cytolytic assay by TRRE treatment to L929 cells. 
     FIG. 5 is a graph depicting the effect of TRRE on preventing mortality in mice treated with lipopolysaccharide (LPS) to induce septic peritonitis. 
     FIG. 6 is a graph depict the effect of various clones on TRRE activity in COS-1 cells. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The invention encompasses factors which modulate tumor necrosis factor receptor (TNFR) releasing enzymatic (TRRE) activity. The invention encompasses factors which increase or decrease TRRE activity. Effective amounts of the compositions of the present invention are those that alter TRRE by at least about 10%, more preferably by at least about 25%, more preferably by at about 50%, and even more preferably by at least about 75%. The invention encompasses nucleic acid sequences that act as templates for RNAs or encode proteins that that substantially alter TRRE in a cell, and methods of use thereof, and methods of screening thereof. TNF is a major proinflammatory and immunomodulatory cytokine produced during immune responses. TNF also regulates the expression of IL-2R leading to enhanced T cell responses mediated by IL-2 and appears to be required for generating proliferative responses in mixed lymphocyte cultures. Additional studies have shown that CD8 + , CTL and lymphokine activated killer cells are optimally induced with TNF, in combination with IL-2, suggesting the importance of this cytokine in regulating cytotoxic effector function. As discussed in detail above, TNF mediates its activity by binding to a TNF-R. Soluble TNF-Rs inhibit TNF activity by two methods: they decrease the available binding sites on a cell and bind to soluble TNF to decrease the local concentration. The present invention encompasses compositions and methods for modulating the level of soluble TNF-R by modulating the cleavage of TNF-R from the cell surface and thus indirectly modulating the effect of TNF. 
     Nucleic acid sequences of clones capable of enhancing TRRE activity are presented in SEQ ID NOs:1 to 10. The corresponding polypeptide sequences thereof are presented in SEQ ID NOs:147 to 154. These sequences were generated from clones designated 2-8, 2-9, 2-14, 2-15, P2-2, P2-10, P2-13, P2-14, and P2-15, each of which enhances 130%, as shown in FIG.  6 . The clones were prepared from a library (Stratagene, La Jolla, Calif.) of Jurkat cells, which have a high TRRE activity, transformed into COS-1 cells, which normally lack TRRE activity, as described in Example 5. Jurkat library clones which produced high TRRE activity in COS-1 cells were isolated and sequenced. This method can also be used to obtain additional genes which enhance TRRE activity. In addition, in a method of obtain clones which reduce TRRE activity, a library of cells with reduced TRRE activity can be introduced into a cell with relatively higher TRRE activity. Those clones which reduce TRRE activity can be thus identified. 
     The sequences of SEQ ID NOs:1 to 10 were analyzed by a BLAST (Basic Local Alignment Search Tool) sequence analysis to determine if they were similar or identical to known genes. All these sequences were found to be novel, except that of clone 2-8 (sequence designation AIM3T3, SEQ ID NO:2), which is highly similarly to the  M. musculus  45S pre-rRNA gene, clone 2-14 (sequence designation AIM4, SEQ ID NO:4), which is highly similar to human arfaptin 2, and clone P2-10 (sequence designation AIM7, SEQ ID NO:7), which is highly similar to the human insulin-like growth factor II receptor. In addition, the sequence of clone 2-15 (sequence designation AIM5, SEQ ID NO:5) is novel but has some similar to human eIF-5A transcription factor. None of these known genes has previously been linked to modulating TRRE activity. 
     In addition to using the Jurkat library (or similar library from a cell expressing high TRRE activity), an in vitro TRRE activity can be used to identify genes which enhance TRRE activity. Briefly, in this assay (described in detail in Example 1), a gene encoding a membrane-bound TNF receptor (TNF-R) is transformed into a cell which normally lacks this gene. These cells and controls are incubated with medium to be tested for TRRE activity. The supernatant is then collected and tested for solubilized TNF-R by ELISA. Mutants, variants, and derivatives of the polypeptides disclosed herein can be assayed for TRRE activity with this assay. In another embodiment, nucleic acids thought to encode proteins or RNAs that affect TRRE activity can be transformed into cells in this assay and tested for their effect on TRRE activity. This invention therefore encompasses polypeptides and genes identified by methods of obtaining polypeptides and genes that enhance TRRE activity. 
     This in vitro TRRE activity assay can also be used to identify factors which inhibit TRRE activity. Antibodies to proteins which enhance TRRE activity can be introduced into the cellular medium along with such proteins to determine if the antibodies block TRRE activity. Anti-sense RNAs to nucleic acids encoding TRRE activity can also be tested in this assay. 
     The terms “polypeptide”, “peptide” and “protein” are used interchangeably herein to refer to polymers of amino acid residues of any length. The polymer can be linear or branched, it can comprise modified amino acids or amino acid analogs, and it can be interrupted or modified by chemical moieties other than amino acids. The terms also encompass an amino acid polymer that has been modified naturally or by chemical intervention; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as conjugation with a labeling or bioactive component. Unless stated or implied otherwise, the term TRRE includes any polypeptide monomer or polymer with TRRE enzymatic specificity, including the intact TRRE, and smaller and larger functionally equivalent polypeptides, as described herein. The present invention encompasses polypeptides encoded by at least 5, preferably at least 10, more preferably at least 15, contiguous amino acids encoded by any of SEQ ID NOs:1 to 10. The invention further encompasses polypeptides represented in SEQ ID NOs: 147 to 154, or functional fragments, variants and derivatives thereof capable of modulating TRRE activity in a cell. 
     A “fusion polypeptide” is a polypeptide comprising regions in a different position in the sequence than occurs in nature. The regions can normally exist in separate proteins and are brought together in the fusion polypeptide; they can normally exist in the same protein but are placed in a new arrangement in the fusion polypeptide; or they can be synthetically arranged. For instance, as described below, the invention encompasses recombinant proteins that are comprised of a functional portion of TRRE and an antibody. Methods of making these fusion proteins are known in the art and are described, for instance, in WO93/07286. 
     A “functionally equivalent fragment” of a TRRE polypeptide varies from the native sequence by addition(s), deletion(s), or substitution(s), or any combination thereof, while preserving at least one functional property of the fragment relevant to the context in which it is being used. A functionally equivalent fragment of a TRRE polypeptide typically has the ability to bind membrane bound TNF-R and enzymatically cleave TNF-R to provide soluble TNF-R. Amino acid substitutions, if present, are preferably conservative substitutions that do not deleteriously affect folding or functional properties of the peptide. Groups of functionally related amino acids within which conservative substitutions can be made are glycine/alanine; valine/isoleucine/leucine; asparagine/glutamine; aspartic acid/glutamic acid; serine/threonine/methionine; lysine/arginine; and phenylalanine/tyrosine/tryptophan. Polypeptides of this invention can be in glycosylated or unglycosylated form, can be modified post-translationally (e.g., removal of signal peptide, transmembrane or cytoplasmic regions, acetylation, and phosphorylation) or can be modified synthetically (e.g., by a labeling group). 
     Effective amounts of a polypeptides of the present invention can be administered to a subject or cell in order to modulate TRRE activity in the subject or cell. In addition, variants, mutants and derivatives of the polypeptides described herein can be tested for TRRE activity in an in vitro assay. Those which display high activity can then be administered to subjects. Alternatively, polynucleotides encoding these polypeptides, variants, mutants or derivatives can be introduced. In the case of TRRE genes in which the gene product is an RNA (e.g., an rRNA), it is preferable to administer a nucleic acid which is a DNA. Administration can be performed locally, parenterally, subcutaneously, intramuscularly, intraperitoneally, intracavity, intrathecally, and intravenously, or via any method known in the art. The preparation of pharmaceutical compositions that contain a polynucleotide or polypeptide as an active ingredient is conducted in accordance with generally accepted procedures for the preparation of pharmaceutical preparations. See, for example,  Remington&#39;s Pharmaceutical Sciences  18 th Edition  (1990), E. W. Martin ed., Mack Publishing Co., PA. Depending on the intended use and mode of administration, it may be desirable to process the active ingredient further in the preparation of pharmaceutical compositions. Appropriate processing may include sterilizing, mixing with appropriate non-toxic and non-interfering components, dividing into dose units, and enclosing in a delivery device. Various methods of delivering proteins and nucleic acids into cells and individuals are known in the art. 
     In addition, the polypeptides and polynucleotides disclosed herein can be used to inhibit or decrease TRRE activity levels in a cell or subject, particularly a subject suffering from an indication characterized by excessive TNF activity. Such inhibitors include metalloprotease inhibitors, an antibody which blocks the effective interaction between TNF receptor and TRRE or a polynucleotide encoding such an antibody, an antisense oligonucleotide specific for a TRRE, and a ribozyme specific for a gene encoding TRRE. Antisense nucleic acids (e.g., antisense RNAs) include those complementary to the sequences of SEQ ID NOs:1 to 10. These can bind to the nucleic acids in a cell and prevent their expression. Alternatively, antisense nucleic acids can be constructed to bind to mRNAs encoded by these sequences to prevent their translation. Furthermore, the polypeptides described in SEQ ID NOs:147 to 154 can be used to generate antibodies. Administration of an effective amount of these antibodies to a cell or subject can reduce TRRE activity in that cell or subject. In addition to an inhibitor of TRRE activity, a subject can be treated with a cytokine such as IL-2, -4, GM-CSF, or GSF and/or a chemotherapeutic agent such as radioisotopes, vinca alkaloids, adriamycin, bleomycin sulfate, Carboplatin, cisplatin, cyclophosphamide, Cytarabine, Dacarbazine, Dactinomycin, Duanorubicin hydrochloride, Doxorubicin hydrochloride, Etoposide, fluorouracil, lomustine, mechlororethamine hydrochloride, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane, pentostatin, pipobroman, procarbaze hydrochloride, streptozotocin, taxol, thioguanine, and uracil mustard. Methods of administering these various agents are known in the art. 
     An “effective amount” in treatment is an amount sufficient to effect beneficial or desired clinical results. An effective amount can be administered in one or more administrations. For purposes of this invention, an effective amount of an adenoviral vector is an amount that is sufficient to palliate, ameliorate, stabilize, reverse, slow or delay the progression of the disease state. 
     Subjects including those who are suspected of being at risk of a pathological effect of any neoplasia, particularly carcinoma, are suitable for treatment with the pharmaceutical compositions of this invention. Those with a history of cancer are especially suitable. Suitable subjects for therapy comprise two groups, which may be distinguished by clinical criteria. Patients with “advanced disease” or “high tumor burden” are those who bear a clinically measurable tumor. A clinically measurable tumor is one that can be detected on the basis of tumor mass (e.g., by palpation, CAT scan, or X-ray; positive biochemical or histopathological markers on their own are insufficient to identify this population). A pharmaceutical composition embodied in this invention is administered to these patients to elicit an anti-tumor response, with the objective of palliating their condition. Ideally, reduction in tumor mass occurs as a result, but any clinical improvement constitutes a benefit. Clinical improvement includes decreased risk or rate of progression or reduction in pathological consequences of the tumor. 
     A second group of suitable subjects is known in the art as the “adjuvant group”. These are individuals who have had a history of cancer, but have been responsive to another mode of therapy. The prior therapy may have included (but is not restricted to) surgical resection, radiotherapy, and traditional chemotherapy. As a result, these individuals have no clinically measurable tumor. However, they are suspected of being at risk for progression of the disease, either near the original tumor site, or by metastases. 
     This adjuvant group can be further subdivided into high-risk and low-risk individuals. The subdivision is made on the basis of features observed before or after the initial treatment. These features are known in the clinical arts, and are suitably defined for each different cancer. Features typical of high risk subgroups are those in which the tumor has invaded neighboring tissues, or involvement of lymph nodes. 
     Another suitable group of subjects is those with a genetic predisposition to cancer but who have not yet evidenced clinical signs of cancer. For instance, women testing positive for a genetic mutation associated with breast cancer, but still of childbearing age, may wish to receive TRRE inhibitor treatment prophylactically to prevent the occurrence of cancer until it is suitable to perform preventive surgery. 
     Of course, crossovers between these two patient groups occur, and the pharmaceutical compositions of this invention can be administered at any time that is appropriate. For example, therapy can be conducted before or during traditional therapy of a patient with high tumor burden, and continued after the tumor becomes clinically undetectable. Therapy can be continued in a patient who initially fell in the adjuvant group, but is showing signs of recurrence. The attending physician can determine how or when the compositions of this invention are to be used. 
     As provided herein, treatment, diagnosis and monitoring of cancers includes any cancers known in the art. These include, but are not limited to, glioblastoma, melanoma, neuroblastoma, adenocarcinoma, soft tissue sarcoma, leukemias, lymphomas and carcinoma. The invention is particularly useful for treatment, diagnosis and monitoring of carcinomas. Carcinomas include, but are not limited to, astrocytoma, oligodendroglioma, ependymoma, medulloblastoma, primitive neural ectodermal tumor, pancreatic ductal adenocarcinoma, small and large cell lung adenocarcinomas, squamous cell carcinoma, bronchoalveolarcarcinoma, epithelial adenocarcinoma and liver metastases thereof, hepatoma, cholangiocarcinoma, ductal and lobular adenocarcinoma, squamous and adenocarcinomas of the uterine cervix, uterine and ovarian epithelial carcinomas, prostatic adenocarcinomas, transitional squamous cell bladder carcinoma, B and T cell lymphomas (nodular and diffuse), plasmacytoma, acute and chronic leukemias, malignant melanoma, soft tissue sarcomas and leiomyosarcomas. 
     Embodied in this invention are compositions comprising polynucleotides with a therapeutically relevant genetic sequence as an active ingredient. The polynucleotides can comprise a portion of a sequence shown in any SEQ ID NOs: 1 to 10 and/or a portion of any sequence encoding at least 5 contiguous amino acids, preferably at least 10, more preferably at least 15, even more preferably 20, of any of the amino acid sequences of SEQ ID NOs: 147 to 154. This portion can comprise at least 10, preferably at least 15, more preferably at least 20, and even more preferably at least 30 contiguous nucleotides of any of the sequences of SEQ ID NOs:1 to 10, or the complementary strand thereof, or any nucleotide which can encode at least 10 contiguous amino acids of any of SEQ ID NOs:147 to 154. The polynucleotide can be administered, for example, to augment or attenuate the natural level of expression of TRRE within a target cell. 
     A polynucleotide for enhancing or attenuating TRRE expression can be introduced into cells as part of any suitable delivery vehicle known in the art. The polynucleotide can be administered to cells or injected into a tissue site as naked DNA, preferably in a supercoiled configuration. It is generally preferred to administer the polynucleotide as part of a composition that enhances expression in the target cell. Components of the composition can include those that protect the polynucleotide until delivery to the cell, enhance binding to or localization near target cells, enhance uptake or endocytosis into cells, promote translocation of the polynucleotide across the membrane into the cytoplasm, or enhance transport of the polynucleotide inside the cell to the site of action. 
     In one example, the composition comprises one half of a ligand-receptor binding pair, the other of which is present on the surface of the target cell. This can promote localization near the cell surface, endocytosis into the cell, or homing to the cell in vivo, or any combination thereof. Suitable components for including in the composition include, but are not limited to, antibodies or antibody fragments specific for the target tissue (for example, a tumor-associated antigen), integrins and integrin ligands optionally specific for the target tissue, and ligands for cytokine receptors on the target tissue. Where the object is to decrease TNF-R levels on the target cell by enhancing TRRE expression, a particularly preferred ligand is TNF itself. In this way, the composition will be focused towards cells with the phenotype to be treated, in preference to other cell types and cells already treated effectively. 
     In another example, the composition comprises a delivery vehicle that protects the polynucleotide and enhances its delivery into the cell. One type of suitable vehicle is a liposome that either encapsulates the polynucleotide, or (in the case of cationic liposomes) binds it by charge association. Another type of suitable vehicle is the capsid or envelope of a virus, defective viral particle, or synthetic viral particle, encapsidating or enveloping the polynucleotide. Preferred amongst such virally related particles are those that are tropic for the target tissue type, and comprise polypeptides (such as the influenza hemagglutinin) that promote fusion and delivery of the polynucleotide. The composition can also optionally comprise genetic elements of a virus that promotes replication of the therapeutic polynucleotide and/or integration into the genome of the target cell. Suitable viral systems for use with this invention include adenovirus vectors, retroviral vectors, adeno-associated viral vectors, sindbis virus vectors, and the like. Preferred are vectors that comprise viral genetic elements required in cis for packaging, the genetic elements required for replication or integration of the therapeutic polynucleotide, but not other viral genetic elements. Such vectors can be produced by packaging systems in which viral elements required only in trans are supplied by a host cell or second virus. See, e.g., Flotte et al. WO 95/13365. 
     It is often preferable to combine several such components and strategies into the composition with the therapeutic polynucleotide. For example, a polynucleotide can be enveloped in an adenovirus vector that expresses a targeting molecule like TNF as part of the viral package. The vector might alternatively express a coupling molecule, such as an avidin binding site, that can then be coupled with biotin-TNF for purposes of targeting to the target cell. 
     The following examples are meant to illustrate, but not limit, the claimed invention. 
     EXAMPLE 1 
     In Vitro TRRE Assay System 
     The objective of this study was to establish an assay system that measures TRRE activity on the human TNF-R in its native conformation integrated into the cell surface membrane. The transfected COS-1 cell line was chosen for the assay system since no background of endogenous p75 TNF-R was observed. Attempts to study and characterize the enzyme responsible for sTNF-R release have been difficult because the presence of an active form of the proteolytic enzyme is indicated only indirectly by the generation of soluble receptors. Studies of release of other membrane bound proteins as well as TNF-R have been carried out by measuring the levels of soluble counterparts by ELISA or by FACS analysis for the presence or absence of the surface antigens. Therefore, the level of the enzyme itself has not yet been quantitated. We therefore devised a novel assay system to detect and quantitate TRRE. It was found that the level of soluble forms released into the medium depends on the level of expression of surface antigens on the membrane and the rate at which the cells can synthesize more and express these proteins on the membrane. In some studies, the enzyme levels and the kinetics of active enzyme formed have been correlated with the levels of soluble forms released and the kinetics of their release. We have now devised a more defined assay system to detect and also quantitate TRRE specifically and enzymes that cleave membrane receptor proteins in general. 
     Membrane-associated TNF-R was chosen as the substrate for TRRE instead of the recombinant TNF-R molecule, because the membrane-associated TNF-R simulates a more physiological microenvironment and substrate for the evaluation of TRRE activity. Membrane-associated TNF-R can also assist in alleviating nonspecific cleavage by other proteases which can occur in nonmembrane-associated forms. Since most human cells express only extremely low levels of both TNF-Rs, human p75 TNF-R-overexpressing cells were constructed by cDNA transfection into monkey COS-1 cells which do not express either TNF-Rs. 
     The cDNA of the human p75 TNF-R was cloned from a λgt10 cDNA library derived from human monocytic U-937 cells (Clontech Laboratories, Palo Alto, Calif.). The cDNA was then subcloned into the EcoRI site of the mammalian expression vector pCDNA3 (Invitrogen, San Diego, Calif.) which contains the neomycin-resistance gene for the selection of transfected cells in the presence of G418. This construct was transfected into COS-1 cells using the calcium phosphate-DNA precipitation method described by Chen and Okayama. 24 hours post transfection, the transfected cells were placed in 600 μg/ml G418 (GIBCO BRL Life Technologies, Gaithersburg, Md.) for the selection of neomycin-resistant clones. The resistant cells were pooled and named C75R. These cells expressed approximately 70,000 receptors/cell by Scatchard analysis. 
     The first 300 bp on both 5′ and 3′ ends of the cloned fragment was sequenced and compared to the reported cDNA sequence of human p75 TNF-R. The cloned sequence was a 2.3 kb fragment covering positions 58-2380 of the reported p75 TNF-R sequence, which encompasses the full length of the p75 TNF-R-coding sequence from positions 90-1475. The 2.3 kb p75 TNF-R cDNA was then subcloned into the multiple cloning site of the pCDNA3 eukaryotic expression vector. The orientation of the p75 TNF-R cDNA was verified by restriction endonuclease mapping. The final 7.7 kb construct, pCDTR2, carried the neomycin-resistance gene for the selection of transfected cells in G418, and the expression of the p75 TNF-R was driven by the cytomegalovirus promoter (FIG.  1 ). The pCDTR2 was then transfected into monkey kidney COS-1 cells using the calcium phosphate-DNA precipitation method. The selected clone in G418 medium, termed C75R, was identified and subcultured. 
       125 I was purchased from ICN Pharmaceuticals, Inc. (Costa Mesa, Calif.) and the human recombinant TNF was radiolabeled using the Chloramine-T method. To determine the level of p75 TNF-R expression on C75R cells, 2×10 5  cells/well were plated into a 24-well culture plate and incubated for 12 to 16 hours in 5% CO 2  at 37° C. They were then incubated with 2-30 ng  125 I radiolabeled human recombinant TNF in the presence or absence of 100-fold excess of unlabeled human TNF at 4° C. for 2 hours. After three washes with ice-cold PBS, cells were lysed with 0.1N NaOH and radioactivity was determined in a Pharmacia Clinigamma counter (Uppsala, Sweden). To determine the effect of TRRE on the surface levels of p75 TNF-R, cells were incubated with or without the TRRE-containing supernatant for 30 min at 37° C., and then the medium was aspirated before incubation with radiolabeled TNF. 
     Soluble p75 TNF-R was generated from C75R cells by incubation with TRRE-containing supernatant. After a 30 min incubation, the supernatant was collected and centrifugally concentrated with Centriprep-10 filter (10,000 MW cut-off membrane) (Amicon, Beverly, Mass.) and applied to 10% acrylamide SDS-PAGE. The proteins were then electrophoretically transferred to a polyvinylidene difluoride membrane (Immobilon) (Millipore, Bedford, Mass.). Immunostaining was performed using the biotin-streptavidin system (Amersham, Amersham, UK) and the peroxidase substrate kit DAB (Vector Laboratories, Burlingame, Calif.). 
     The results obtained are shown in FIG. 2, C75R had a very high level of specific binding of radiolabeled  125 I-TNF, while parental COS-1 cells did not. The number of TNF-R expressed on C75R was determined to be 60,000-70,000 receptors/cell by Scatchard analysis (FIG. 2, inset). The level of TNF-R expression in this clone was 40 to 50 times higher than that of THP-1 cells. The Kd value calculated from the TNF binding assay of C75R was 5.6×10 −10  M. This Kd value was in close agreement to the values previously reported for native p75 TNF-R. Thus, transfected COS-1 cells expressed high levels of human p75 TNF-R in a form that appeared to be similar to native TNF-R. 
     In order to measure the effect of TRRE on membrane-bound TNF-R, the following experiment was performed. C75R cells were seeded at a density of 2×10 5  cells/well in a 24-well cell culture plate and incubated for 12 to 16 hours at 37° C. in 5% CO 2 . The medium in the wells was aspirated, replaced with fresh medium alone or with TRRE medium, and incubated for 30 min at 37° C. Throughout the examples, the “TRRE-medium” was that collected by stimulation of THP-1 cells with PMA followed by incubation of the cells in fresh medium for 2 hours as described. After this incubation, the medium was replaced with fresh medium containing 30 ng/ml  125 I-labeled TNF. After 2 hours at 4° C., the cells were lysed with 0.1 N NaOH and the level of bound radioactivity was measured. The level of specific binding of C75R by  125 I-TNF was significantly decreased after incubation with TRRE. The radioactive count was 1,393 cpm on the cells incubated with TRRE compared to 10,567 cpm on the cells not treated with TRRE, a loss of 87% of binding capacity. 
     In order to determine the size of the p75 TNF-R cleared from C75R by TRRE, the following experiment was performed. 15×10 6  C75R cells were seeded in a 150 mm cell culture plate and incubated at 37° C. in 5% CO 2  for 12 to 16 hours. TRRE medium was incubated with C75R cells in the 150 mm plate for 30 min and the resulting supernatant was collected and centrifuged. The concentrated sample was applied to 10% acrylamide SDS-PAGE and electrophoretically transferred to a polyvinylidene difluoride membrane (Immobilon). Immunostaining resulted in a single band of 40 kDa, similar to the size found in biological fluids (FIG.  3 ). 
     The following method and assay were used throughout the Examples to measure TRRE activity. C75R cells and COS-1 cells were seeded into 24-well culture plates at a density of 2.5×10 5  cells/ml/well and incubated overnight (for 12 to 16 hours) in 5% CO 2  at 37° C. After aspirating the medium in the well, 300 μl of TRRE medium was incubated in each well of both the C75R and COS-1 plates for 30 min in 5% CO 2  at 37° C. (corresponding to A and C mentioned below, respectively). Simultaneously, C75R cells in 24-well plates were also incubated with 300 μl of fresh medium or buffer (corresponding to B mentioned below). The supernatants were collected, centrifuged, and then assayed for the concentration of soluble p75 TNF-R by ELISA as described above. 
     The following values were assigned and calculations made. A=(amount of soluble p75 TNF-R in a C75R plate treated with the TRRE containing sample); i.e. the total amount of sTNF-R in a C75R plate. B=(amount of soluble p75 TNF-R spontaneously released in a C75R plate treated with only medium or buffer containing the same reagent as the corresponding samples but without exogenous TRRE); i.e. the spontaneous release of sTNF-R from C75R cells. C=(amount of soluble p75 TNF-R in a COS-1 plate treated with the TRRE sample or the background level of soluble p75 TNF-R released by THP-1.); i.e. the degraded value of transferred (pre-existing) sTNF-R in the TRRE sample during 30 min incubation in a COS-1 plate. This corresponds to the background level of sTNF-R degraded in a C75R plate. 
     The net release of soluble p75 TNF-R produced only by TRRE activity existing in the initial sample is calculated as follows: (Net release of soluble p75 TNF-R only by TRRE)=A−B−C. We assigned the net release value of soluble p75 TNF-R as the amount of TRRE activity and defined 1 pg of soluble p75 TNF-R net release (A−B−C) as one unit (U) of TRRE activity. 
     Once the TRRE assay was devised, the time course of receptor shedding was assayed by the following method. TRRE-medium was incubated with C75R and COS-1 cells for varying lengths of time between 5 and 90 min. The supernatants were then collected and assayed for the level of soluble p75 TNF-R by ELISA and the net TRRE activity was calculated as described above. Detectable levels of soluble receptor were released by TRRE within 5 min and increased up to 30 min (FIG.  4 A). Subsequent experiments with longer incubation times showed that the level of TRRE remained relatively constant after 30 min, presumably from the depletion of substrates (FIG.  4 B). Therefore, 30 min was determined to be the optimal incubation time for this assay system. 
     The binding assay clearly showed that the parental COS-1 cells did not bind human  125 I-TNF, whereas the transfected C75R cells showed strong specific binding. Scatchard analysis indicated receptor levels of 70,000 per cell which were 40 to 50 times higher than that typically found on other cell lines. This higher level of substrate allowed detection of TRRE activity with much more sensitivity than with other cell lines. The Kd value calculated from Scatchard analysis was 5.6×10 −10  M, similar to the values previously reported for the native human p75 TNF-R. Thus, the transfected cells provided the membrane form of the receptor in its native configuration, resulting in an excellent source of substrate. 
     When C75R cells were incubated with TRRE medium, soluble p75 TNF-R was released into the supernatant which was measurable by ELISA. The amount of receptors released corresponded to level of TRRE activity. As C75R cells were incubated with TRRE medium, another well of C75R cells was simultaneously incubated with medium or buffer alone to measure the level of spontaneous release by C75R. The spontaneous release can be due to an endogenous source of proteolytic enzyme, a homolog of the human TRRE of monkey origin. In addition, TRRE medium was incubated with the parent COS-1 cells to detect the level of soluble receptors that was pre-existing in the sample. For this purpose, rather than directly measuring the level of soluble receptors in the supernatant by ELISA, we incubated the sample with COS-1 cells because we found that after incubation for 30 min with COS-1 cells, significant degradation of the soluble receptors was observed. The level of initial soluble receptors in the supernatant may decrease up to 50% after a 30 min incubation with COS-1 cells. Incorporating these two sources of background soluble receptors was the most accurate way to calculate the net TRRE activity. 
     The premise that increase in the level of soluble receptors in the supernatant was due to the proteolytic cleavage of membrane bound receptors was also supported by the loss of binding of  125 I-labeled TNF to C75R cells after incubation with TRRE. Since the receptor generated by TRRE was similar in size to that found in biological fluids, this reinforced the finding that TRRE generates sTNF-R in vivo. 
     The induction patterns of TRRE and known MMPs by PMA stimulation are quite different. In order to induce MMPs, monocytic U-937 cells, fibrosarcoma HT-1080 cells, or peritoneal exudate macrophages (PEM) usually have to be stimulated for one to three days with LPS or PMA. On the other hand, as compared with this prolonged induction, TRRE is released very quickly in culture supernatant following 30 min of PMA-stimulation. As disclosed in Example 2, TRRE is stored in the cell very close to the cell membrane to be secreted immediately by PMA-stimulation, and TRRE is synthesized very quickly within 2 hours also by PMA-stimulation. Therefore, judging from zymography gel data and the different induction patterns by PMA, TRRE cannot be classified into one of the pre-existing MMP families, despite their resemblance regarding metal-requirement and involvement of serine proteases in their activation. 
     Soluble TNF-R has been shown to bind to TNF or LT and form a complex consisting of 3 sTNF-R with 3 TNF or LT. Banner et al. (1993). According to gel filtration analysis presented above, the profile of TRRE and soluble p75 TNF-R was quite similar, with both peaks approximately at 150 kDa. Since the molecular size of soluble p75 TNF-R was reported to be 40 kDa, this suggests that sTNF-R exist as a complex formed with TRRE or TNF, or otherwise as homo oligomers. The hypothesis that TRRE and sTNF-R form a complex in vitro was confirmed by the experiment that 25% TRRE activity was recovered from soluble p75 TNF-R affinity column. This means that free TRRE has the ability to bind to its catalytic product, sTNF-R. The remaining 75% which did not combine to the affinity column may already be bound to sTNF-R or may not have enough affinity to bind to sTNF-R even though it is in a free form. 
     Although a considerable amount of enzyme product (EP) complex is thought to exist in the reacting solution, TRRE retained 86% of its activity after treated once with excessive substrate, suggesting that this complex can be easily separated when it meets new substrate. This EP complex does not seem to inhibit the enzymatic reaction of TRRE significantly. While sTNF-R is a potent inhibitor against the biological activities of TNF and LT, it was also shown that sTNF-R has another role in stabilizing TNF activity in vitro. Aderka et al. (1992)  J. Exp. Med.  175:323-329. Thus sTNF-R might act as a stabilizer not only for TNF, but also for TRRE by composing complex formation. This EP complex between TRRE and sTNF-R may be formed presumably under in vitro conditions, however it is possible that TRRE, sTNF-R and TNF make up several types of complexes in vivo as well as in vitro, and therefore may have physiological significance. 
     EXAMPLE 2 
     Biological Effect of TRRE 
     In this Example, the effect and biological significance of TRRE is investigated, including (a) substrate specificity and (b) function in vitro. 
     Fluorescein isothiocyanate (FITC)-conjugated anti-CD54, FITC-conjugated goat anti-rabbit and mouse antibodies, mouse monoclonal anti-CD30, anti-CD11b and anti-IL-1R (Serotec, Washington D.C.) were utilized in this study. Rabbit polyclonal anti-p55 and p75 TNF-R were constructed according to the method described by Yamamoto et al. (1978)  Cell Immunol.  38:403-416. THP-1 cells were treated for 30 min with 1,000 and/or 5,000 U/ml of TRRE eluted from the DEAE-Sephadex column and transferred to 12×75 mm polystyrene tubes (Fischer Scientific, Pittsburgh, Pa.) at 1×10 5  cells/100 μl/tube. The cells were then pelleted by centrifugation at 350×g for 5 min at 4° C. and stained directly with 10 μl FITC-conjugated anti-CD54 (diluted in cold PBS/0.5% sodium aside), indirectly with FITC-conjugated anti-mouse antibody after treatment of mouse monoclonal anti-CD11b, IL-1R and CD30 and also indirectly with FITC-conjugated anti-rabbit antibody after treatment of rabbit polyclonal anti-p55 and p75 TNF-R. 
     THP-1 cells stained with each of the antibodies without treatment of TRRE were utilized as negative controls. The tubes were incubated for 45 min at 4° C., agitated every 15 min, washed twice with PBS/2%FCS, repelleted and then resuspended in 200 μl of 1% paraformaldehyde. These labeled THP-1 cells were analyzed using a fluorescence activated cell sorter (FACS) (Becton-Dickinson, San Jose, Calif.) with a 15 mW argon laser with an excitation of 488 nm. Fluorescent signals were gated on the basis of forward and right angle light scattering to eliminate dead cells and aggregates from analysis. Gated signals (10 4 ) were detected at 585 BP filter and analyzed using Lysis II software. Values were expressed as percentage of positive cells, which was calculated by dividing mean channel fluorescence intensity (MFI) of stained THP-1 cells treated with TRRE by the MFI of the cells without TRRE treatment (negative control cells). 
     In order to test the in vitro TNF cytolytic assay by TRRE treatment the L929 cytolytic assay was performed according to the method described by Gatanaga et al. (1990b). Briefly, L929 cells, an adherent murine fibroblast cell line, were plated (70,000 cells/0.1 ml/well in a 96-well plate) overnight. Monolayered L929 cells were pretreated for 30 min with 100, 500 or 2,500 U/mI of partially-purified TRRE and then exposed to serial dilutions of recombinant human TNF for 1 hour. After washing the plate with RPMI-1640 with 10% FCS to remove the TRRE and TNF, the cells were incubated for 18 hours in RPMI-1640 with 10% FCS containing 1 μg/ml actinomycin D at 37° C. in 5% CO 2 . Culture supernatants were then aspirated and 50 μl of 1% crystal violet solution was added to each well. The plates were incubated for 15 min at room temperature. After the plates were washed with tap water and air-dried, the cells stained with crystal violet were lysed by 100 μl per well of 100 mM HCl in methanol. The absorbance at 550 nm was measured using an EAR 400 AT plate reader (SLT-Labinstruments, Salzburg, Austria). 
     TRRE was originally defined as a protease which truncated the human p75 TNF-R that was overexpressed on cDNA-transduced COS-1 cells (C75R). To investigate whether TRRE may truncate not only p75 but also p55 TNF-R on human cells, partially-purified TRRE from human THP-1 cells was applied to THP-1 cells which express low levels of both p55 and p75 TNF-R (approximately 1,500 receptors/cell by Scatchard analysis, data not shown). TRRE eluate from the DEAE-Sephadex column was added to THP-1 cells (5×10 6  cells/ml) at a final TRRE concentration of 1,000 U/ml for 30 min. The concentration of soluble p55 and p75 TNF-R in that supernatant was measured by soluble p55 and p75 TNF-R ELISA. TRRE was found to truncate both human p55 and p75 TNF-R on THP-1 cells and released 2,382 and 1,662 pg/ml soluble p55 and p75 TNF-R, respectively (FIG.  4 ). Therefore,TRRE was capable of truncating human p75 TNF-R on C75R cells and both human p55 and p75 TNF-R on THP-1 cells. 
     EXAMPLE 3 
     Use of TRRE in Treating Septic Shock 
     The following protocol was followed to test the effects of TRRE in preventing mortality in test animals which were treated with lipopolysaccharides (LPS) to induce sepsis and septic shock. 
     Generally, mice were injected with lethal or sublethal levels of LPS, and then with a control buffer or TRRE. Samples of peripheral blood were then collected at intervals to establish if TRRE blocked TNF-induced production of other cytokines in the bloodstream. Animals were assessed grossly for the ability of TRRE to block the clinical effects of shock and then euthanized and tissues examined by histopathological methods. 
     More specifically, adult Balb/c mice, the traditional animal model for septic shock studies [see, for example, Mack et al. (1997)  J. Surg. Res.  69:399-407; and Seljelid et al. (1997)  Scand. J. Immunol.  45:683-7], were placed in a restraining device and injected intravenously via the tail vein with a 0.1 ml solution containing 10 ng to 10 mg of LPS in phosphate buffer saline (PBS). These levels of LPS induce mild to lethal levels of shock in this strain of mice. Shock results from changes in vascular permeability, fluid loss, and dehydration, and is often accompanied by symptoms including lethargy, a hunched, stationary position, rumpled fur, cessation of eating, cyanosis, and, in serious cases, death within 12 to 24 hours. Control mice received an injection of PBS. Different amounts (2,000 or 4,000 U) of purified human TRRE were injected IV in a 0.1 ml volume within an hour prior to or after LPS injection. Serum (0.1 ml) was collected with a 27 gauge needle and 1 ml syringe IV from the tail vein at 30, 60 and 90 minutes after LPS injection. This serum was heparinized and stored frozen at −20° C. Samples from multiple experiments were tested by ELISA for the presence of sTNF-R, TNF, IL-8 and IL-6. Animals were monitored over the next 12 hours for the clinical effects of shock. Selected animals were euthanized at periods from 3 to 12 hours after treatment, autopsied and various organs and tissues fixed in formalin, imbedded in paraffin, sectioned and stained by hematoxalin-eosin (H and E). Tissue sections were subjected to histopathologic and immunopathologic examination. 
     As shown in FIG. 5, mice injected with LPS alone or LPS and a control buffer demonstrated rapid mortality. 50% of the test animals were dead after 8 hours (LPS) or 9 hours (LPS plus control buffer), and 100% of the animals were dead at 15 hours. In contrast, when injections of LPS were accompanied by injections of a 2,000 U of TRRE, death was delayed and death rates were lower. Only 40% of the animals were dead at 24 hours. When 4,000 U of TRRE was injected along with LPS, all of the animals had survived at 24 hours. Thus, TRRE is able to counteract the mortality induced by LPS in test animals. 
     EXAMPLE 4 
     Effect of TRRE on the Necrotizing Activity of Human TNF in Vivo 
     The following protocol was followed to test the effects of TRRE in affecting tumor necrosis in test animals in which tumors were produced, and in which TNF was subsequently injected. 
     Generally, on Day 0, cutaneous Meth A tumors were produced on the abdominal wall of fifteen BALB/c mice by intradermal injection of 2×20 5  Meth A tumor cells. 
     On Day 7, the mice were divided into three groups of five mice each and treated as follows: 
     Group 1: Injected intravenously with TNF (1 μg/mouse). 
     Group 2: Injected intravenously with TNF (1 μg/mouse) and injected intratumorally with TRRE (400 units/mouse, 6, 12 hours after TNF injection). 
     Group 3: Injected intravenously with TNF (1 μg/mouse) and injected intratumorally with control medium (6, 12 hours after TNF injection). 
     On Day 8, tumor necrosis was measured with the following results: 
     
       
         
               
               
             
               
               
               
             
           
               
                   
                   
               
               
                   
                 % of necrosis 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Group 1: 
                 100 (5/5)  
               
               
                   
                 Group 2: 
                 20 (1/5) 
               
               
                   
                 Group 3: 
                 80 (4/5) 
               
               
                   
                   
               
             
          
         
       
     
     Therefore, injections of TRRE greatly reduced the ability of TNF to induce necrosis in Meth A tumors in BALB/c mice. 
     EXAMPLE 5 
     Clones Involved in TRRE Activity 
     Nine clones involved in TRRE activity were obtained and designated clones 2-8, 2-9, 2-14, 2-15, P2-2, P2-10, P2-13, P2-14, and P2-15; the DNA sequences represented by SEQ ID NOs:1 to 10, with partial sequences of clone 2-8 represented by SEQ ID NOs:2 and 3. While not wishing to be bound by any particular theory, the inventors suggest that none of these clones encodes the TRRE itself, but these clones may be templates for RNAs or encode proteins involved in TRRE expression or function. 
     1. Obtaining Clones Involved in TRRE Activity 
     Clones 2-8, 2-9, 2-14, 2-15, P2-2, P2-10, P2-13, P2-14, and P2-15 (represented by SEQ ID NOs:1 to 10) were selected from a library of 10 6  Jurkat T cell (ATCC #TIB-152) cDNA inserts in the ZAP Express™/EcoRI vector (catalog no. 938201, Stratagene, La Jolla, Calif.). Jurkat cells have a high TRRE activity (850 TRRE U/ml at 10 −7 M PMA). The library was divided into 48 groups of DNA and transformed into COS-1 cells, which normally lack TRRE activity. Once these cells were grown out, the TRRE assay (described above) was performed, and five positive groups selected. DNA from each of these five groups and transfected into  E. coli , with 15 plates per group. DNA was prepared from these cells and then transfected again into COS-1 cells. Again, once the cells were grown out, the TRRE activity was tested. Two positive groups were selected and transfected into  E. coli , yielding 98 colonies. DNA was prepared from 96 of these colonies and transfected into COS-1 cells. The TRRE assay was performed again, and nine positive clones selected that substantially increased TRRE activity. These clones were designated 2-8, 2-9, 2-14, 2-15, P2-2, P2-10, P2-13, P2-14, and P2-15. The Production of TRRE activity from these clones is demonstrated in FIG.  6 . This figure shows that each clone is able to substantially increase (by 85% to 130%) TRRE activity compared to the control. 
     These nine clones were then sequenced. The strategy used to sequence the inserts in the clones included a combination of procedures which are summarized below: 
     1. Plasmid DNA was prepared using a modified alkaline lysis procedure. 
     2. DNA sequencing was performed using DyeDeoxy termination reactions (ABI). Base-specific fluorescent dyes were used as labels. 
     3. Sequencing reactions were analyzed on 5.75% Long Ranger™ gels by an ABI 373A-S or on 5.0% Long Ranger™ M gels by an ABI 377 automated sequencer. 
     4. Subsequent data analysis was performed using Sequencher™ 3.0 software. 
     5. Standard primers T7X, T3X, -40, -48 Reverse, and BK Reverse (BKR) were used in sequencing reactions. For each clone, several additional internal sequencing primers (listed below) were synthesized. 
     The sequence alignment printout reports generated using Sequencher™ 3.0 software and edited by hand are presented below. 
     NCBI BLAST (Basic Local Alignment Search Tool) sequence analysis [Altschul et al. (1990)  J. Mol. Biol.  215:403-410] was performed to determine if any known sequences were significantly similar to these sequences. Both the DNA sequences of the clones and the corresponding ORFs (if any) were compared to sequences available in databases. 
     The following clones were obtained and sequenced: 
     
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                   
                 Sequence 
                 Length 
                   
                 SEQ ID 
               
               
                 Clone 
                 Designation 
                 (bp) 
                 Homology 
                 NO: 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 2-9 
                 AIM2 
                 4,047 
                 novel 
                 1 
               
               
                 2-8* 
                 AIM3T3 
                 739 
                 similar to  M. musculus  45S 
                 2 
               
               
                   
                   
                   
                 pre-rRNA gene 
               
               
                   
                 AIM3T7 
                 233 
                 novel 
                 3 
               
               
                 2-14 
                 AIM4 
                 2,998 
                 human arfaptin 2 
                 4 
               
               
                 2-15 
                 AIM5 
                 4,152 
                 novel 
                 5 
               
               
                 P2-2 
                 AIM6 
                 3,117 
                 novel 
                 6 
               
               
                 P2-10 
                 AIM7 
                 3,306 
                 Human Insulin-like Growth 
                 7 
               
               
                   
                   
                   
                 factor II Receptor 
               
               
                 P1-13 
                 AIM8 
                 4,218 
                 novel 
                 8 
               
               
                 P2-14 
                 AIM9 
                 1,187 
                 novel 
                 9 
               
               
                 P2-15 
                 AIM10 
                 3,306 
                 novel 
                 10 
               
               
                   
               
               
                 *Clone 2-8 (AIM3) was only partially sequenced, generating two partial sequences of 739 and 233 bp, designated AIM3T3 and AIM3T7, respectively.  
               
             
          
         
       
     
     2. Clone 2-9 (AIM2) 
     The internal sequencing primers synthesized and used to obtain the sequence of this clone were: 
     
       
         
               
               
             
               
               
               
               
             
           
               
                   
                   
               
               
                   
                 SEQ ID 
               
               
                   
                 NO: 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                 AIM2 
                 AP1 
                 5′ TGC GGG GCC AGA GTG GGC TG 3′ 
                 11 
               
               
                 AIM2 
                 AP2 
                 5′ GCA GTC CTG GCC TGC GGA TG 3′ 
                 12 
               
               
                 AIM2 
                 AP3 
                 5′ GTC GAC AGG AGA ATT GGT TC 3′ 
                 13 
               
               
                 AIM2 
                 AP4 
                 5′ GCC TGG GTT CGG TGC GGG AC 3′ 
                 14 
               
               
                 AIM2 
                 AP5 
                 5′ TGG TCG GGT GTT TGT GAG TG 3′ 
                 15 
               
               
                 AIM2 
                 AP6 
                 5′ CCT CTT CCG TCT CCT CAG TG 3′ 
                 16 
               
               
                 AIM2 
                 AP7 
                 5′ GGA TTG CTA GTC TCA CAG AC 3′ 
                 17 
               
               
                 AIM2 
                 AP8 
                 5′ TTA AGG GTG GCT GAA GGG AC 3′ 
                 18 
               
               
                 AIM2 
                 AP9 
                 5′ ACC TTC CCT CCC TGT CAC AG 3′ 
                 19 
               
               
                 AIM2 
                 AP10 
                 5′ TGG TCG GGT GTT TGT GAG TG 3′ 
                 20 
               
               
                 AIM2 
                 AP11 
                 5′ ACA CCA TTC CAG AAA TTC AG 3′ 
                 21 
               
               
                 AIM2 
                 AP12 
                 5′ AAA CTG CAG GTG GCT GAG TC 3′ 
                 22 
               
               
                 AIM2 
                 AP13 
                 5′ GTC CTA ATG TTT TCA GGG AG 3′ 
                 23 
               
               
                 AIM2 
                 AP14 
                 5′ AAA ACC TAT GGT TAC AAT TC 3′ 
                 24 
               
               
                 AIM2 
                 AP15 
                 5′ TCC TAG ACA TGG TTC AAG TG 3′ 
                 25 
               
               
                 AIM2 
                 AP16 
                 5′ GAT ATA ATT AGT TCT CCA TC 3′ 
                 26 
               
               
                 AIM2 
                 AP17 
                 5′ ATG CCT GTT CCA GGC TGC AC 3′ 
                 27 
               
               
                 AIM2 
                 AP18 
                 5′ GGA CGG CGA CCT CCA CCC AC 3′ 
                 28 
               
               
                 AIM2 
                 AP19 
                 5′ GGG CTC CTC CGA CGC CTG AG 3′ 
                 29 
               
               
                 AIM2 
                 AP20 
                 5′ AGT CTA GCC CTG GCC TTG AC 3′ 
                 30 
               
               
                 AIM2 
                 AP21 
                 5′ GTC ACT GGG GAC TCC GGC AG 3′ 
                 31 
               
               
                 AIM2 
                 AP22 
                 5′ CAG CTT TCC CTG GGC ACA TG 3′ 
                 32 
               
               
                 AIM2 
                 AP23 
                 5′ CAC AGC TGT CTC AAG CCC AG 3′ 
                 33 
               
               
                 AIM2 
                 AP24 
                 5′ ACT GTT CCC CCT ACA TGA TG 3′ 
                 34 
               
               
                 AIM2 
                 AP25 
                 5′ ATC ATA TCC TCT TGC TGG TC 3′ 
                 35 
               
               
                 AIM2 
                 AP26 
                 5′ GTT CCC AGA GCT TGT CTG TG 3′ 
                 36 
               
               
                 AIM2 
                 AP27 
                 5′ GTT TGG CAG ACT CAT AGT TG 3′ 
                 37 
               
               
                 AIM2 
                 AP28 
                 5′ TAG CAG GGA GCC ATG ACC TG 3′ 
                 38 
               
               
                   
               
             
          
         
       
     
     The sequence of AIM2 is presented in SEQ ID NO:1. The complementary strand of the AIM2 sequence is SEQ ID NO:147. The longest ORF in the AIM2 sequence is 474 AA long and represented in SEQ ID NO:148. 
     The BLAST search did not reveal any sequences with significant similarity to the AIM2 sequence. 
     3. Clone 2-8 (AIM3) 
     Of all the clones obtained, only this clone was not sequenced in its entirety. Two partial sequences of length 739 and 233 were obtained and designated AIM3T3 and AIM3T7. The internal sequencing primers synthesized and used to obtain the sequence of this clone were: 
     
       
         
               
               
             
               
               
               
               
             
           
               
                   
                   
               
               
                   
                 SEQ ID 
               
               
                   
                 NO: 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                 AIM3 
                 AP1 
                 5′ CTT GGC GCC AGA AGC GAG AG 3′ 
                 39 
               
               
                 AIM3 
                 AP2 
                 5′ CCT CTC TCT CTC TCT CTC TC 3′ 
                 40 
               
               
                 AIM3 
                 AP3 
                 5′ TCC CCG CTG ATT CCG CCA AG 3′ 
                 41 
               
               
                 AIM3 
                 AP4 
                 5′ CTT TTT GAA TTC GGC ACG AG 3′ 
                 42 
               
               
                 AIM3 
                 AP5 
                 5′ CCC CTG GTC CGC ACC AGT TC 3′ 
                 43 
               
               
                 AIM3 
                 AP6 
                 5′ GAG AAG GGT CGG GGC GGC AG 3′ 
                 44 
               
               
                 AIM3 
                 AP7 
                 5′ AAA TCA CAT CGC GTC AAC AC 3′ 
                 45 
               
               
                 AIM3 
                 AP8 
                 5′ TAA GAG AGT CAT AGT TAC TC 3′ 
                 46 
               
               
                   
               
             
          
         
       
     
     The sequences of AIM3T3 and AIM3T7 are presented in SEQ ID NOs:2 and 3, respectively. The BLAST search revealed that the AIM3T3 sequence may be homologous to the mouse ( M. musculus ) 28S ribosomal RNA [Hassouna et al. (1984)  Nucleic Acids Res.  12:3563-3583] and the  M. musculus  45S pre-rRNA genes [Accession No. X82564, Goegel et al.,  Chromosoma , in press]. The complementary sequence of the AIM3T3 sequence showed 99% similarity over 408 bp beginning with nt 221 of SEQ ID NO:2 to the former and 97% similarity over the same span to the latter. 
     The BLAST search did not reveal any known sequence homologous to the AIM3T7 sequence. 
     4. Clone 2-14 (AIM4) 
     The internal sequencing primers synthesized and used to obtain the sequence of this clone were: 
     
       
         
               
               
             
               
               
               
               
             
           
               
                   
                   
               
               
                   
                 SEQ ID 
               
               
                   
                 NO: 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                 AIM4 
                 AP1 
                 5′ GCT CTA GAA GTA CTC TCG AG 3′ 
                 47 
               
               
                 AIM4 
                 AP2 
                 5′ ACT CTG GCC ATC AGG AGA TC 3′ 
                 48 
               
               
                 AIM4 
                 AP3 
                 5′ CAG GCG TTG TAG ATG TTC TG 3′ 
                 49 
               
               
                 AIM4 
                 AP4 
                 5′ AGT GGC AGG CAG AAG TAA TG 3′ 
                 50 
               
               
                 AIM4 
                 AP5 
                 5′ GGT TGG AGA ACT GGA TGT AG 3′ 
                 51 
               
               
                 AIM4 
                 AP6 
                 5′ CTA TTC AGA TGC AAC GCC AG 3′ 
                 52 
               
               
                 AIM4 
                 AP7 
                 5′ CCA TGG CAC ACA GAG CAG AC 3′ 
                 53 
               
               
                 AIM4 
                 AP8 
                 5′ GCT ACC ATG CAG AGA CAC AG 3′ 
                 54 
               
               
                 AIM4 
                 AP9 
                 5′ CAG GCT GAC AAG AAA ATC AG 3′ 
                 55 
               
               
                 AIM4 
                 AP10 
                 5′ GGC ACG CAT AGA GGA GAG AC 3′ 
                 56 
               
               
                 AIM4 
                 AP11 
                 5′ TGG GTG ATG CCT TTG CTG AC 3′ 
                 57 
               
               
                 AIM4 
                 AP12 
                 5′ AAA ACA AGA TCA AGG TGA TG 3′ 
                 58 
               
               
                 AIM4 
                 AP13 
                 5′ TTG CCC ACA TTG CTA TGG TG 3′ 
                 59 
               
               
                 AIM4 
                 AP14 
                 5′ GAC CAA GAT CAG AAG TAG AG 3′ 
                 60 
               
               
                 AIM4 
                 AP15 
                 5′ CCC CTG GGC CAA TGA TGT TG 3′ 
                 61 
               
               
                 AIM4 
                 AP16 
                 5′ TCT TCC CAC CAT AGC AAT G 3′ 
                 62 
               
               
                 AIM4 
                 AP17 
                 5′ TGG TCT TGG TGA CCA ATG TG 3′ 
                 63 
               
               
                 AIM4 
                 AP18 
                 5′ ACA CCT CGG TGA CCC CTG TG 3′ 
                 64 
               
               
                 AIM4 
                 AP19 
                 5′ TCT CCA AGT TCG GCA CAG TG 3′ 
                 65 
               
               
                   
               
             
          
         
       
     
     The sequence of AIM4 is presented in SEQ ID NO:4. 
     The complementary strand of the AIM4 sequence is SEQ ID NO:149. The longest ORF in the AIM4 sequence is 236 AA long and represented in SEQ ID NO:150. 
     The BLAST search revealed that this clone may be homologous or identical to the human arfaptin 2, putative target protein of ADP-ribosylation factor (GENBANK locus HSU52522, accession U52522). 
     5. Clone 2-15 (AIM5) 
     The internal sequencing primers synthesized and used to obtain the sequence of this clone were: 
     
       
         
               
               
             
               
               
               
               
             
           
               
                   
                   
               
               
                   
                 SEQ ID 
               
               
                   
                 NO: 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                 AIM5 
                 AP1 
                 5′ ACA TGG GCT GCA CTC ACG AC 3′ 
                 66 
               
               
                 AIM5 
                 AP2 
                 5′ GAT CCT CTG AAC CTG CAG AG 3′ 
                 67 
               
               
                 AIM5 
                 AP3 
                 5′ GGA AAT GAG GTG GGG CGA TC 3′ 
                 68 
               
               
                 AIM5 
                 AP4 
                 5′ CTT TGC CTT GGA CAA GGA TG 3′ 
                 69 
               
               
                 AIM5 
                 AP5 
                 5′ GCA CCT GCC ATT GGG GGT AG 3′ 
                 70 
               
               
                 AIM5 
                 AP6 
                 5′ GGT GGA AGC CAT TGA CGG TG 3′ 
                 71 
               
               
                 AIM5 
                 AP7 
                 5′ TGC GTC TCT CGT CGC TGC TG 3′ 
                 72 
               
               
                 AIM5 
                 AP8 
                 5′ GCG GAA ACT CTG TGG TGC TG 3′ 
                 73 
               
               
                 AIM5 
                 AP9 
                 5′ AGG ATT GCC TTC CTC TAC TG 3′ 
                 74 
               
               
                 AIM5 
                 AP10 
                 5′ TGT CTG TTT CAC CAG GGC AG 3′ 
                 75 
               
               
                 AIM5 
                 AP11 
                 5′ CCA GTG CCT CTA TGC ATG TC 3′ 
                 76 
               
               
                 AIM5 
                 AP12 
                 5′ AGG AAG CCC ACG CAC ACC AC 3′ 
                 77 
               
               
                 AIM5 
                 AP13 
                 5′ CCC TTT GTT CCC TGA TCT TC 3′ 
                 78 
               
               
                 AIM5 
                 AP14 
                 5′ CGC TCG GGA TCC AGG TCA TC 3′ 
                 79 
               
               
                 AIM5 
                 AP15 
                 5′ TCG AGG TTC AGA GCG TAG TG 3′ 
                 80 
               
               
                   
               
             
          
         
       
     
     The sequence of AIM5 is presented in SEQ ID NO:5. 
     The BLAST search revealed that the AIM5 sequence is novel. However, it displays some similarity, but not complete similarity, to Human Initiation Factor 5A (eIF-5A) [Koettnitz et al. (1995)  Gene  159:283-284] and Human Initiation Factor 4D (eIF 4D) [Smit-McBride et al. (1989)  J. Biol. Chem.  264:1578-1583]. 
     6. Clone P2-2 (AIM6) 
     The internal sequencing primers synthesized and used to obtain the sequence of this clone were: 
     
       
         
               
               
             
               
               
               
               
             
           
               
                   
                   
               
               
                   
                 SEQ ID 
               
               
                   
                 NO: 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                 AIM6 
                 AP1 
                 5′ TCT TGG ATC TCT GGC ACC TC 3′ 
                 81 
               
               
                 AIM6 
                 AP2 
                 5′ CCA TCA GAG TGA AGG AGG AG 3′ 
                 82 
               
               
                 AIM6 
                 AP3 
                 5′ CCA TCT TCC ACT GGT CAG AG 3′ 
                 83 
               
               
                 AIM6 
                 AP4 
                 5′ CTC CTT CTC TTG GAT CTC TG 3′ 
                 84 
               
               
                 AIM6 
                 AP5 
                 5′ TTA CTT CAG CAC TGT TAG TC 3′ 
                 85 
               
               
                 AIM6 
                 AP6 
                 5′ AGG GAG GTA GCT CAA AGC TC 3′ 
                 86 
               
               
                 AIM6 
                 AP7 
                 5′ TGG GTC CAC AGT TCG CAC AG 3′ 
                 87 
               
               
                 AIM6 
                 AP8 
                 5′ CAA CTC TGT GAT GGC TCC AG 3′ 
                 88 
               
               
                 AIM6 
                 AP9 
                 5′ AGC AGG GTT CTG TTC AAG AC 3′ 
                 89 
               
               
                 AIM6 
                 AP10 
                 5′ CCA TTG GGT GCT AGT CTC TC 3′ 
                 90 
               
               
                 AIM6 
                 AP11 
                 5′ CAG CCA TGC TGT CCC AGC AG 3′ 
                 91 
               
               
                 AIM6 
                 AP12 
                 5′ CTG GAC CTG AGG TAG CGC TG 3′ 
                 92 
               
               
                 AIM6 
                 AP13 
                 5′ ATA ACC ACC CTG AGG CAC TG 3′ 
                 93 
               
               
                   
               
             
          
         
       
     
     Sequence analysis of the AIM6 clone sequence revealed the ORF represented in SEQ ID NO:151. 
     The sequence of AIM6 is presented in SEQ ID NO:6. The longest ORF in the AIM6 sequence is 1038 AA long and represented in SEQ ID NO:151. 
     The BLAST search did not reveal any sequences of known function with significant similarity to the AIM6 sequence. 
     7. Clone P2-10 (AIM7) 
     The internal sequencing primers synthesized and used to obtain the sequence of this clone were: 
     
       
         
               
               
             
               
               
               
               
             
           
               
                   
                   
               
               
                   
                 SEQ ID 
               
               
                   
                 NO: 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                 AIM7 
                 AP1 
                 5′ CCT GCA GGT CGA CAC TAG TG 3′ 
                 94 
               
               
                 AIM7 
                 AP2 
                 5′ AAT TGG AAT GAG GAG GAC TG 3′ 
                 95 
               
               
                 AIM7 
                 AP3 
                 5′ GCT CTA GAA GTA CTC TCG AG 3′ 
                 96 
               
               
                 AIM7 
                 AP4 
                 5′ ATT GTA TGA CAA TGC ACC AG 3′ 
                 97 
               
               
                 AIM7 
                 AP5 
                 5′ TCC ACA GAG GGC TTC ATC AC 3′ 
                 98 
               
               
                 AIM7 
                 AP6 
                 5′ CCT GAC TGG CCT AAG CAC AG 3′ 
                 99 
               
               
                 AIM7 
                 AP7 
                 5′ AAG CCT CAT AAC CAC CAG TG 3′ 
                 100 
               
               
                 AIM7 
                 AP8 
                 5′ TGT CAA CGG TGA CAA GTG TG 3′ 
                 101 
               
               
                 AIM7 
                 AP9 
                 5′ TTG TAC ACC AGC TGC AGG TC 3′ 
                 102 
               
               
                 AIM7 
                 AP10 
                 5′ GGG TGT GGT GCA GAT GAG TC 3′ 
                 103 
               
               
                 AIM7 
                 AP11 
                 5′ ATC ACA CTC TTA TAG CTC AG 3′ 
                 104 
               
               
                 AIM7 
                 AP12 
                 5′ GTG GGA AGC TTT CCT CAG AC 3′ 
                 105 
               
               
                 AIM7 
                 AP13 
                 5′ TGA TGA ACA TGG GCC TGG AG 3′ 
                 106 
               
               
                   
               
             
          
         
       
     
     The sequence of AIM7 is presented as SEQ ID NO:7. The longest ORF in the AIM7 sequence is 849 AA long and represented in SEQ ID NO:152. 
     The BLAST search revealed that this clone may be the Human Insulin-like Growth Factor II Receptor [Morgan et al. (1987)  Nature  329:301-307] or the Human Cation-Independent Mannose 6-Phosphate Receptor mRNA [Oshima et al. (1988)  J. Biol. Chem.  263:2553-2562]. The AIM7 sequence showed 99% identity to both sequences over 2520 nucleotides beginning with nt 12 of SEQ ID NO:7 and 99% similarity to the latter over the same span. 
     7. Clone P2-13 (AIM8) 
     The internal sequencing primers synthesized and used to obtain the sequence of this clone were: 
     
       
         
               
               
             
               
               
               
               
             
           
               
                   
                   
               
               
                   
                 SEQ ID 
               
               
                   
                 NO: 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                 AIM8 
                 AP1 
                 5′ CAT TGT GGA TGT ACT ACC AC 3′ 
                 107 
               
               
                 *AIM8 
                 AP2 
                 5′ TGT GTT TTG CAA CCT GAG TG 3′ 
                 108 
               
               
                 AIM8 
                 AP3 
                 5′ ATA GTG GCA CCA CTT ACG AG 3′ 
                 109 
               
               
                 AIM8 
                 AP4 
                 5′ AAT TCT GCA ACG TGA TGG CG 3′ 
                 110 
               
               
                 AIM8 
                 AP5 
                 5′ CAC AAG ATG CCT CGT CTG TG 3′ 
                 111 
               
               
                 AIM8 
                 AP6 
                 5′ AAT CCG GAC AAG GTA CAG TC 3′ 
                 112 
               
               
                 AIM8 
                 AP7 
                 5′ GCA CGA GTG GCA CAA GCG TG 3′ 
                 113 
               
               
                 AIM8 
                 AP8 
                 5′ GCA AGC GTG TGG TGT CAG TG 3′ 
                 114 
               
               
                 AIMB 
                 AP9 
                 5′ TGT TTG AAC AGG CTC TGG AC 3′ 
                 115 
               
               
                 AIM8 
                 AP10 
                 5′ CGG CAT GGC AAT GAG GAC AC 3′ 
                 116 
               
               
                 AIM8 
                 AP11 
                 5′ AGG ACG AGA TGG ACC TCC AG 3′ 
                 117 
               
               
                 AIM8 
                 AP12 
                 5′ CCC TCT GTC CTC TAG CCC AC 3′ 
                 118 
               
               
                   
               
               
                 *Primers did not produce useable sequence data.  
               
             
          
         
       
     
     The sequence of AIM8 is presented as SEQ ID NO:8. 
     The longest ORF in the AIM8 sequence is 852 AA long and represented in SEQ ID NO:153. 
     The BLAST search did not reveal significant similarity of the AIM8 sequence to any sequence in the database. 
     9. Clone P2-14 (AIM9) 
     The internal sequencing primers synthesized and used to obtain the sequence of this clone were: 
     
       
         
               
               
             
               
               
               
               
             
           
               
                   
                   
               
               
                   
                 SEQ ID 
               
               
                   
                 NO: 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                 AIM9 
                 AP1 
                 5′ TCT TGA GGG GAC TGA CTC TG 3′ 
                 119 
               
               
                 AIM9 
                 AP2 
                 5′ TGA GTG AGG AGG CAG ATG TC 3′ 
                 120 
               
               
                 AIM9 
                 AP3 
                 5′ TGG CTT TGA AGA AAG AGC TG 3′ 
                 121 
               
               
                 AIM9 
                 AP4 
                 5′ GCA AAA GAC CAG GCT GAC TG 3′ 
                 122 
               
               
                 AIM9 
                 AP5 
                 5′ TGC AGC TCC TTG GTC TTC TC 3′ 
                 123 
               
               
                 *AIM9 
                 AP6 
                 5′ GAT TCA CAG TCC CAA GGC TC 3′ 
                 124 
               
               
                   
               
               
                 *Primers did not produce useable sequence data.  
               
             
          
         
       
     
     The sequence of AIM9 is presented as SEQ ID NO:9. No ORFS longer than 149 AA long were found in the AIM9 sequence. 
     The BLAST search did not reveal any sequences which had significant similarity to the AIM9 sequence. 
     10. Clone P2-15 (AIM10) 
     The internal sequencing primers synthesized and used to obtain the sequence of this clone were: 
     
       
         
               
               
             
               
               
               
               
             
           
               
                   
                   
               
               
                   
                 SEQ ID 
               
               
                   
                 NO: 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                 AIM10 
                 AP1 
                 5′ ATC TGG ATG AGG CGG TTG AG 3′ 
                 125 
               
               
                 AIM10 
                 AP2 
                 5′ GGT CAC TCT CCG ACG AGG AG 3′ 
                 126 
               
               
                 AIM10 
                 AP3 
                 5′ GGA TCC AAA GTT CGT CTC TG 3′ 
                 127 
               
               
                 AIM10 
                 AP4 
                 5′ CGC TGT GTG TCT GAT CCC TC 3′ 
                 128 
               
               
                 AIM10 
                 AP5 
                 5′ ATG AAG GTA AAC CCC GGG AG 3′ 
                 129 
               
               
                 AIM10 
                 AP6 
                 5′ TGG TCT CTG GCT CTG AGC AC 3′ 
                 130 
               
               
                 AIM10 
                 AP7 
                 5′ GCC TGG AGA AGC CCA GTC TG 3′ 
                 131 
               
               
                 AIM10 
                 AP8 
                 5′ CAC ACT CTG GAC CGT TGC TG 3′ 
                 132 
               
               
                 AIM10 
                 AP9 
                 5′ AAA GCT CCG CAG CCG CAG TG 3′ 
                 133 
               
               
                 AIM10 
                 AP10 
                 5′ TCT TCC AGG AAG CTG CGG TC 3′ 
                 134 
               
               
                 AIM10 
                 AP11 
                 5′ GAT GGT GGG GCA GCA TTG AG 3′ 
                 135 
               
               
                 AIM10 
                 AP12 
                 5′ GTC ACC AGT GGT GCC TGC AG 3′ 
                 136 
               
               
                 AIM10 
                 AP13a 
                 5′ ACC TCA CGG TTG CCA ACC TG 3′ 
                 137 
               
               
                 AIM10 
                 AP13b 
                 5′ CGC AAC AGC GTC TCC CTC TG 3′ 
                 138 
               
               
                 AIM10 
                 AP14 
                 5′ AGT ACC TTC ATA AGT TCT TC 3′ 
                 139 
               
               
                 AIM10 
                 AP15 
                 5′ TCC CAG ACT TCA ACC TTC AC 3′ 
                 140 
               
               
                 AIM10 
                 AP16 
                 5′ AAA CAT CTT CCC GGT CGG AC 3′ 
                 141 
               
               
                 AIM10 
                 AP17 
                 5′ GCT GAG CAC CTT TAC CTC AC 3′ 
                 142 
               
               
                 AIM10 
                 AP18 
                 5′ GAC GTC CGT CCG GGA AGA TG 3′ 
                 143 
               
               
                 AIM10 
                 AP19 
                 5′ ACA CAG GAG ATG CAG GTC AC 3′ 
                 144 
               
               
                 AIM10 
                 AP20 
                 5′ GAG TCT TCC ATG AAG AAC AG 3′ 
                 145 
               
               
                 AIM10 
                 AP21 
                 5′ GCA GTG AGG AAG GTA AGG AG 3′ 
                 146 
               
               
                   
               
               
                 *Primers did not produce useable sequence data.  
               
             
          
         
       
     
     The sequence of AIM10 is presented as SEQ ID NO:10. The longest ORF in the AIM10 sequence is 693 AA long and represented in SEQ ID NO:154. 
     The BLAST search did not reveal any sequences with significant similarity to the AIM10 sequence. 
     Thus, cloning the TRRE gene yielded nine clones, each of which encoded a protein having TRRE activity. These clones were designated 2-8, 2-9, 2-14, 2-15, P2-2, P2-10, P2-13, P2-14, and P2-15, which encode sequences designated AIM2, AIM3T3/AIM3T7, AIM4, AIM5, AIM6, AIM7, AIM8, AIM9, and AIM10, and shown in SEQ ID NOs:1 to 10. Each clone increases TRRE activity of COS-1 cells in vitro. Sequence analysis of these clones indicated that AIM3 may be homologous to  M musculus  45S pre-rRNA gene; AIM5, Human eIF-5A transcription factor; and AIM7, Human Insulin-like Growth Factor II Receptor. Without wishing to be bound by any particular theory, the inventors suggest that some or all of these clones may be templates for RNAs or encode proteins which are involved in transcription and/or translation of TRRE. Alternatively, some or all of these factors may be involved in increasing the activity of TRRE (e.g., acting as an accessory protein). 
     Clonal DNA may be directly injected into test animals in order to test the ability of these nucleic acids to induce TRRE activity, counteract septic shock and/or affect tumor necrosis, as is described in detail in Examples 3 and 4. Alternatively, proteins or RNA can be generated from the clonal DNA and similarly tested in animals. 
     Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity and understanding, it will be apparent to those skilled in the art that certain changes and modifications can be practiced. Therefore, the description and examples should not be construed as limiting the scope of the invention which is delineated by the appended claims. 
     
       
         
           
             154 
           
           
             
               4047 base pairs 
               nucleic acid 
               double 
               linear 
             
             
               Genomic DNA 
             
             1
 AAGCTTTTTG CTTTCCTTCC CCGGGAAAGG CCGGGGCCAG AGACCCGCAC TCGGACCAGG    60
 CGGGGGCTGC GGGGCCAGAG TGGGCTGGGG AGGGCTGGGA GGGCGTCTGG GGCCGGCTCC   120
 TCCAGGCTGG GGGCCGCCAG CTCCGGGAAG GCAGTCCTGG CCTGCGGATG GGGCCGCGCG   180
 TGGGGCCCGG CGGGGCGGCC TCGGGAGGCG TCCAGGCTGC GGGAGCGGGA GGAGCGGCCG   240
 TGCGGGCGCC AGCGCCGTGG GTGGAGGTCG CCGTCCCTCC TGAGGGGCAG CCAGTGCGTT   300
 TGGGACCCGG GAGCAGAGCC CGCGCCTCCC CAGCGGCCTC CCCGGGGGTC TCACCGGGTC   360
 ACCCGAGAGC GGAGGCCCCG GCTCCGCAGA AACCCGGGGC GGCCGCGGGG AAGCAGCGCC   420
 CTCAGGCGTC GGAGGAGCCC CCAGAAGGAC CTCGCGCCTT CCCGCCGGGC TCCGACCGCC   480
 TGGGTTCGGT GCGGGACGGC CCAGGCCGCC AGGACCCCCA AGCGCAGCTC AGTCTGCGGG   540
 GCACGACCCA GAGGCCAGCA GCAGAGGACG GGGCCGGGGC CGGGAGAGGG CGGGGAGGGC   600
 GCTCCTGGGA GGTCAAGGCC AGGGCTAGAC TTTCAGGGTC ATGGCCTGGC CCCTCATCCC   660
 CAGGGAGGTG AGGGGGCTCT GTGAGCAGAG GGGGCCCCGG TGGAGAAGGC GCTGCTAGCC   720
 AGGGGCGGGG CAGGAGCCCA GGTGGGGACT TAAGGGTGGC TGAAGGGACC CTCAGGCTGC   780
 AGGGATAGGG AGGGAAGCTA GGGGTGTGGC TTGGGGAGGT GCTGGGGGAC CGCGGGCGCC   840
 CTTTATTCTG AAGCCGAATG TGCTGCCGGA GTCCCCAGTG ACCTAGAAAT CCATTTCAAG   900
 ATTTTCAGGA GTTTCAGGTG GAGACAAAGG CCAGGCCCAG GTGAAAATGT GGCAGTGACA   960
 GAGTATGGGG TGAGAACCAC GGAGAGAGGA AGTCCCCGAG GCGGATGATG GGACAGAGAG  1020
 CGGGGACCAG AATTTTTTAA AACGCATCTG AGATGCGTTT GGCAGACTCA TAGTTGTTTT  1080
 CCTTTCACGG AGAAAGTGTG GGCAGAAGCC AGCTCTAAAG CCCAGGCTGC CCAGCCTGCA  1140
 CTGGCAGAGC TGACGGAAGG CCAGGGCAGA GCCTTCCCTC CCTGTCACAG ACATGAGCCC  1200
 TGGAGATCTG GAATGAGGCA GATGTGCCCA GGGAAAGCTG ATCCGCCCCG ACCCAGGGCC  1260
 CCCCGGGTGC CCCTTTGAGC GTGGAATCGT TGCCAGGTCA TGGCTCCCTG CTATCGAACA  1320
 CCGGACACGG GTCGTGTGCT GCACCTGGCA GTTGCAGGAC CGACACCCAC AATGCCTTAA  1380
 GAGGTGATGA CTGCCTTCCA GGGGCCTGGC TGGCTGACAC TTTGCATGGC TCCTGGAGAA  1440
 GAGGGATTGA GTGGAGTCCA CGGGTCATGG CCACGTCCTG GGTGCTGCCT CTGAGGCAGG  1500
 GCCCGGCTGG GGTGAGAAGG GGCTGGAGAC AGGTTCCTGC CAGTTCAGCC TCTAACCGGT  1560
 GGTCTTCATG CCTAGGAACC CACTGGGGGC TTATGAAACT GCAGGTGGCT GAGTCCTTGC  1620
 CATGGGGTCT CTCCTTCAGG AGGTCTGGGT GGGGCCGGAG ACTGTACCCC ACAAAGGGTC  1680
 CCAGGTGAGG CGGATGTGGC CTGGCGCTGT GTGGCTCTGG ACCTAGTCCT TGGGCTTGGG  1740
 CTGGCGCCCA GGGCCTGGGC TTGAGACAGC TGTGACGCAG GCAAGCCATT TACCCCGTTT  1800
 GTGGGGACAT TACATCTTCC TAGCTTGGAA CACACAGGCA GCCAGGGTTG TTATCCACAT  1860
 TCCTCCTCCA TGTTCTTCTC TTGAGAACTT TTACCAGGTA TGTCAGGAGC TGGGCTCCAC  1920
 CAGGGAGACT CAAGTGGAAA GCCCTCATCC TTGTCCTCCA GGAGACAGGA AAACCTATGG  1980
 TTACAATTCC AGGGACAAGA GCGATGCATG TGAGGTGTGG CAAATCTCAC TGTTCAACTG  2040
 GAGAAATCAG AGACAGCTTC CTGGAGGCAG TGACACCTGG ACAGGCTTCT CCACAGGAGG  2100
 AAGCGAGTGA GAGAAGCCAA CTGGGATGGA CCCATCATGT AGGGGGAACA GTGCGCGCAG  2160
 AACCAACAAC CACCCCCACC CTAGGCCCAG AGCTCACGGA GAGAGCTGGG CCTCTCGGGG  2220
 TGACTACATA GTTCCCTGCT GGATCTTAGG TCTTGTCCTT GGGCAGCTCT GCTGAGACCT  2280
 CTATGCCTGT TCCAGGCTGC ACCAAGGTTT TGTGACTATT GGTCTGGGGT TGTTTTGCAG  2340
 CAACTGAAGT GTTCTGTTGT AAAACAGGCA CTTGATTTGC TGGAAGGAAT GCTGTTTGTT  2400
 CTTGCTGCGA CAAACATTGA GCAGCATTTA GTGGGCGGTT TATATCTTGT GGAGTAATGG  2460
 GTGTTTTTGA AGTCTGTCCT GGGTACTGCA CATTAAAAGG AATATCATTT TCTGAAACAT  2520
 TGCTATTTTC CACACCAGAA ATCATATCCT CTTGCTGGTC CATGTCTGAA GACCTTACAC  2580
 GAGAAAGTCT TAATGTAAGT TTAGTAGAGT CCTTGGATGG AGAACTAATT ATATCATACA  2640
 TTGCCGCTTT CTCACTCTGC TCTTTTTCAT CCTTGCCTAA TTTCATTTTC TTCTGCTTCT  2700
 TTTGTTTTCT TTCTGGAGAA TCTAGCAAGA TATCTGGTGG AACATCTCGA GGTGATGAAC  2760
 AAGGTAGAGA CTGAGATTGT AGGATTAAAG GTGGTCTTGA GCCTTTAGGA GTTCCTTCAC  2820
 TTCCAGCAGG GGAGCATACT GGCTGTGGAG ATCTCAAGGG AAAAGATGCA GCATTCCTCA  2880
 TTGTTGAAGA ATCTCCATCG TCACTACTTA GCCTGTGCAC CATGTGTAGG TAGTCCTCAC  2940
 TTGAACCATG TCTAGGATTA TCAGCATGAT GATTAGCTGA ATTGCCAGAC AACGGACCAG  3000
 AAACTTTATT ATCATGTATG TTTCTCAAAC CACCTGCAAC AATGGGACTT GATACCGATG  3060
 CTTGTTGCAT CTGTGGATGT GTTGTGTAAC TTGAAGGATG GGAATATGGC ATGTATCCTG  3120
 CAGGGCTTTG TGGGGCGTAT GGACTAGGCA CTGGGCTATT TTGCTGTGGC ATAAATCTGT  3180
 TCCCAGAGCT TGTCTGTGGT GGCACAAACC GGCTGGAGGG GCTATGTGAG ATAGTGGTTT  3240
 GTTGATAATT GGAAGATGCA GGACTACTGT GCATGGAATT CTGAGAAAGT TTATACTGAG  3300
 ACATCATCAT TCCACTTTGT ACATATCTGT TCTGCATGCT TTTCTCCCTG AAAACATTAG  3360
 GACTCCTTGC CAGGACGGCC TGCAACAAGA CTGGTATGTC ACCTTCTGGG TCATCACTGC  3420
 CAAGGTTATC TTTCAACTCT ATGTGATCTG TTGATACCTG GTTGAGGCTA TGGACAAGCT  3480
 GTGAAACCAA ATTGTCATCC CTACAAGCCA AAAGGCAGTT CACCTCTTCT GCTATTCGTG  3540
 CATTAAAGAG AAGGCTCTTT GTAGTTGTAG CAGGTAAAGG AGATGGAAGA GGCAGCTGGT  3600
 TCAGGAGGTC TGTGAGACTA GCAATCCCCG CAAGAGTAGT AATGGGGACA TGGGGCATAT  3660
 CCCCATTCAT CCTGAATTTC TGGAATGGTG TTGCCTATAA AAGTACTTAG TTCAGGTGCC  3720
 AGCTGTCATT ACTTCCCATT TCCCAAACAC TGGGCGAATC GGCGTCTGAA TCCAAGGGGA  3780
 GGCCGAGGCC GCTGTGGCGA GAGACTATAA TCCGGGCCGG GAGGGGGGGC GGCTACGGCT  3840
 CCTCTTCCGT CTCCTCAGTG CGGGGAACAT GTAGAGCCGG GGGGAGACCA GCCGAGAAGA  3900
 CAAATCGTTG CTTCTTCTTC CTCCTCCTCC TCCTTCTCCC ACATAGAAAC ACTCACAAAC  3960
 ACCCGACCAC GGGCCCGAGC TACCGGGGGG GCATCGCCGC GGGCCCGGGA ACCAATTCTC  4020
 CTGTCGGCGG GGGCGTCCTT TGGATCC                                      4047
 
           
           
             
               739 base pairs 
               nucleic acid 
               double 
               linear 
             
             
               Genomic DNA 
             
             2
 GGATCCAAAG GTCAAACTCC CCACCTGGCA CTGTCCCCGG AGCGGGTCGC GCCCGGCCGG    60
 CGCGCGGCCG GGCGCTTGGC GCCAGAAGCG AGAGCCCCTC GGGGCTCGCC CCCCCGCCTC   120
 ACCGGGTCAG TGAAAAAACG ATCAGAGTAG TGGTATTTCA CCGGCGGCCC GCAGGGCCGG   180
 CGGACCCCGC CCCGGGCCCC TCGCGGGGAC ACCGGGGGGG CGCCGGGGGC CTCCCACTTA   240
 TTCTACACCT CTCATGTCTC TTCACCGTGC CAGACTAGAG TCAAGCTCAA CAGGGTCTTC   300
 TTTCCCCGCT GATTCCGCCA AGCCCGTTCC CTTGGCTGTG GTTTCGCTGG ATAGTAGGTA   360
 GGGACAGTGG GAATCTCGTT CATCCATTCA TGCGCGTCAC TAATTAGATG ACGAGGCATT   420
 TGGCTACCTT AAGAGAGTCA TAGTTACTCC CGCCGTTTAC CCGCGCTTCA TTGAATTTCT   480
 TCACTTTGAC ATTCAGAGCA CTGGGCAGAA ATCACATCGC GTCAACACCC GCCGCGGGCC   540
 TTCGCGATGC TTTGTTTTAA TTAAACAGTC GGATTCCCCT GGTCCGCACC AGTTCTAAGT   600
 CGGCTGCTAG GCGCCGGCCG AAGCGAGGCG CCGCGCGGAA CCGCGGCCCC CGGGGCGGAC   660
 CCGCGGGGGG GACCGGGCCG CGGCCCCTCC GCCGCCTGCC GCCGCCGCCG CCGCCGCGCG   720
 CCGAAGAAGA AGGGGGAAA                                                739
 
           
           
             
               233 base pairs 
               nucleic acid 
               double 
               linear 
             
             
               Genomic DNA 
             
             3
 CAAGAGTGGC GGCCGCAGCA GGCCCCCCGG GTGCCCGGGC CCCCCTCGAG GGGGACAGTG    60
 CCCCCGCCGC GGGGGCCCCG CGGCGGGCCG CCGCCGGCCC CTGCCGCCCC GACCCTTCTC   120
 CCCCCGCCGC CGCCCCCACG CGGCGCTCCC CCGGGGAGGG GGGAGGACGG GGAGCGGGGG   180
 AGAGAGAGAG AGAGAGAGGG CGCGGGGTGG CTCGTGCCGA ATTCAAAAAG CTT          233
 
           
           
             
               2998 base pairs 
               nucleic acid 
               double 
               linear 
             
             
               Genomic DNA 
             
             4
 GGATCCAAAG AATTCGGCAC GAGGTAGTCA CGGCTCTTGT CATTGTTGTA CTTGACGTTG    60
 AGGCTGGTGA GCTTGGAAAA GTCGATGCGC AGCGTGCAGC AGGCGTTGTA GATGTTCTGC   120
 CCGTCCAGCG ACAGCTTGGC GTGCTGGGCG CTCACGGGGT CCGCATACTG CAGCAGGGCC   180
 TGGAACTGGT TGTTCTTGGT GAAGGTGATG ATCTTCAACA CTGTGCCGAA CTTGGAGAAA   240
 ATCTGGTGCA GCACATCCAG GGTCACAGGG TAGAAGAGGT TCTCCACGAT GATCCTGAGC   300
 ACGGGGCTCT GCCCGGCCAT CGCCATCCCT GCATCCACGG CCGCCGCCGA GGCAGCCAAG   360
 GCCAGGTTCC CCGACTGGAC CGAGTTCACC GCCTGCAGGG CCGCCTGGGC CCGCGCCTGG   420
 TTGGGAGAGC TGTCGGTCTT CAGCTCCTTG TGGTTGGAGA ACTGGATGTA GATGGGCTGG   480
 CCGCGCAGCA CAGGGGTCAC CGAGGTGTAG TAGTTCACCA TGGTATTGGC AGCCTCCTCC   540
 GTGTTCATCT CGATGAAGGC CTGGTTTTTC CCCTTCAGCA TCAGGAGGTT GGTGACCTTC   600
 CCAAAGGGCA GCCCCAGGGA GATGACTTCC CCCTCCGTGA CGTCGATGGG GAGCTTCCGG   660
 ATGTGGATCA CTCTAGAGGG GACGCCTGCA CTTCGGCTGT CACCTTTGAA CTTCTTGCTG   720
 TCATTTCCGT TTGCTGCAGA AGCCGAGTTG CTGCTCATGA TAAACGGTCC GTTAGTGACA   780
 CAAGTAGAGA AAAGCTCGTC AGATCCCCGC TTTGTACCAA CGGCTATATC TGGGACAATG   840
 CCGTCCATGG CACACAGAGC AGACCCGCGG GGGACGGAGT GGAGGCGCCG GAATCCTGGA   900
 GCTAGAGCTG CAGATTGAGT TGCTGCGTGA GACGAAGCGC AAGTATGAGA GTGTCCTGCA   960
 GCTGGGCCGG GCACTGACAG CCCACCTCTA CAGCCTGCTG CAGACCCAGC ATGCACTGGG  1020
 TGATGCCTTT GCTGACCTCA GCCAGAAGTC CCCAGAGCTT CAGGAGGAAT TTGGCTACAA  1080
 TGCAGAGACA CAGAAACTAC TATGCAAGAA TGGGGAAACG CTGCTAGGAG CCGTGAACTT  1140
 CTTTGTCTCT AGCATCAACA CATTGGTCAC CAAGACCATG GAAGACACGC TCATGACTGT  1200
 GAAACAGTAT GAGGCTGCCA GGCTGGAATA TGATGCCTAC CGAACAGACT TAGAGGAGCT  1260
 GAGTCTAGGC CCCCGGGATG CAGGGACACG TGGTCGACTT GAGAGTGCCC AGGCCACTTT  1320
 CCAGGCCCAT CGGGACAAGT ATGAGAAGCT GCGGGGAGAT GTGGCCATCA AGCTCAAGTT  1380
 CCTGGAAGAA AACAAGATCA AGGTGATGCA CAAGCAGCTG CTGCTCTTCC ACAATGCTGT  1440
 GTCCGCCTAC TTTGCTGGGA ACCAGAAACA GCTGGAGCAG ACCCTGCAGC AGTTCAACAT  1500
 CAAGCTGCGG CCTCCAGGAG CTGAGAAACC CTCCTGGCTA GAGGAGCAGT GAGCTGCTCC  1560
 CAGCCCAACT TGGCTATCAA GAAAGACATT GGGAAGGGCA GCCCCAGGGT GTGGGAGATT  1620
 GGACATGGTA CATCCTTTGT CACTTGCCCT CTGGCTTGGG CTCCTTTTTC TGGCTGGGGC  1680
 CTGACACCAG TTTTGCCCAC ATTGCTATGG TGGGAAGAGG GCCTGGAGGC CCAGAAGTTG  1740
 CTGCCCTGTC TATCTTCCTG GCCACAGGGC TTCATTCCCA GATCTTTTCC TTCCACTTCA  1800
 CAGCCAACGG CTATGACAAA ACCACTCCCT GGCCAATGGC ATCACTCTTC AGGCTGGGGT  1860
 GTGCTCCCTG ACCAATGACA GAGCCTGAAA ATGCCCTGTC AGCCAATGGC AGCTCTTCTC  1920
 GGACTCCCCT GGGCCAATGA TGTTGCGTCT AATACCCTTT GTCTCTCCTC TATGCGTGCC  1980
 CATTGCAGAG AAGGGGACTG GGACCAAAGG GGTGGGGATA ATGGGGAGCC CCATTGCTGG  2040
 CCTTGCATCT GAATAGGCCT ACCCTCACCA TTTATTCACT AATACATTTT ATTTGTGTTC  2100
 TCTAATTTAA AATTACCTTT TCATCTTGCT TGATTTTCCT TCAGCTAAAT TAGAAATTTG  2160
 TAGTTTTTCC CCTAAAAAAT TCAATGGCAT TCTTTCTTAT AAATTACATT CTCTGATTTT  2220
 CTTGTCAGCC TGCTTCAAGG AAATCCATGT GTTCAAAATG CTTGCTCGCA GTTTGCTCCA  2280
 TACCAAATGG TTGCTTAACC CAAATATCTG AGCAGCAAAT TGAGCTGATC CTTCTGGAGA  2340
 AAGTACGGTT GAACAGCCAA GACCACTGGG TAGTCGAAGA GAAGACCACA CATCCTGAAC  2400
 TCCCCAGTCT GGTGTGAGGG GAGGACAGCT GATAACTGGA TATGCAGTGT TCCCAGACAT  2460
 CACTGGTCCC AAACCATTAC TTCTGCCTGC CACTGCCACA AATACAGTAG GAATGCCATC  2520
 CCCTTCATAC TCAGCTTTAA TCCTCAGAGT TTCATCTGGT CCTTTATGCG CAGATGTTAC  2580
 TCGAAGTTCA CATGGAATGC CAAAATTTCC ACAGGCCTTC TTGATTTTTT CACAGTGACC  2640
 AAGATCAGAA GTAGAGCCCA TCAACACTAC AACCCTGCAC TGACTTTCTG ATTTCAAAAG  2700
 CAACTCTACT CTCTCTGCAA CCCACTCAAA GTTTTTCTTT ACCATTTGGA GCCCTTCAGG  2760
 AGTTACTTCT TTGAGGTCCC GATAAGACTG TTTGTCTTTC TGTTGGCTTC GATCTCCTGA  2820
 TGGCCAGAGT CTCCAGGAAT CATTGTCAAT AACATCAGCA AGAACAATTT CTTTGGTGGT  2880
 TACATCAACA CCAAATTCAA TCTTCATATC AACCAGTGTA CAATTCTGGG GCAACCAGGA  2940
 TTTCTCCAGT ATTTCAAATA TAGCCTGTGT AGCATCTCGT GCCGAATTCA AAAAGCTT    2998
 
           
           
             
               4152 base pairs 
               nucleic acid 
               double 
               linear 
             
             
               Genomic DNA 
             
             5
 AAGCTTTTTG TGAAAACCCT AGGATATGTC CCCTCCCTCA CCACACCCAA CCCCCCGCCC    60
 CTGCCCCAGG ACATGACGAT GCCTCACACA CACACACACA CACACATACA CACAAGGCCG   120
 TGAGCTGCAC GCAGGAACAT GGGCTGCACT CACGACAACA TTGAAAAAAT ATACATTATA   180
 TATGTACACC CGGGGCCCCC ACGTCCCCTC CCGTCCCCGC AGCCTGGCCA CACCAGGTCA   240
 CGGAGGAGGG GCCGGGGCTG CAGGACCTCA GGACTGCAAG GGCAGGAAGG GAAACAGGAC   300
 AAGAAAGGAA GGAAGTTGGA AAGGAGGGAG AAATGGGGTC CCCAGACTGA AATGGAAATG   360
 AGGTGGGGCG ATCATAAGAG AAGCAGGGAC GATGGTCCAG CTGAGGGAGC CCTGCAGAGG   420
 GGGAAAAGCT TCCCATGGAC AGGAGAGAGA AGGGAAGGGG AGAGGAGAGG GTTTCCTTCA   480
 ATCCCACCCC CAGCCCCAGC CCCAGCCCCA GCCATTGCAA TCGTCACCCT CTCCCCAACA   540
 CAGTGAGTGC TAAGGGGGCA GCTGCCATTG GGGGTAGAAA GGCAGCTGAA GTCCAGCCCA   600
 CTTTCCAACC CAGCCAGCCC CAGTGCAAGG GGCACACCAG GAGCATGACA GCCCAGAAGT   660
 GAGGGATGGG GGGCCGGGGG AGGGGCAGGG CGGACTCCAG AGGGCCCGCT GGGGTTTTGA   720
 AATGAAAGGA GGACTGGTTC TGAAGCCTCT CTCCCTCTTG GTCTCTGTGT TCCCAGAAAG   780
 TCCTTCTCCC ATGTCTGGAG TGTCTGTTTC ACCAGGGCAG AATTCCCCCT CTGCGTGGGG   840
 AGAGGTGTAG GCCTTAGTAG CGGTGTGGGG GGGTCTCGAT GATGCGTCTC TCGTCGCTGC   900
 TGGGGGAATC GGCCACCTCC GAGTCACTGC TGTCCTCATC CTCCTGCTGG CCCCCAACAG   960
 CCCCCGTCAC ACAGGACTGC CGATTCTGGT AGGACTCCAT GGGGTTCACA ATGATGGTGA  1020
 GAGCTGAGTC ATCCCAGAAG AGGTCTGGGT CCTTGGGGTC ACTGGAGGCC CCTGGAGGCC  1080
 CGCCGGCCCC TGAGACGCGG CGGTGAAGGG AATGGATGCG CACCAGGCCC AGGACGACCA  1140
 TGAGCACCAG GAAGCCCACG CACACCACAA TGATGAGGGT TGCGGCGCTG GGTATCATGG  1200
 AGTTTCTGTG GGAGCTGGCT AGGCTGTGTC CAGCCATCTC AGGCGGGGGC TGGTGACCAC  1260
 GGTGCAGGAA CTGCTGGGAG CTGAGCACGT GGCTGGGGTG GGCAACCCGG TTCATGCTGT  1320
 GCAGGACATT GACCTCCACG ATGAATTCAT TGCTGGAGTA ACGGCCATTC ATTTCCGAGC  1380
 AGGAAAGCCG GAACTTCCTG GTGTAGAGGG CAGCTCCGTG TCGCAGCCGA TAACGAGCCT  1440
 GCCTCAGGAT CTCTTCATAC ACAGTGATGC TCTCCACCCC AGCAATAGTG AGGTAGGCAG  1500
 ATGTGTTGGT GAGCTCCAGC CCCCGCTGCT GCAGAGAGGT TGTGTCCAGG AGCAGGCTTT  1560
 CCCGCTCGGG ATCCAGGTCA TCCCCCACCA GAGAAATTTC ACAGCCATCC AGGTTGTGCA  1620
 CAATCTCATC CGACATGCGT GTGTCTGTCA CTGTGCCCTG CCAACTCTCA TCCTTTTTGG  1680
 CCTCCACCTG GTGAGAAATG GAGCAGGTGA TTTGAAGATC AGGGAACAAA GGGACGCCGT  1740
 TGGTTCCCTC AAAGTCCACA GCTGGGCGGG CAAAATGAGC AGTGCCACTC AGCAGGATCT  1800
 GGGGGGCGTC AGGCTGAAGG ACGACCACGT AGCCCTCCAC TTCAGGGATG GAGACGCAGG  1860
 ACTCTTCGCT GAAGCACTTG ACAGCAGTGG TGAGGCGCAG GGGCCTGACG CCGGGCGTGG  1920
 CAAAGCGCAG AGTGTTCATG TAAGCCACAT GCTGCAGGGC ATGGTTGAAG GTCTCCACAT  1980
 CATCCCCCTC CAGGGTGAGC AGGGACTGTG AGGGGTTCAC GTGGACCTTC ATGCCTTTGC  2040
 CCAGGCTCTC GAAATCCCTA TAGTCCAGCC CCTCCCGACA TGCATAGAGG CACTCGATGA  2100
 CCTCGCGGCT CTCCAGGCGA CCTGAGCGCA CGCTGAAACC AGCCAGGTAG CCATGGAAGT  2160
 AGTGGTGGAT CGACAAAGGG TCTCCTTGGG TGGTGTCTGT ACTGTTGTCT CCCTTTTCCT  2220
 TCTCTTTGTT CTTCTCCTCA GTCCAGCAGG CCCCAATCAT GAGAGCAGGC TCCCTTCGGG  2280
 GTGGGTGGAT GAGGCCATTG TCATGGATGA GGGCAGGGTC GAAGGAGATG CCGTCGGTAT  2340
 AGAGTGTGAC TGTGGGGAAC TCGAGGTTCA GAGCGTAGTG GTGCCACTCA TCATCACAGA  2400
 CCTGCTCCAG CTTCCAGAGG AACTTGACTG GGCGGGCACT CTCAAGCAGG GGCCAGTAGA  2460
 GGAAGGCAAT CCTACAGCCG TGGACAGTCA GCGAGTAGTG AGAGAAGCCG TCCTCATTCT  2520
 GGACAGTGTT ACATACGATG GTTTCCTCTT CCTTCTTGCC CTTGTTGGGA GTTACGCCAT  2580
 GCTTCATCCA GAAGGACAGG GTGAAGTGGT CACTGAGGCT GTCCTGGGGC CCAGAGCCCA  2640
 GCCCACTGGG GCCACCCAGG GGCACCTGCA CAGCCTGGGT GCCATTGAAC CAGTAGATCA  2700
 GGCTGCTGTC CTGGCTGTAG TGCACCGAGA GTCCTGCTGT CCAGTTGGCA TTGGGGCCAG  2760
 GCATGGGCAA CAGATCCACT TCCCCAGTGG CAGCACCACA GAGTTTCCGC AGCGCCCGCT  2820
 CTGAGTAGTT GTCACGGTCA CAGCCCTTGG CCACATGGCT GGTCTGCAGC TCTATGGTGG  2880
 CCTGAATGTT CCAGAGTGGT TCATCACAGG TCTCCAGGCG GATACCAGGG AACAAAGCCA  2940
 AGCTCCCAGC ACCTGGTGCA TATTCGATCC TTTTGTTCCA GCCTTGCCAG CTGGGTTTAC  3000
 AGGTGGGCTT CACCTGAATC TCCACCTCAG CATCATCTGC TGCCCGCTTC TTCCCACAGT  3060
 CATAAGCTGT CACTGTAAAC TTATAGAGCC TCTCACCACT GTACTGCAGC TTCTCTGTGT  3120
 TCTCAATGTT CCCGTCATTG TCAATGAGGA AAGGGGTGTT GGGTGTGAGA ATCTCATAGT  3180
 AGCAGATCTG GCTGTACTGG GGGGAGCAGT CACCGTCAAT GGCTTCCACC CGCAGGATGC  3240
 GATCGTACAG CTTCCCCTCT GTCACAGCCG CACGATACAG CCGTTCCACA AACACTGGGG  3300
 CAAACTCGTT CACATCGTTG ACCCGCACAT GCACAGTGGC CTTGTGGGAC TTCTTGGTGT  3360
 TGGCCCCGTC GGGGCCCTCG CCACAGTCAT AGGCCTGGAT GGTGAAGGTG TGTTCCTTCT  3420
 GGGCCTCGCA GTCCACAGGC TCCTTGGCCC GGATCAGCCC CTCTCCTGTC GCCTTGTCAA  3480
 GGATCACAGC CTCAAAGGGC ACCCCAGACC CATGGAGCCG GAAGCCGCAG ATCTCACCTG  3540
 CATAGCGCAG CGGGGCATCC TTGTCCAAGG CAAAGAGTGG TGGATTCAGT AGGACCGTGT  3600
 TGTCATTCTC CATGACGATG CCCTGGTACT CTGCCTCAAT CCATGGCTTG TGCTTGTTGG  3660
 CTTTGTTACA GGAGCAGGAC GCGAGCAGAG AGGCCAGCAG AAGGGGCAGC AGCAGGAGGG  3720
 TCATGGTGCG GCGTGGGGCA GGGCAGGGCC AGGCGTTTGC CTCCCCTGGG AGCCTCCAGC  3780
 CTGCGGATTC CACCTTGCGG GAGGGATACA GGGGGGGAAA ACCAAAATAA AACGTCAAAT  3840
 AAATTGTGTA GGAGGAGTCC AGCTTAGGAC CGGGCCAGAG CCAGGCCAGG CTCGGGGAGG  3900
 GGGCCTCTGC AGGTTCAGAG GATCACTGCT GCCACCACCG CCACCCTGGG AGCCAGTTAT  3960
 TTTGCCATGG CCTTGATTGC AACAGCTGCC TCCTCTGTCA TGGCAGACAG CACCGTGATC  4020
 AGGATCTCTT CTCCACAGTC GTACTTCTGC TCAATCTCCT TGCCAAGGTC TCCCTCAGGG  4080
 AGACGAAGGT CCTCTCGTAC CTCCCCGCTG TCCTGGAGCA GTGATAGGTA CCCATCCTGG  4140
 ATCTTTGGAT CC                                                      4152
 
           
           
             
               3117 base pairs 
               nucleic acid 
               double 
               linear 
             
             
               Genomic DNA 
             
             6
 GGATCCAAAG ATTCGGCACG AGTGGCCACA TCATGAACCT CCAGGCCCAG CCCAAGGCTC    60
 AGAACAAGCG GAAGCGTTGC CTCTTTGGGG GCCAGGAACC AGCTCCCAAG GAGCAGCCCC   120
 CTCCCCTGCA GCCCCCCCAG CAGTCCATCA GAGTGAAGGA GGAGCAGTAC CTCGGGCACG   180
 AGGGTCCAGG AGGGGCAGTC TCCACCTCTC AGCCTGTGGA ACTGCCCCCT CCTAGCAGCC   240
 TGGCCCTGCT GAACTCTGTG GTGTATGGGC CTGAGCGGAC CTCAGCAGCC ATGCTGTCCC   300
 AGCAGGTGGC CTCAGTAAAG TGGCCCAACT CTGTGATGGC TCCAGGGCGG GGCCCGGAGC   360
 GTGGAGGAGG TGGGGGTGTC AGTGACAGCA GCTGGCAGCA GCAGCCAGGC CAGCCTCCAC   420
 CCCATTCAAC ATGGAACTGC CACAGTCTGT CCCTCTACAG TGCAACCAAG GGGAGCCCGC   480
 ATCCTGGAGT GGGAGTCCCG ACTTACTATA ACCACCCTGA GGCACTGAAG CGGGAGAAAG   540
 CGGGGGGCCC ACAGCTGGAC CGCTATGTGC GACCAATGAT GCCACAGAAG GTGCAGCTGG   600
 AGGTAGGGCG GCCCCAGGCA CCCCTGAATT CTTTCCACGC AGCCAAGAAA CCCCCAAACC   660
 AGTCACTGCC CCTGCAACCC TTCCAGCTGG CATTCGGCCA CCAGGTGAAC CGGCAGGTCT   720
 TCCGGCAGGG CCCACCGCCC CCAAACCCGG TGGCTGCCTT CCCTCCACAG AAGCAGCAGC   780
 AGCAGCAGCA ACCACAGCAG CAGCAGCAGC AGCAGCAGGC AGCCCTACCC CAGATGCCGC   840
 TCTTTGAGAA CTTCTATTCC ATGCCACAGC AACCCTCGCA GCAACCCCAG GACTTTGGCC   900
 TGCAGCCAGC TGGGCCACTG GGACAGTCCC ACCTGGCTCA CCACAGCATG GCACCCTACC   960
 CCTTCCCCCC CAACCCAGAT ATGAACCCAG AACTGCGCAA GGCCCTTCTG CAGGACTCAG  1020
 CCCCGCAGCC AGCGCTACCT CAGGTCCAGA TCCCCTTCCC CCGCCGCTCC CGCCGCCTCT  1080
 CTAAGGAGGG TATCCTGCCT CCCAGCGCCC TGGATGGGGC TGGCACCCAG CCTGGGCAGG  1140
 AGGCCACTGG CAACCTGTTC CTACATCACT GGCCCCTGCA GCAGCCGCCA CCTGGCTCCC  1200
 TGGGGCAGCC CCATCCTGAA GCTCTGGGAT TCCCGCTGGA GCTGAGGGAG TCGCAGCTAC  1260
 TGCCTGATGG GGAGAGACTA GCACCCAATG GCCGGGAGCG AGAGGCTCCT GCCATGGGCA  1320
 GCGAGGAGGG CATGAGGGCA GTGAGCACAG GGGACTGTGG GCAGGTGCTA CGGGGCGGAG  1380
 TGATCCAGAG CACGCGACGG AGGCGCCGGG CATCCCAGGA GGCCAATTTG CTGACCCTGG  1440
 CCCAGAAGGC TGTGGAGCTG GCCTCACTGC AGAATGCAAA GGATGGCAGT GGTTCTGAAG  1500
 AGAAGCGGAA AAGTGTATTG GCCTCAACTA CCAAGTGTGG GGTGGAGTTT TCTGAGCCTT  1560
 CCTTAGCCAC CAAGCGAGCA CGAGAAGACA GTGGGATGGT ACCCCTCATC ATCCCAGTGT  1620
 CTGTGCCTGT GCGAACTGTG GACCCAACTG AGGCAGCCCA GGCTGGAGGT CTTGATGAGG  1680
 ACGGGAAGGG TCTTGAACAG AACCCTGCTG AGCACAAGCC ATCAGTCATC GTCACCCGCA  1740
 GGCGGTCCAC CCGAATCCCC GGGACAGATG CTCAAGCTCA GGCGGAGGAC ATGAATGTCA  1800
 AGTTGGAGGG GGAGCCTTCC GTGCGGAAAC CAAAGCAGCG GCCCAGGCCC GAGCCCCTCA  1860
 TCATCCCCAC CAAGGCGGGC ACTTTCATCG CCCCTCCCGT CTACTCCAAC ATCACCCCAT  1920
 ACCAGAGCCA CCTGCGCTCT CCCGTGCGCC TAGCTGACCA CCCCTCTGAG CGGAGCTTTG  1980
 AGCTACCTCC CTACACGCCG CCCCCCATCC TCAGCCCTGT GCGGGAAGGC TCTGGCCTCT  2040
 ACTTCAATGC CATCATATCA ACCAGCACCA TCCCTGCCCC TCCTCCCATC ACGCCTAAGA  2100
 GTGCCCATCG CACGCTGCTC CGGACTAACA GTGCTGAAGT AACCCCGCCT GTCCTCTCTG  2160
 TGATGGGGGA GGCCACCCCA GTGAGCATCG AGCCACGGAT CAACGTGGGC TCCCGGTTCC  2220
 AGGCAGAAAT CCCCTTGATG AGGGACCGTG CCCTGGCAGC TGCAGATCCC CACAAGGCTG  2280
 ACTTGGTGTG GCAGCCATGG GAGGACCTAG AGAGCAGCCG GGAGAAGCAG AGGCAAGTGG  2340
 AAGACCTGCT GACAGCCGCC TGCTCCAGCA TTTTCCCTGG TGCTGGCACC AACCAGGAGC  2400
 TGGCCCTGCA CTGTCTGCAC GAATCCAGAG GAGACATCCT GGAAACGCTG AATAAGCTGC  2460
 TGCTGAAGAA GCCCCTGCGG CCCCACAACC ATCCGCTGGC AACTTATCAC TACACAGGCT  2520
 CTGACCAGTG GAAGATGGCC GAGAGGAAGC TGTTCAACAA AGGCATTGCC ATCTACAAGA  2580
 AGGATTTCTT CCTGGTGCAG AAGCTGATCC AGACCAAGAC CGTGGCCCAG TGCGTGGAGT  2640
 TCTACTACAC CTACAAGAAG CAGGTGAAAA TCGGCCGCAA TGGGACTCTA ACCTTTGGGG  2700
 ATGTGGATAC GAGCGATGAG AAGTCGGCCC AGGAAGAGGT TGAAGTGGAT ATTAAGACTT  2760
 CCCAAAAGTT CCCAAGGGTG CCTCTTCCCA GAAGAGAGTC CCCAAGTGAA GAGAGGCTGG  2820
 AGCCCAAGAG GGAGGTGAAG GAGCCCAGGA AGGAGGGGGA GGAGGAGGTG CCAGAGATCC  2880
 AAGAGAAGGA GGAGCAGGAA GAGGGGCGAG AGCGCAGCAG GCGGGCAGCG GCAGTCAAAG  2940
 CCACGCAGAC ACTACAGGCC AATGAGTCGG CCAGTGACAT CCTCATCCTC CGGAGCCACG  3000
 AGTCCAACGC CCCTGGGTCT GCCGGTGGCC AGGCCTCGGA GAAGCCAAGG GAAGGGACAG  3060
 GGAAGTCACG AAGGGCACTA CCTTTTTCAG AAAAAAAAAA AAAAAAACAA AAAGCTT     3117
 
           
           
             
               3306 base pairs 
               nucleic acid 
               double 
               linear 
             
             
               Genomic DNA 
             
             7
 GAATTCGGCA CGAGGTCAGT TTCCTGTGGA ACACAGAGGC TGCCTGTCCC ATTCAGACAA    60
 CGACGGATAC AGACCAGGCT TGCTCTATAA GGGATCCCAA CAGTGGATTT GTGTTTAATC   120
 TTAATCCGCT AAACAGTTCG CAAGGATATA ACGTCTCTGG CATTGGGAAG ATTTTTATGT   180
 TTAATGTCTG CGGCACAATG CCTGTCTGTG GGACCATCCT GGGAAAACCT GCTTCTGGCT   240
 GTGAGGCAGA AACCCAAACT GAAGAGCTCA AGAATTGGAA GCCAGCAAGG CCAGTCGGAA   300
 TTGAGAAAAG CCTCCAGCTG TCCACAGAGG GCTTCATCAC TCTGACCTAC AAAGGGCCTC   360
 TCTCTGCCAA AGGTACCGCT GATGCTTTTA TCGTCCGCTT TGTTTGCAAT GATGATGTTT   420
 ACTCAGGGCC CCTCAAATTC CTGCATCAAG ATATCGACTC TGGGCAAGGG ATCCGAAACA   480
 CTTACTTTGA GTTTGAAACC GCGTTGGCCT GTGTTCCTTC TCCAGTGGAC TGCCAAGTCA   540
 CCGACCTGGC TGGAAATGAG TACGACCTGA CTGGCCTAAG CACAGTCAGG AAACCTTGGA   600
 CGGCTGTTGA CACCTCTGTC GATGGGAGAA AGAGGACTTT CTATTTGAGC GTTTGCAATC   660
 CTCTCCCTTA CATTCCTGGA TGCCAGGGCA GCGCAGTGGG GTCTTGCTTA GTGTCAGAAG   720
 GCAATAGCTG GAATCTGGGT GTGGTGCAGA TGAGTCCCCA AGCCGCGGCG AATGGATCTT   780
 TGAGCATCAT GTATGTCAAC GGTGACAAGT GTGGGAACCA GCGCTTCTCC ACCAGGATCA   840
 CGTTTGAGTG TGCTCAGATA TCGGGCTCAC CAGCATTTCA GCTTCAGGAT GGTTGTGAGT   900
 ACGTGTTTAT CTGGAGAACT GTGGAAGCCT GTCCCGTTGT CAGAGTGGAA GGGGACAACT   960
 GTGAGGTGAA AGACCCAAGG CATGGCAACT TGTATGACCT GAAGCCCCTG GGCCTCAACG  1020
 ACACCATCGT GAGCGCTGGC GAATACACTT ATTACTTCCG GGTCTGTGGG AAGCTTTCCT  1080
 CAGACGTCTG CCCCACAAGT GACAAGTCCA AGGTGGTCTC CTCATGTCAG GAAAAGCGGG  1140
 AACCGCAGGG ATTTCACAAA GTGGCAGGTC TCCTGACTCA GAAGCTAACT TATGAAAATG  1200
 GCTTGTTAAA AATGAACTTC ACGGGGGGGG ACACTTGCCA TAAGGTTTAT CAGCGCTCCA  1260
 CAGCCATCTT CTTCTACTGT GACCGCGGCA CCCAGCGGCC AGTATTTCTA AAGGAGACTT  1320
 CAGATTGTTC CTACTTGTTT GAGTGGCGAA CGCAGTATGC CTGCCCACCT TTCGATCTGA  1380
 CTGAATGTTC ATTCAAAGAT GGGGCTGGCA ACTCCTTCGA CCTCTCGTCC CTGTCAAGGT  1440
 ACAGTGACAA CTGGGAAGCC ATCACTGGGA CGGGGGACCC GGAGCACTAC CTCATCAATG  1500
 TCTGCAAGTC TCTGGCCCCG CAGGCTGGCA CTGAGCCGTG CCCTCCAGAA GCAGCCGCGT  1560
 GTCTGCTGGG TGGCTCCAAG CCCGTGAACC TCGGCAGGGT AAGGGACGGA CCTCAGTGGA  1620
 GAGATGGCAT AATTGTCCTG AAATACGTTG ATGGCGACTT ATGTCCAGAT GGGATTCGGA  1680
 AAAAGTCAAC CACCATCCGA TTCACCTGCA GCGAGAGCCA AGTGAACTCC AGGCCCATGT  1740
 TCATCAGCGC CGTGGAGGAC TGTGAGTACA CCTTTGCCTG GCCCACAGCC ACAGCCTGTC  1800
 CCATGAAGAG CAACGAGCAT GATGACTGCC AGGTCACCAA CCCAAGCACA GGACACCTGT  1860
 TTGATCTGAG CTCCTTAAGT GGCAGGGCGG GATTCACAGC TGCTTACAGC GAGAAGGGGT  1920
 TGGTTTACAT GAGCATCTGT GGGGAGAATG AAAACTGCCC TCCTGGCGTG GGGGCCTGCT  1980
 TTGGACAGAC CAGGATTAGC GTGGGCAAGG CCAACAAGAG GCTGAGATAC GTGGACCAGG  2040
 TCCTGCAGCT GGTGTACAAG GATGGGTCCC CTTGTCCCTC CAAATCCGGC CTGAGCTATA  2100
 AGAGTGTGAT CAGTTTCGTG TGCAGGCCTG AGGCCGGGCC AACCAATAGG CCCATGCTCA  2160
 TCTCCCTGGA CAAGCAGACA TGCACTCTCT TCTTCTCCTG GCACACGCCG CTGGCCTGCG  2220
 AGCAAGCGAC CGAATGTTCC GTGAGGAATG GAAGCTCTAT TGTTGACTTG TCTCCCCTTA  2280
 TTCATCGCAC TGGTGGTTAT GAGGCTTATG ATGAGAGTGA GGATGATGCC TCCGATACCA  2340
 ACCCTGATTT CTACATCAAT ATTTGTCAGC CACTAAATCC CATGCACGGA GTGCCCTGTC  2400
 CTGCCGGAGC CGCTGTGTGC AAAGTTCCTA TTGATGGTCC CCCCATAGAT ATCGGCCGGG  2460
 TAGCAGGACC ACCAATACTC AATCCAATAG CAAATGAGAT TTACTTGAAT TTTGAAAGCA  2520
 GTACTCCTTG CCAGGAATTC AGTTGTAAAT AAAATTGAAC CTGCTCAACA GCTGAGGGAG  2580
 ACTAGAAATG ATGGGTCCAT ATCCTGGTGC ATTGTCATAC AATTCAAACA ATGGTGCAGC  2640
 TACCAGCTTG TAATTTTTAG GGACTGCAAA CAAGGCTTTT TCTTGAAGCT GAACCAGAAA  2700
 CAACTTCTTA TGTTCCTTAG GCTTTGTAAT ATGTGCAGGA ATATATGGAT ACTGAGGAGG  2760
 TTCAAAATTT GGTCTCCACC AGTTACCAAT GCAATCGTCA ATGACCCAGT CTTGCAAAAC  2820
 TCCATCCTGA CGACCCAGTA TCTCTGTCAT TAAGCGTTTT AGTCCTTCAA CTTCATCTTC  2880
 TCCTGGGTTA AGTTCACCAC CAGGTAGTTT GAAGAAAGTT GTTCCCAGCT GCAGCAGTAA  2940
 CACATGGGGT AGCCGGTGCT CATGTACAAT CAGAACCCCT TCTACAGTCC TCCTCATTCC  3000
 AATTTTATCA AATTCTTCCC TCATGCGCTG AAATCTGGCT GCAACAGAGC TGTCCTTCTC  3060
 GTAGAGGGGC TCTTTTGTAC CAAAAGTATA ATTGGTAAGA GGGTACAGGT TGATGGTGCG  3120
 CTCCAGGGTG AGGGGCTTCG TCTGCTGGAT GTACTTGTTG CCGAACTGAG TGACCCCCCG  3180
 GGGCCAGCCG GTCTGCGAGC GATTGGGCGG TACCACAGAC ATGCTGGCGA GCTCCGGCGC  3240
 TGACGGCGAG CAGAAAGTGG CAGGCAGGGT AGACTTTCCC CGTGCGGGAA GCCTCGTGCC  3300
 GAATTC                                                             3306
 
           
           
             
               4218 base pairs 
               nucleic acid 
               double 
               linear 
             
             
               Genomic DNA 
             
             8
 GAATTCGGCA CGAGAATGGA TCAACCTCAA CAACACGTTA AAGCTAGACG AAAGAAGTAA    60
 TACACAGTGT ATGAGTCTCA CATGAAATAC CCGGATGTAA ATCCAAAGAA ACAGGAAGCA   120
 GATTGGTGGT TGCCAGGGAC AAGGGCGGTG GGAGGAGAAA ATGGAGAGTA ACGGGACTTT   180
 ACTTTTGGAG TGATGAGAAT GTTTTGGAGC TAGATAGAAG TGGTGGTTGT ACACCATTGT   240
 GGATGTACTA CCACTTAATT GTTCACTTAA AAAGTTAATT TATGTGAATT GCATCTTAAT   300
 TAAAAACAAG GATAACATTC CAACTCCTGG ACATTATCCT TCCTTTCCAT TTGATGTCAG   360
 GCCCGTGTTA GAATTCTCAT CCGGTTTGGT CACTGCACTT AAGATGTGGA GAAATTAGGA   420
 CGCACAGTTA AGAGGAAGGA TAACACTGAT TAAGGTAGTG CTTTTCTAGG TTTCCCCTAA   480
 ACAATTTAAC AGATGGATAG TGGCACCACT TACGAGATGG AAAAACCAGC GGAAGGAAGA   540
 TTTGGGGGAG AAGTTAAGTT TGTCTTGGGC CTGTGTTTTG CAACCTGAGT GTAAAAGACA   600
 TATGTTAAGT CTTCAGTGGC GAAACACTAA AACTAGAAAT GGATCAGAAT TTTATCTTTG   660
 GATGTGACTT CTCAAGGATG GTCTTGTCAC TTCAGTGCCT GGTCAAATGA CAAGATGGGC   720
 AATCTTTTCC TGAAGGTCCA AGCACCTGAA CGTGGCAGGG TGACCCGATT CCGATTTGCT   780
 TAGAACAATC CTAGTTCATG CCTATTGTCC CTCATGTAAT TAATATCACT CTCAAAATGT   840
 CTCATTTTGT GCAATAAATT CTGCAACGTG ATGGCGCGAC TCTCGCGGCC CGAGCGGCCG   900
 GACCTTGTCT TCGAGGAAGA GGACCTCCCC TATGAGGAGG AAATCATGCG GAACCAATTC   960
 TCTGTCAAAT GCTGGCTTCA CTACATCGAG TTCAAACAGG GCGCCCCGAA GCCCAGGCTC  1020
 AATCAGCTAT ACGAGCGGGC ACTCAAGCTG CTGCCCTGCA GCTACAAACT CTGGTACCGA  1080
 TACCTGAAGG CGCGTCGGGC ACAGGTGAAG CATCGCTGTG TGACCGACCC TGCCTATGAA  1140
 GATGTCAACA ACTGTCATGA GAGGGCCTTT GTGTTCATGC ACAAGATGCC TCGTCTGTGG  1200
 CTAGATTACT GCCAGTTCCT CATGGACCAG GGGCGCGTCA CACACACCCG CCGCACCTTC  1260
 GACCGTGCCC TCCGGGCACT GCCCATCACG CAGCACTCTC GAATTTGGCC CCTGTATCTG  1320
 CGCTTCCTGC GCTCACACCC ACTGCCTGAG ACAGCTGTGC GAGGCTATCG GCGCTTCCTC  1380
 AAGCTGAGTC CTGAGAGTGC AGAGGAGTAC ATTGAGTACC TCAAGTCAAG TGACCGGCTG  1440
 GATGAGGCCG CCCAGCGCCT GGCCACCGTG GTGAACGACG AGCGTTTCGT GTCTAAGGCC  1500
 GGCAAGTCCA ACTACCAGCT GTGGCACGAG CTGTGCGACC TCATCTCCCA GAATCCGGAC  1560
 AAGGTACAGT CCCTCAATGT GGACGCCATC ATCCGCGGGG GCCTCACCCG CTTCACCGAC  1620
 CAGCTGGGCA AGCTCTGGTG TTCTCTCGCC GACTACTACA TCCGCAGCGG CCATTTCGAG  1680
 AAGGCTCGGG ACGTGTACGA GGAGGCCATC CGGACAGTGA TGACCGTGCG GGACTTCACA  1740
 CAGGTGTTTG ACAGCTACGC CCAGTTCGAG GAGAGCATGA TCGCTGCAAA GATGGAGACC  1800
 GCCTCGGAGC TGGGGCGCGA GGAGGAGGAT GATGTGGACC TGGAGCTGCG CCTGGCCCGC  1860
 TTCGAGCAGC TCATCAGCCG GCGGCCCCTG CTCCTCAACA GCGTCTTGCT GCGCCAAAAC  1920
 CCACACCACG TGCACGAGTG GCACAAGCGT GTCGCCCTGC ACCAGGGCCG CCCCCGGGAG  1980
 ATCATCAACA CCTACACAGA GGCTGTGCAG ACGGTGGACC CCTTCAAGGC CACAGGCAAG  2040
 CCCCACACTC TGTGGGTGGC GTTTGCCAAG TTTTATGAGG ACAACGGACA GCTGGACGAT  2100
 GCCCGTGTCA TCCTGGAGAA GGCCACCAAG GTGAACTTCA AGCAGGTGGA TGACCTGGCA  2160
 AGCGTGTGGT GTCAGTGCGG AGAGCTGGAG CTCCGACACG AGAACTACGA TGAGGCCTTG  2220
 CGGCTGCTGC GAAAGGCCAC GGCGCTGCCT GCCCGCCGGG CCGAGTACTT TGATGGTTCA  2280
 GAGCCCGTGC AGAACCGCGT GTACAAGTCA CTGAAGGTCT GGTCCATGCT CGCCGACCTG  2340
 GAGGAGAGCC TCGGCACCTT CCAGTCCACC AAGGCCGTGT ACGACCGCAT CCTGGACCTG  2400
 CGTATCGCAA CACCCCAGAT CGTCATCAAC TATGCCATGT TCCTGGAGGA GCACAAGTAC  2460
 TTCGAGGAGA GCTTCAAGGC GTACGAGCGC GGCATCTCGC TGTTCAAGTG GCCCAACGTG  2520
 TCCGACATCT GGAGCACCTA CCTGACCAAA TTCATTGCCC GCTATGGGGG CCGCAAGCTG  2580
 GAGCGGGCAC GGGACCTGTT TGAACAGGCT CTGGACGGCT GCCCCCCAAA ATATGCCAAG  2640
 ACCTTGTACC TGCTGTACGC ACAGCTGGAG GAGGAGTGGG GCCTGGCCCG GCATGCCATG  2700
 GCCGTGTACG AGCGTGCCAC CAGGGCCGTG GAGCCCGCCC AGCAGTATGA CATGTTCAAC  2760
 ATCTACATCA AGCGGGCGGC CGAGATCTAT GGGGTCACCC ACACCCGCGG CATCTACCAG  2820
 AAGGCCATTG AGGTGCTGTC GGACGAGCAC GCGCGTGAGA TGTGCCTGCG GTTTGCAGAC  2880
 ATGGAGTGCA AGCTCGGGGA GATTGACCGC GCCCGGGCCA TCTACAGCTT CTGCTCCCAG  2940
 ATCTGTGACC CCCGGACGAC CGGCGCGTTC TGGCAGACGT GGAAGGACTT TGAGGTCCGG  3000
 CATGGCAATG AGGACACCAT CAAGGAAATG CTGCGTATCC GGCGCAGCGT GCAGGCCACG  3060
 TACAACACGC AGGTCAACTT CATGGCCTCG CAGATGCTCA AGGTCTCGGG CAGTGCCACG  3120
 GGCACCGTGT CTGACCTGGC CCCTGGGCAG AGTGGCATGG ACGACATGAA GCTGCTGGAA  3180
 CAGCGGGCAG AGCAGCTGGC GGCTGAGGCG GAGCGTGACC AGCCCTTGCG CGCCCAGAGC  3240
 AAGATCCTGT TCGTGAGGAG TGACGCCTCC CGGGAGGAGC TGGCAGAGCT GGCACAGCAG  3300
 GTCAACCCCG AGGAGATCCA GCTGGGCGAG GACGAGGACG AGGACGAGAT GGACCTGGAG  3360
 CCCAACGAGG TTCGGCTGGA GCAGCAGAGC GTGCCAGCCG CAGTGTTTGG GAGCCTGAAG  3420
 GAAGACTGAC CCGTCCCCTC GTGCCGAATT CGGCACGAGC AAGACCAGCC CCCAGATCAT  3480
 TTGCCTCAAA GGTTTTCCCT CGAAGTCACA AATGTTTCAA GGAATCTCAA ATTTTACAAA  3540
 GTTTGAAGTG TGGGCATTGG TGGCCTGTGG CTGTGTCCTC TCTCTGTAGC TGTTTTCTCC  3600
 CTACATCCCT GAAAGGAAGT TGAGCCTGCT CCTCCATCCG CAGACCTCCC TTTCCAGCGC  3660
 CCAGGGCATG GGGTGCTGTG AGGGCAGCAT GCTAGGTGTG ACCGTGCTCC TGGCCTCCAG  3720
 GCCCGTGTCC CTCTGTCCTC TAGCCCACTA AGGCCCTGGC CCATTTGTGC TAAACAGGCA  3780
 GTCGGACCTA GAAAGAGCAG ACAATCTCTC TGGGTCACCA GTCTGGCTAG GAGCTGGTCT  3840
 CCTGACTGGG ATCCAGGCCT TCTCCCCTGC CCATGTGAAT TCCCAGGGGC AGAGCCTGAA  3900
 ATGTTGAACA CAGCACTGGC CAAAGAGATG TCACCGTGGG AACCGAGGCT CTCTTCTCCT  3960
 CCTGCCTGCT TTCGTGGGTT CAGAGTAGCT GAGGCTTGTC TGAGAGGAGT TGGAGTGCTG  4020
 GTTTTCACCC TGGTTGGTGT GCTTTGCTTT GAGGGCACTT AGAAAGCCCA GCCCAGCCCT  4080
 TGCTCCTGCC CTGCACACAG CGGAGCGACT TTTCTAGGTA TGCTCTTGAT TTCTGCAGAA  4140
 GCAGCAGGTG GCATGGAGCC AAGAGGAAGT GTGACTGAAA CTGTCCACTC ATAGCCCGGC  4200
 TGCCGTATTG AGAGGGCT                                                4218
 
           
           
             
               1187 base pairs 
               nucleic acid 
               double 
               linear 
             
             
               Genomic DNA 
             
             9
 GAGCTCGCGC GCCTGCAGGT CGACACTAGT GGATCCAAAG AATTCGGCAC GAGGGAAACT    60
 CAACGGTGTA CGAGTGGAGG ACAGGGACAG AGCCCTCTGT GGTGGAACGA CCCCACCTCG   120
 AGGAGCTTCC TGAGCAGGTG GCAGAAGATG CGATTGACTG GGGCGACTTT GGGGTAGAGG   180
 CAGTGTCTGA GGGGACTGAC TCTGGCATCT CTGCCGAGGC TGCTGGAATC GACTGGGGCA   240
 TCTTCCCGGA ATCAGATTCA AAGGATCCTG GAGGTGATGG GATAGACTGG GGAGACGATG   300
 CTGTTGCTTT GCAGATCACA GTGCTGGAAG CAGGAACCCA GGCTCCAGAA GGTGTTGCCA   360
 GGGGCCCAGA TGCCCTGACA CTGCTTGAAT ACACTGAGAC CCGGAATCAG TTCCTTGATG   420
 AGCTCATGGA GCTTGAGATC TTCTTAGCCC AGAGAGCAGT GGAGTTGAGT GAGGAGGCAG   480
 ATGTCCTGTC TGTGAGCCAG TTCCAGCTGG CTCCAGCCAT CCTGCAGGGC CAGACCAAAG   540
 AGAAGATGGT TACCATGGTG TCAGTGCTGG AGGATCTGAT TGGCAAGCTT ACCAGTCTTC   600
 AGCTGCAACA CCTGTTTATG ATCCTGGCCT CACCAAGGTA TGTGGACCGA GTGACTGAAT   660
 TCCTCCAGCA AAAGCTGAAG CAGTCCCAGC TGCTGGCTTT GAAGAAAGAG CTGATGGTGC   720
 AGAAGCAGCA GGAGGCACTT GAGGAGCAGG CGGCTCTGGA GCCTAAGCTG GACCTGCTAC   780
 TGGAGAAGAC CAAGGAGCTG CAGAAGCTGA TTGAAGCTGA CATCTCCAAG AGGTACAGCG   840
 GGCGCCCTGT GAACCTGATG GGAACCTCTC TGTGACACCC TCCGTGTTCT TGCCTGCCCA   900
 TCTTCTCCGC TTTTGGGATG AAGATGATAG CCAGGGCTGT TGTTTTGGGG CCCTTCAAGG   960
 CAAAAGACCA GGCTGACTGG AAGATGGAAA GCCACAGGAA GGAAGCGGCA CCTGATGGTG  1020
 ATCTTGGCAC TCTCCATGTT CTCTACAAGA AGCTGTGGTG ATTGGCCCTG TGGTCTATCA  1080
 GGCGAAAACC ACAGATTCTC CTTCTAGTTA GTATAGCGCA AAAAGCTTCT CGAGAGTACT  1140
 TCTAGAGCGG CCGCGGGCCC ATCGATTTTC CACCCGGGTG GGGTACC                1187
 
           
           
             
               3306 base pairs 
               nucleic acid 
               double 
               linear 
             
             
               Genomic DNA 
             
             10
 CCCTCACTAA AGGGAACAAA AGCTGGAGCT CGCGCGCCTG CAGGTCGACA CTAGTGGATC    60
 GAAAGTTCGT TACGCCAAGC TCGAAATTAA CTCTGGGCTG ACCCATAAAC ATTTGTCTGA   120
 TCTAGGATAT AGTTGCGTTT CTTGCGGGCA GCAATCTGGA TGAGGCGGTT GAGGCACTGG   180
 GTGGCCTGCT GGATCAGGAC ATCCCAGCGG CCAGCATAGT TCCGCTGCCG GCGTAGGCCC   240
 ATCACCCGCA TCTTATCCAT GATGGCATTG GTACCCAGGA TGTTGTACTT CTTGGAAGGG   300
 TTGGAGGCTG CATGTTTGAT GGCCCATGTG GTCTTGCCAG CAGCAGGCAG GCCCACCATC   360
 ATCAGAATCT CACATTCTGC CTTGCTCTTT GGTCCAACGG TGCCCCGGAT ACGCTCACTA   420
 AGGGGAAGGT GCTGGATGAA GGTAAACCCC GGGAGGACAG AACAGTAGGG CTCTGCTCTC   480
 TGTCCGAAGT TGAACTCCAC TGCGCAATTC TTCACCAGGA CATGAGGATA GAGGGCCTGA   540
 CCCCCCAAGG CTTCCTTCTG GATTCGGAAA GCAATGCCCA TCCACTTTCC ATTCTTGGTA   600
 AAAGACAGTT CCACGTCATT TCCACATTCA AAATCCGCAA AGCAGCCAAT CACCGGAGAG   660
 CTCTGCGGTG CTAGGAGAGC GGCTGGGCCC GCAGACTGGG GGGAAAGCTC CGCAGCCGCA   720
 GTGGGCCCCA GGATCAGGCC CCGCGTGGCC TGGAGAAGCC CAGTCTGGGC TGGAGCGGGA   780
 GCTGGACAGT GTGGCCTTGC GTTCGCCCCC GGGAGCGCTG CGAGTGTCGC GGCCTCGGGT   840
 GGATTTGCTG AGCACCAATA CCTCACGGTT GCCAACCTGG GGTTTTAGCT CCCTTGGTTT   900
 TAATCCCCTA GGGGCGGGTG GGGGCACGGG AGGAAGGATG GGCCAGCTGG GTGCAATCCT   960
 GCTGTAAGCC AGCCATTCCT TGATTTCTTA GAATTAACTA AACGGTCGCG CCGGAGGCCG  1020
 CGGGGGCCGG AGCGGAGCAG CCGCGGCTGA GGTTCCCGAG TCGGCCGCTC GGGGCTGCGC  1080
 TCCGCCGCCG GGACCCCGGC CTCTGGCCGC GCCGGCTCCG GCCTCCGGGG GGGCCGGGGC  1140
 CGCCGGGACA TGGTGCCAGT CGCACCCCTT CCCCGCCGCC GCTGAGCTCG CCGGCCGCGC  1200
 CCGGGCTGGG ACGTCCGAGC GGGAAGATGT TTTCCGCCCT GAAGAAGCTG GTGGGGTCGG  1260
 ACCAGGCCCC GGGCCGGGAC AAGAACATCC CCGCCGGGCT GCAGTCCATG AACCAGGCGT  1320
 TGCAGAGGCG CTTCGCCAAG GGGGTGCAGT ACAACATGAA GATAGTGATC CGGGGAGACA  1380
 GGAACACGGG CAAGACAGCG CTGTGGCACC GCCTGCAGGG CCGGCCGTTC GTGGAGGAGT  1440
 ACATCCCCAC ACAGGAGATC CAGGTCACCA GCATCCACTG GAGCTACAAG ACCACGGATG  1500
 ACATCGTGAA GGTTGAAGTC TGGGATGTAG TAGACAAAGG AAAATGCAAA AAGCGAGGCG  1560
 ACGGCTTAAA GATGGAGAAC GACCCCCAGG AGNCGGAGTC TGAAATGGCC CTGGATGCTG  1620
 AGTTCCTGGA CGTGTACAAG AACTGCAACG GGGTGGTCAT GATGTTCGAC ATTACCAAGC  1680
 AGTGGACCTT CAATTACATT CTCCGGGAGC TTCCAAAAGT GCCCACCCAC GTGCCAGTGT  1740
 GCGTGCTGGG GAACTACCGG GACATGGGCG AGCACCGAGT CATCCTGCCG GACGACGTGC  1800
 GTGACTTCAT CGACAACCTG GACAGACCTC CAGGTTCCTC CTACTTCCGC TATGCTGAGT  1860
 CTTCCATGAA GAACAGCTTC GGCCTAAAGT ACCTTCATAA GTTCTTCAAT ATCCCATTTT  1920
 TGCAGCTTCA GAGGGAGACG CTGTTGCGGC AGCTGGAGAC GAACCAGCTG GACATGGACG  1980
 CCACGCTGGA GGAGCTGTCG GTGCAGCAGG AGACGGAGGA CCAGAACTAC GGCATCTTCC  2040
 TGGAGATGAT GGAGGCTCGC AGCCGTGGCC ATGCGTCCCC ACTGGCGGCC AACGGGCAGA  2100
 GCCCATCCCC GGGCTCCCAG TCACCAGTCC TGCCTGCACC CGCTGTGTCC ACGGGGAGCT  2160
 CCAGCCCCGG CACACCCCAG CCCGCCCCAC AGCTGCCCCT CAATGCTGCC CCACCATCCT  2220
 CTGTGCCCCC TGTACCACCC TCAGAGGCCC TGCCCCCACC TGCGTGCCCC TCAGCCCCCG  2280
 CCCCACGGCG CAGCATCATC TCTAGGCTGT TTGGGACGTC ACCTGCCACC GAGGCAGCCC  2340
 CTCCACCTCC AGAGCCAGTC CCGGCCGCAC AGGGCCCAGC AACGGTCCAG AGTGTGGAGG  2400
 ACTTTGTTCC TGACGACCGC CTGGACCGCA GCTTCCTGGA AGACACAACC CCCGCCAGGG  2460
 ACGAGAAGAA GGTGGGGGCC AAGGCTGCCC AGCAGGACAG TGACAGTGAT GGGGAGGCCC  2520
 TGGGCGGCAA CCCGATGGTG GCAGGGTTCC AGGACGATGT GGACCTCGAA GACCAGCCAC  2580
 GTGGGAGTCC CCCGCTGCCT GCAGGCCCCG TCCCCAGTCA AGACATCACT CTTTCGAGTG  2640
 AGGAGGAAGC AGAAGTGGCA GCTCCCACAA AAGGCCCTGC CCCAGCTCCC CAGCAGTGCT  2700
 CAGAGCCAGA GACCAAGTGG TCCTCCATAC CAGCTTCGAA GCCACGGAGG GGGACAGCTC  2760
 CCACGAGGAC CGCAGCACCC CCCTGGCCAG GCGGTGTCTC TGTTCGCACA GGTCCGGAGA  2820
 AGCGCAGCAG CACCAGGCCC CCTGCTGAGA TGGAGCCGGG GAAGGGTGAG CAGGCCTCCT  2880
 CGTCGGAGAG TGACCCCGAG GGACCCATTG CTGCACAAAT GCTGTCCTTC GTCATGGATG  2940
 ACCCCGACTT TGAGAGCGAG GGATCAGACA CACAGCGCAG GGCGGATGAC TTTCCCGTGC  3000
 GAGATGACCC CTCCGATGTG ACTGACGAGG ATGAGGGCCC TGCCGAGCCG CCCCCACCCC  3060
 CCAAGCTCCC TCTCCCCGCC TTCAGACTGA AGAATGACTC GGACCTCTTC GGGCTGGGGC  3120
 TGGAGGAGGC CGGACCCAAG GAGAGCAGTG AGGAAGGTAA GGAGGGCAAA ACCCCCTCTA  3180
 AGGAGAAGAA AAAAAAAACA AAAAGCTTCT CGAGAGTACT TCTAGAGCGG CCGCGGGCCC  3240
 ATCGATTTTC CACCCGGGTG GGGTACCAGG TAAGTGTACC CAATTCGCCC TATAGTGAGT  3300
 CGTATT                                                             3306
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             11
 TGCGGGGCCA GAGTGGGCTG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             12
 GCAGTCCTGG CCTGCGGATG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             13
 GTCGACAGGA GAATTGGTTC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             14
 GCCTGGGTTC GGTGCGGGAC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             15
 TGGTCGGGTG TTTGTGAGTG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             16
 CCTCTTCCGT CTCCTCAGTG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             17
 GGATTGCTAG TCTCACAGAC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             18
 TTAAGGGTGG CTGAAGGGAC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             19
 ACCTTCCCTC CCTGTCACAG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             20
 TGGTCGGGTG TTTGTGAGTG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             21
 ACACCATTCC AGAAATTCAG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             22
 AAACTGCAGG TGGCTGAGTC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             23
 GTCCTAATGT TTTCAGGGAG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             24
 AAAACCTATG GTTACAATTC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             25
 TCCTAGACAT GGTTCAAGTG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             26
 GATATAATTA GTTCTCCATC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             27
 ATGCCTGTTC CAGGCTGCAC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             28
 GGACGGCGAC CTCCACCCAC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             29
 GGGCTCCTCC GACGCCTGAG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             30
 AGTCTAGCCC TGGCCTTGAC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             31
 GTCACTGGGG ACTCCGGCAG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             32
 CAGCTTTCCC TGGGCACATG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             33
 CACAGCTGTC TCAAGCCCAG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             34
 ACTGTTCCCC CTACATGATG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             35
 ATCATATCCT CTTGCTGGTC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             36
 GTTCCCAGAG CTTGTCTGTG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             37
 GTTTGGCAGA CTCATAGTTG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             38
 TAGCAGGGAG CCATGACCTG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             39
 CTTGGCGCCA GAAGCGAGAG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             40
 CCTCTCTCTC TCTCTCTCTC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             41
 TCCCCGCTGA TTCCGCCAAG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             42
 CTTTTTGAAT TCGGCACGAG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             43
 CCCCTGGTCC GCACCAGTTC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             44
 GAGAAGGGTC GGGGCGGCAG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             45
 AAATCACATC GCGTCAACAC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             46
 TAAGAGAGTC ATAGTTACTC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             47
 GCTCTAGAAG TACTCTCGAG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             48
 ACTCTGGCCA TCAGGAGATC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             49
 CAGGCGTTGT AGATGTTCTG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             50
 AGTGGCAGGC AGAAGTAATG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             51
 GGTTGGAGAA CTGGATGTAG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             52
 CTATTCAGAT GCAACGCCAG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             53
 CCATGGCACA CAGAGCAGAC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             54
 GCTACCATGC AGAGACACAG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             55
 CAGGCTGACA AGAAAATCAG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             56
 GGCACGCATA GAGGAGAGAC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             57
 TGGGTGATGC CTTTGCTGAC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             58
 AAAACAAGAT CAAGGTGATG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             59
 TTGCCCACAT TGCTATGGTG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             60
 GACCAAGATC AGAAGTAGAG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             61
 CCCCTGGGCC AATGATGTTG                                                20
 
           
           
             
               19 base pairs 
               nucleic acid 
               single 
               linear 
             
             62
 TCTTCCCACC ATAGCAATG                                                 19
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             63
 TGGTCTTGGT GACCAATGTG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             64
 ACACCTCGGT GACCCCTGTG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             65
 TCTCCAAGTT CGGCACAGTG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             66
 ACATGGGCTG CACTCACGAC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             67
 GATCCTCTGA ACCTGCAGAG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             68
 GGAAATGAGG TGGGGCGATC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             69
 CTTTGCCTTG GACAAGGATG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             70
 GCACCTGCCA TTGGGGGTAG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             71
 GGTGGAAGCC ATTGACGGTG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             72
 TGCGTCTCTC GTCGCTGCTG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             73
 GCGGAAACTC TGTGGTGCTG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             74
 AGGATTGCCT TCCTCTACTG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             75
 TGTCTGTTTC ACCAGGGCAG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             76
 CCAGTGCCTC TATGCATGTC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             77
 AGGAAGCCCA CGCACACCAC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             78
 CCCTTTGTTC CCTGATCTTC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             79
 CGCTCGGGAT CCAGGTCATC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             80
 TCGAGGTTCA GAGCGTAGTG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             81
 TCTTGGATCT CTGGCACCTC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             82
 CCATCAGAGT GAAGGAGGAG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             83
 CCATCTTCCA CTGGTCAGAG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             84
 CTCCTTCTCT TGGATCTCTG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             85
 TTACTTCAGC ACTGTTAGTC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             86
 AGGGAGGTAG CTCAAAGCTC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             87
 TGGGTCCACA GTTCGCACAG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             88
 CAACTCTGTG ATGGCTCCAG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             89
 AGCAGGGTTC TGTTCAAGAC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             90
 CCATTGGGTG CTAGTCTCTC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             91
 CAGCCATGCT GTCCCAGCAG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             92
 CTGGACCTGA GGTAGCGCTG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             93
 ATAACCACCC TGAGGCACTG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             94
 CCTGCAGGTC GACACTAGTG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             95
 AATTGGAATG AGGAGGACTG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             96
 GCTCTAGAAG TACTCTCGAG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             97
 ATTGTATGAC AATGCACCAG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             98
 TCCACAGAGG GCTTCATCAC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             99
 CCTGACTGGC CTAAGCACAG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             100
 AAGCCTCATA ACCACCAGTG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             101
 TGTCAACGGT GACAAGTGTG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             102
 TTGTACACCA GCTGCAGGTC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             103
 GGGTGTGGTG CAGATGAGTC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             104
 ATCACACTCT TATAGCTCAG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             105
 GTGGGAAGCT TTCCTCAGAC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             106
 TGATGAACAT GGGCCTGGAG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             107
 CATTGTGGAT GTACTACCAC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             108
 TGTGTTTTGC AACCTGAGTG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             109
 ATAGTGGCAC CACTTACGAG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             110
 AATTCTGCAA CGTGATGGCG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             111
 CACAAGATGC CTCGTCTGTG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             112
 AATCCGGACA AGGTACAGTC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             113
 GCACGAGTGG CACAAGCGTG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             114
 GCAAGCGTGT GGTGTCAGTG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             115
 TGTTTGAACA GGCTCTGGAC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             116
 CGGCATGGCA ATGAGGACAC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             117
 AGGACGAGAT GGACCTCCAG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             118
 CCCTCTGTCC TCTAGCCCAC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             119
 TCTTGAGGGG ACTGACTCTG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             120
 TGAGTGAGGA GGCAGATGTC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             121
 TGGCTTTGAA GAAAGAGCTG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             122
 GCAAAAGACC AGGCTGACTG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             123
 TGCAGCTCCT TGGTCTTCTC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             124
 GATTCACAGT CCCAAGGCTC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             125
 ATCTGGATGA GGCGGTTGAG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             126
 GGTCACTCTC CGACGAGGAG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             127
 GGATCCAAAG TTCGTCTCTG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             128
 CGCTGTGTGT CTGATCCCTC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             129
 ATGAAGGTAA ACCCCGGGAG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             130
 TGGTCTCTGG CTCTGAGCAC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             131
 GCCTGGAGAA GCCCAGTCTG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             132
 CACACTCTGG ACCGTTGCTG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             133
 AAAGCTCCGC AGCCGCAGTG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             134
 TCTTCCAGGA AGCTGCGGTC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             135
 GATGGTGGGG CAGCATTGAG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             136
 GTCACCAGTG GTGCCTGCAG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             137
 ACCTCACGGT TGCCAACCTG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             138
 CGCAACAGCG TCTCCCTCTG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             139
 AGTACCTTCA TAAGTTCTTC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             140
 TCCCAGACTT CAACCTTCAC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             141
 AAACATCTTC CCGGTCGGAC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             142
 GCTGAGCACC TTTACCTCAC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             143
 GACGTCCGTC CGGGAAGATG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             144
 ACACAGGAGA TGCAGGTCAC                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             145
 GAGTCTTCCA TGAAGAACAG                                                20
 
           
           
             
               20 base pairs 
               nucleic acid 
               single 
               linear 
             
             146
 GCAGTGAGGA AGGTAAGGAG                                                20
 
           
           
             
               4047 base pairs 
               nucleic acid 
               double 
               linear 
             
             
               Genomic DNA 
             
             
               Coding Sequence 
                378...1799 
               
 
             
             147
 GGATCCAAAG GACGCCCCCG CCGACAGGAG AATTGGTTCC CGGGCCCGCG GCGATGCCCC    60
 CCCGGTAGCT CGGGCCCGTG GTCGGGTGTT TGTGAGTGTT TCTATGTGGG AGAAGGAGGA   120
 GGAGGAGGAA GAAGAAGCAA CGATTTGTCT TCTCGGCTGG TCTCCCCCCG GCTCTACATG   180
 TTCCCCGCAC TGAGGAGACG GAAGAGGAGC CGTAGCCGCC CCCCCTCCCG GCCCGGATTA   240
 TAGTCTCTCG CCACAGCGGC CTCGGCCTCC CCTTGGATTC AGACGCCGAT TCGCCCAGTG   300
 TTTGGGAAAT GGGAAGTAAT GACAGCTGGC ACCTGAACTA AGTACTTTTA TAGGCAACAC   360
 CATTCCAGAA ATTCAGG ATG AAT GGG GAT ATG CCC CAT GTC CCC ATT ACT      410
                    Met Asn Gly Asp Met Pro His Val Pro Ile Thr
                     1               5                  10
 ACT CTT GCG GGG ATT GCT AGT CTC ACA GAC CTC CTG AAC CAG CTG CCT     458
 Thr Leu Ala Gly Ile Ala Ser Leu Thr Asp Leu Leu Asn Gln Leu Pro
             15                  20                  25
 CTT CCA TCT CCT TTA CCT GCT ACA ACT ACA AAG AGC CTT CTC TTT AAT     506
 Leu Pro Ser Pro Leu Pro Ala Thr Thr Thr Lys Ser Leu Leu Phe Asn
         30                  35                  40
 GCA CGA ATA GCA GAA GAG GTG AAC TGC CTT TTG GCT TGT AGG GAT GAC     554
 Ala Arg Ile Ala Glu Glu Val Asn Cys Leu Leu Ala Cys Arg Asp Asp
     45                  50                  55
 AAT TTG GTT TCA CAG CTT GTC CAT AGC CTC AAC CAG GTA TCA ACA GAT     602
 Asn Leu Val Ser Gln Leu Val His Ser Leu Asn Gln Val Ser Thr Asp
 60                  65                  70                  75
 CAC ATA GAG TTG AAA GAT AAC CTT GGC AGT GAT GAC CCA GAA GGT GAC     650
 His Ile Glu Leu Lys Asp Asn Leu Gly Ser Asp Asp Pro Glu Gly Asp
                 80                  85                  90
 ATA CCA GTC TTG TTG CAG GCC GTC CTG GCA AGG AGT CCT AAT GTT TTC     698
 Ile Pro Val Leu Leu Gln Ala Val Leu Ala Arg Ser Pro Asn Val Phe
             95                  100                 105
 AGG GAG AAA AGC ATG CAG AAC AGA TAT GTA CAA AGT GGA ATG ATG ATG     746
 Arg Glu Lys Ser Met Gln Asn Arg Tyr Val Gln Ser Gly Met Met Met
         110                 115                 120
 TCT CAG TAT AAA CTT TCT CAG AAT TCC ATG CAC AGT AGT CCT GCA TCT     794
 Ser Gln Tyr Lys Leu Ser Gln Asn Ser Met His Ser Ser Pro Ala Ser
     125                 130                 135
 TCC AAT TAT CAA CAA ACC ACT ATC TCA CAT AGC CCC TCC AGC CGG TTT     842
 Ser Asn Tyr Gln Gln Thr Thr Ile Ser His Ser Pro Ser Ser Arg Phe
 140                 145                 150                 155
 GTG CCA CCA CAG ACA AGC TCT GGG AAC AGA TTT ATG CCA CAG CAA AAT     890
 Val Pro Pro Gln Thr Ser Ser Gly Asn Arg Phe Met Pro Gln Gln Asn
                 160                 165                 170
 AGC CCA GTG CCT AGT CCA TAC GCC CCA CAA AGC CCT GCA GGA TAC ATG     938
 Ser Pro Val Pro Ser Pro Tyr Ala Pro Gln Ser Pro Ala Gly Tyr Met
             175                 180                 185
 CCA TAT TCC CAT CCT TCA AGT TAC ACA ACA CAT CCA CAG ATG CAA CAA     986
 Pro Tyr Ser His Pro Ser Ser Tyr Thr Thr His Pro Gln Met Gln Gln
         190                 195                 200
 GCA TCG GTA TCA AGT CCC ATT GTT GCA GGT GGT TTG AGA AAC ATA CAT    1034
 Ala Ser Val Ser Ser Pro Ile Val Ala Gly Gly Leu Arg Asn Ile His
     205                 210                 215
 GAT AAT AAA GTT TCT GGT CCG TTG TCT GGC AAT TCA GCT AAT CAT CAT    1082
 Asp Asn Lys Val Ser Gly Pro Leu Ser Gly Asn Ser Ala Asn His His
 220                 225                 230                 235
 GCT GAT AAT CCT AGA CAT GGT TCA AGT GAG GAC TAC CTA CAC ATG GTG    1130
 Ala Asp Asn Pro Arg His Gly Ser Ser Glu Asp Tyr Leu His Met Val
                 240                 245                 250
 CAC AGG CTA AGT AGT GAC GAT GGA GAT TCT TCA ACA ATG AGG AAT GCT    1178
 His Arg Leu Ser Ser Asp Asp Gly Asp Ser Ser Thr Met Arg Asn Ala
             255                 260                 265
 GCA TCT TTT CCC TTG AGA TCT CCA CAG CCA GTA TGC TCC CCT GCT GGA    1226
 Ala Ser Phe Pro Leu Arg Ser Pro Gln Pro Val Cys Ser Pro Ala Gly
         270                 275                 280
 AGT GAA GGA ACT CCT AAA GGC TCA AGA CCA CCT TTA ATC CTA CAA TCT    1274
 Ser Glu Gly Thr Pro Lys Gly Ser Arg Pro Pro Leu Ile Leu Gln Ser
     285                 290                 295
 CAG TCT CTA CCT TGT TCA TCA CCT CGA GAT GTT CCA CCA GAT ATC TTG    1322
 Gln Ser Leu Pro Cys Ser Ser Pro Arg Asp Val Pro Pro Asp Ile Leu
 300                 305                 310                 315
 CTA GAT TCT CCA GAA AGA AAA CAA AAG AAG CAG AAG AAA ATG AAA TTA    1370
 Leu Asp Ser Pro Glu Arg Lys Gln Lys Lys Gln Lys Lys Met Lys Leu
                 320                 325                 330
 GGC AAG GAT GAA AAA GAG CAG AGT GAG AAA GCG GCA ATG TAT GAT ATA    1418
 Gly Lys Asp Glu Lys Glu Gln Ser Glu Lys Ala Ala Met Tyr Asp Ile
             335                 340                 345
 ATT AGT TCT CCA TCC AAG GAC TCT ACT AAA CTT ACA TTA AGA CTT TCT    1466
 Ile Ser Ser Pro Ser Lys Asp Ser Thr Lys Leu Thr Leu Arg Leu Ser
         350                 355                 360
 CGT GTA AGG TCT TCA GAC ATG GAC CAG CAA GAG GAT ATG ATT TCT GGT    1514
 Arg Val Arg Ser Ser Asp Met Asp Gln Gln Glu Asp Met Ile Ser Gly
     365                 370                 375
 GTG GAA AAT AGC AAT GTT TCA GAA AAT GAT ATT CCT TTT AAT GTG CAG    1562
 Val Glu Asn Ser Asn Val Ser Glu Asn Asp Ile Pro Phe Asn Val Gln
 380                 385                 390                 395
 TAC CCA GGA CAG ACT TCA AAA ACA CCC ATT ACT CCA CAA GAT ATA AAC    1610
 Tyr Pro Gly Gln Thr Ser Lys Thr Pro Ile Thr Pro Gln Asp Ile Asn
                 400                 405                 410
 CGC CCA CTA AAT GCT GCT CAA TGT TTG TCG CAG CAA GAA CAA ACA GCA    1658
 Arg Pro Leu Asn Ala Ala Gln Cys Leu Ser Gln Gln Glu Gln Thr Ala
             415                 420                 425
 TTC CTT CCA GCA AAT CAA GTG CCT GTT TTA CAA CAG AAC ACT TCA GTT    1706
 Phe Leu Pro Ala Asn Gln Val Pro Val Leu Gln Gln Asn Thr Ser Val
         430                 435                 440
 GCT GCA AAA CAA CCC CAG ACC AAT AGT CAC AAA ACC TTG GTG CAG CCT    1754
 Ala Ala Lys Gln Pro Gln Thr Asn Ser His Lys Thr Leu Val Gln Pro
     445                 450                 455
 GGA ACA GGC ATA GAG GTC TCA GCA GAG CTG CCC AAG GAC AAG ACC TAAGA  1804
 Gly Thr Gly Ile Glu Val Ser Ala Glu Leu Pro Lys Asp Lys Thr
 460                 465                 470
 TCCAGCAGGG AACTATGTAG TCACCCCGAG AGGCCCAGCT CTCTCCGTGA GCTCTGGGCC  1864
 TAGGGTGGGG GTGGTTGTTG GTTCTGCGCG CACTGTTCCC CCTACATGAT GGGTCCATCC  1924
 CAGTTGGCTT CTCTCACTCG CTTCCTCCTG TGGAGAAGCC TGTCCAGGTG TCACTGCCTC  1984
 CAGGAAGCTG TCTCTGATTT CTCCAGTTGA ACAGTGAGAT TTGCCACACC TCACATGCAT  2044
 CGCTCTTGTC CCTGGAATTG TAACCATAGG TTTTCCTGTC TCCTGGAGGA CAAGGATGAG  2104
 GGCTTTCCAC TTGAGTCTCC CTGGTGGAGC CCAGCTCCTG ACATACCTGG TAAAAGTTCT  2164
 CAAGAGAAGA ACATGGAGGA GGAATGTGGA TAACAACCCT GGCTGCCTGT GTGTTCCAAG  2224
 CTAGGAAGAT GTAATGTCCC CACAAACGGG GTAAATGGCT TGCCTGCGTC ACAGCTGTCT  2284
 CAAGCCCAGG CCCTGGGCGC CAGCCCAAGC CCAAGGACTA GGTCCAGAGC CACACAGCGC  2344
 CAGGCCACAT CCGCCTCACC TGGGACCCTT TGTGGGGTAC AGTCTCCGGC CCCACCCAGA  2404
 CCTCCTGAAG GAGAGACCCC ATGGCAAGGA CTCAGCCACC TGCAGTTTCA TAAGCCCCCA  2464
 GTGGGTTCCT AGGCATGAAG ACCACCGGTT AGAGGCTGAA CTGGCAGGAA CCTGTCTCCA  2524
 GCCCCTTCTC ACCCCAGCCG GGCCCTGCCT CAGAGGCAGC ACCCAGGACG TGGCCATGAC  2584
 CCGTGGACTC CACTCAATCC CTCTTCTCCA GGAGCCATGC AAAGTGTCAG CCAGCCAGGC  2644
 CCCTGGAAGG CAGTCATCAC CTCTTAAGGC ATTGTGGGTG TCGGTCCTGC AACTGCCAGG  2704
 TGCAGCACAC GACCCGTGTC CGGTGTTCGA TAGCAGGGAG CCATGACCTG GCAACGATTC  2764
 CACGCTCAAA GGGGCACCCG GGGGGCCCTG GGTCGGGGCG GATCAGCTTT CCCTGGGCAC  2824
 ATCTGCCTCA TTCCAGATCT CCAGGGCTCA TGTCTGTGAC AGGGAGGGAA GGCTCTGCCC  2884
 TGGCCTTCCG TCAGCTCTGC CAGTGCAGGC TGGGCAGCCT GGGCTTTAGA GCTGGCTTCT  2944
 GCCCACACTT TCTCCGTGAA AGGAAAACAA CTATGAGTCT GCCAAACGCA TCTCAGATGC  3004
 GTTTTAAAAA ATTCTGGTCC CCGCTCTCTG TCCCATCATC CGCCTCGGGG ACTTCCTCTC  3064
 TCCGTGGTTC TCACCCCATA CTCTGTCACT GCCACATTTT CACCTGGGCC TGGCCTTTGT  3124
 CTCCACCTGA AACTCCTGAA AATCTTGAAA TGGATTTCTA GGTCACTGGG GACTCCGGCA  3184
 GCACATTCGG CTTCAGAATA AAGGGCGCCC GCGGTCCCCC AGCACCTCCC CAAGCCACAC  3244
 CCCTAGCTTC CCTCCCTATC CCTGCAGCCT GAGGGTCCCT TCAGCCACCC TTAAGTCCCC  3304
 ACCTGGGCTC CTGCCCCGCC CCTGGCTAGC AGCGCCTTCT CCACCGGGGC CCCCTCTGCT  3364
 CACAGAGCCC CCTCACCTCC CTGGGGATGA GGGGCCAGGC CATGACCCTG AAAGTCTAGC  3424
 CCTGGCCTTG ACCTCCCAGG AGCGCCCTCC CCGCCCTCTC CCGGCCCCGG CCCCGTCCTC  3484
 TGCTGCTGGC CTCTGGGTCG TGCCCCGCAG ACTGAGCTGC GCTTGGGGGT CCTGGCGGCC  3544
 TGGGCCGTCC CGCACCGAAC CCAGGCGGTC GGAGCCCGGC GGGAAGGCGC GAGGTCCTTC  3604
 TGGGGGCTCC TCCGACGCCT GAGGGCGCTG CTTCCCCGCG GCCGCCCCGG GTTTCTGCGG  3664
 AGCCGGGGCC TCCGCTCTCG GGTGACCCGG TGAGACCCCC GGGGAGGCCG CTGGGGAGGC  3724
 GCGGGCTCTG CTCCCGGGTC CCAAACGCAC TGGCTGCCCC TCAGGAGGGA CGGCGACCTC  3784
 CACCCACGGC GCTGGCGCCC GCACGGCCGC TCCTCCCGCT CCCGCAGCCT GGACGCCTCC  3844
 CGAGGCCGCC CCGCCGGGCC CCACGCGCGG CCCCATCCGC AGGCCAGGAC TGCCTTCCCG  3904
 GAGCTGGCGG CCCCCAGCCT GGAGGAGCCG GCCCCAGACG CCCTCCCAGC CCTCCCCAGC  3964
 CCACTCTGGC CCCGCAGCCC CCGCCTGGTC CGAGTGCGGG TCTCTGGCCC CGGCCTTTCC  4024
 CGGGGAAGGA AAGCAAAAAG CTT                                          4047
 
           
           
             
               474 amino acids 
               amino acid 
               single 
               linear 
             
             
               protein 
             
             internal 
             148
 Met Asn Gly Asp Met Pro His Val Pro Ile Thr Thr Leu Ala Gly Ile
  1               5                  10                  15
 Ala Ser Leu Thr Asp Leu Leu Asn Gln Leu Pro Leu Pro Ser Pro Leu
             20                  25                  30
 Pro Ala Thr Thr Thr Lys Ser Leu Leu Phe Asn Ala Arg Ile Ala Glu
         35                  40                  45
 Glu Val Asn Cys Leu Leu Ala Cys Arg Asp Asp Asn Leu Val Ser Gln
     50                  55                  60
 Leu Val His Ser Leu Asn Gln Val Ser Thr Asp His Ile Glu Leu Lys
 65                  70                  75                  80
 Asp Asn Leu Gly Ser Asp Asp Pro Glu Gly Asp Ile Pro Val Leu Leu
                 85                  90                  95
 Gln Ala Val Leu Ala Arg Ser Pro Asn Val Phe Arg Glu Lys Ser Met
             100                 105                 110
 Gln Asn Arg Tyr Val Gln Ser Gly Met Met Met Ser Gln Tyr Lys Leu
         115                 120                 125
 Ser Gln Asn Ser Met His Ser Ser Pro Ala Ser Ser Asn Tyr Gln Gln
     130                 135                 140
 Thr Thr Ile Ser His Ser Pro Ser Ser Arg Phe Val Pro Pro Gln Thr
 145                 150                 155                 160
 Ser Ser Gly Asn Arg Phe Met Pro Gln Gln Asn Ser Pro Val Pro Ser
                 165                 170                 175
 Pro Tyr Ala Pro Gln Ser Pro Ala Gly Tyr Met Pro Tyr Ser His Pro
             180                 185                 190
 Ser Ser Tyr Thr Thr His Pro Gln Met Gln Gln Ala Ser Val Ser Ser
         195                 200                 205
 Pro Ile Val Ala Gly Gly Leu Arg Asn Ile His Asp Asn Lys Val Ser
     210                 215                 220
 Gly Pro Leu Ser Gly Asn Ser Ala Asn His His Ala Asp Asn Pro Arg
 225                 230                 235                 240
 His Gly Ser Ser Glu Asp Tyr Leu His Met Val His Arg Leu Ser Ser
                 245                 250                 255
 Asp Asp Gly Asp Ser Ser Thr Met Arg Asn Ala Ala Ser Phe Pro Leu
             260                 265                 270
 Arg Ser Pro Gln Pro Val Cys Ser Pro Ala Gly Ser Glu Gly Thr Pro
         275                 280                 285
 Lys Gly Ser Arg Pro Pro Leu Ile Leu Gln Ser Gln Ser Leu Pro Cys
     290                 295                 300
 Ser Ser Pro Arg Asp Val Pro Pro Asp Ile Leu Leu Asp Ser Pro Glu
 305                 310                 315                 320
 Arg Lys Gln Lys Lys Gln Lys Lys Met Lys Leu Gly Lys Asp Glu Lys
                 325                 330                 335
 Glu Gln Ser Glu Lys Ala Ala Met Tyr Asp Ile Ile Ser Ser Pro Ser
             340                 345                 350
 Lys Asp Ser Thr Lys Leu Thr Leu Arg Leu Ser Arg Val Arg Ser Ser
         355                 360                 365
 Asp Met Asp Gln Gln Glu Asp Met Ile Ser Gly Val Glu Asn Ser Asn
     370                 375                 380
 Val Ser Glu Asn Asp Ile Pro Phe Asn Val Gln Tyr Pro Gly Gln Thr
 385                 390                 395                 400
 Ser Lys Thr Pro Ile Thr Pro Gln Asp Ile Asn Arg Pro Leu Asn Ala
                 405                 410                 415
 Ala Gln Cys Leu Ser Gln Gln Glu Gln Thr Ala Phe Leu Pro Ala Asn
             420                 425                 430
 Gln Val Pro Val Leu Gln Gln Asn Thr Ser Val Ala Ala Lys Gln Pro
         435                 440                 445
 Gln Thr Asn Ser His Lys Thr Leu Val Gln Pro Gly Thr Gly Ile Glu
     450                 455                 460
 Val Ser Ala Glu Leu Pro Lys Asp Lys Thr
 465                 470
 
           
           
             
               2998 base pairs 
               nucleic acid 
               double 
               linear 
             
             
               Genomic DNA 
             
             
               Coding Sequence 
                26...799 
               
 
             
             149
 AAGCTTTTTG AATTCGGCAC GAGAT GCT ACA CAG GCT ATA TTT GAA ATA CTG      52
                             Ala Thr Gln Ala Ile Phe Glu Ile Leu
                              1               5
 GAG AAA TCC TGG TTG CCC CAG AAT TGT ACA CTG GTT GAT ATG AAG ATT     100
 Glu Lys Ser Trp Leu Pro Gln Asn Cys Thr Leu Val Asp Met Lys Ile
 10                  15                  20                  25
 GAA TTT GGT GTT GAT GTA ACC ACC AAA GAA ATT GTT CTT GCT GAT GTT     148
 Glu Phe Gly Val Asp Val Thr Thr Lys Glu Ile Val Leu Ala Asp Val
                 30                  35                  40
 ATT GAC AAT GAT TCC TGG AGA CTC TGG CCA TCA GGA GAT CGA AGC CAA     196
 Ile Asp Asn Asp Ser Trp Arg Leu Trp Pro Ser Gly Asp Arg Ser Gln
             45                  50                  55
 CAG AAA GAC AAA CAG TCT TAT CGG GAC CTC AAA GAA GTA ACT CCT GAA     244
 Gln Lys Asp Lys Gln Ser Tyr Arg Asp Leu Lys Glu Val Thr Pro Glu
         60                  65                  70
 GGG CTC CAA ATG GTA AAG AAA AAC TTT GAG TGG GTT GCA GAG AGA GTA     292
 Gly Leu Gln Met Val Lys Lys Asn Phe Glu Trp Val Ala Glu Arg Val
     75                  80                  85
 GAG TTG CTT TTG AAA TCA GAA AGT CAG TGC AGG GTT GTA GTG TTG ATG     340
 Glu Leu Leu Leu Lys Ser Glu Ser Gln Cys Arg Val Val Val Leu Met
 90                  95                  100                 105
 GGC TCT ACT TCT GAT CTT GGT CAC TGT GAA AAA ATC AAG AAG GCC TGT     388
 Gly Ser Thr Ser Asp Leu Gly His Cys Glu Lys Ile Lys Lys Ala Cys
                 110                 115                 120
 GGA AAT TTT GGC ATT CCA TGT GAA CTT CGA GTA ACA TCT GCG CAT AAA     436
 Gly Asn Phe Gly Ile Pro Cys Glu Leu Arg Val Thr Ser Ala His Lys
             125                 130                 135
 GGA CCA GAT GAA ACT CTG AGG ATT AAA GCT GAG TAT GAA GGG GAT GGC     484
 Gly Pro Asp Glu Thr Leu Arg Ile Lys Ala Glu Tyr Glu Gly Asp Gly
         140                 145                 150
 ATT CCT ACT GTA TTT GTG GCA GTG GCA GGC AGA AGT AAT GGT TTG GGA     532
 Ile Pro Thr Val Phe Val Ala Val Ala Gly Arg Ser Asn Gly Leu Gly
     155                 160                 165
 CCA GTG ATG TCT GGG AAC ACT GCA TAT CCA GTT ATC AGC TGT CCT CCC     580
 Pro Val Met Ser Gly Asn Thr Ala Tyr Pro Val Ile Ser Cys Pro Pro
 170                 175                 180                 185
 CTC ACA CCA GAC TGG GGA GTT CAG GAT GTG TGG TCT TCT CTT CGA CTA     628
 Leu Thr Pro Asp Trp Gly Val Gln Asp Val Trp Ser Ser Leu Arg Leu
                 190                 195                 200
 CCC AGT GGT CTT GGC TGT TCA ACC GTA CTT TCT CCA GAA GGA TCA GCT     676
 Pro Ser Gly Leu Gly Cys Ser Thr Val Leu Ser Pro Glu Gly Ser Ala
             205                 210                 215
 CAA TTT GCT GCT CAG ATA TTT GGG TTA AGC AAC CAT TTG GTA TGG AGC     724
 Gln Phe Ala Ala Gln Ile Phe Gly Leu Ser Asn His Leu Val Trp Ser
         220                 225                 230
 AAA CTG CGA GCA AGC ATT TTG AAC ACA TGG ATT TCC TTG AAG CAG GCT     772
 Lys Leu Arg Ala Ser Ile Leu Asn Thr Trp Ile Ser Leu Lys Gln Ala
     235                 240                 245
 GAC AAG AAA ATC AGA GAA TGT AAT TTA TAAGAAAGAA TGCCATTGAA TTTTTTA   826
 Asp Lys Lys Ile Arg Glu Cys Asn Leu
 250                 255
 GGGGAAAAAC TACAAATTTC TAATTTAGCT GAAGGAAAAT CAAGCAAGAT GAAAAGGTAA   886
 TTTTAAATTA GAGAACACAA ATAAAATGTA TTAGTGAATA AATGGTGAGG GTAGGCCTAT   946
 TCAGATGCAA GGCCAGCAAT GGGGCTCCCC ATTATCCCCA CCCCTTTGGT CCCAGTCCCC  1006
 TTCTCTGCAA TGGGCACGCA TAGAGGAGAG ACAAAGGGTA TTAGACGCAA CATCATTGGC  1066
 CCAGGGGAGT CCGAGAAGAG CTGCCATTGG CTGACAGGGC ATTTTCAGGC TCTGTCATTG  1126
 GTCAGGGAGC ACACCCCAGC CTGAAGAGTG ATGCCATTGG CCAGGGAGTG GTTTTGTCAT  1186
 AGCCGTTGGC TGTGAAGTGG AAGGAAAAGA TCTGGGAATG AAGCCCTGTG GCCAGGAAGA  1246
 TAGACAGGGC AGCAACTTCT GGGCCTCCAG GCCCTCTTCC CACCATAGCA ATGTGGGCAA  1306
 AACTGGTGTC AGGCCCCAGC CAGAAAAAGG AGCCCAAGCC AGAGGGCAAG TGACAAAGGA  1366
 TGTACCATGT CCAATCTCCC ACACCCTGGG GCTGCCCTTC CCAATGTCTT TCTTGATAGC  1426
 CAAGTTGGGC TGGGAGCAGC TCACTGCTCC TCTAGCCAGG AGGGTTTCTC AGCTCCTGGA  1486
 GGCCGCAGCT TGATGTTGAA CTGCTGCAGG GTCTGCTCCA GCTGTTTCTG GTTCCCAGCA  1546
 AAGTAGGCGG ACACAGCATT GTGGAAGAGC AGCAGCTGCT TGTGCATCAC CTTGATCTTG  1606
 TTTTCTTCCA GGAACTTGAG CTTGATGGCC ACATCTCCCC GCAGCTTCTC ATACTTGTCC  1666
 CGATGGGCCT GGAAAGTGGC CTGGGCACTC TCAAGTCGAC CACGTGTCCC TGCATCCCGG  1726
 GGGCCTAGAC TCAGCTCCTC TAAGTCTGTT CGGTAGGCAT CATATTCCAG CCTGGCAGCC  1786
 TCATACTGTT TCACAGTCAT GAGCGTGTCT TCCATGGTCT TGGTGACCAA TGTGTTGATG  1846
 CTAGAGACAA AGAAGTTCAC GGCTCCTAGC AGCGTTTCCC CATTCTTGCA TAGTAGTTTC  1906
 TGTGTCTCTG CATTGTAGCC AAATTCCTCC TGAAGCTCTG GGGACTTCTG GCTGAGGTCA  1966
 GCAAAGGCAT CACCCAGTGC ATGCTGGGTC TGCAGCAGGC TGTAGAGGTG GGCTGTCAGT  2026
 GCCCGGCCCA GCTGCAGGAC ACTCTCATAC TTGCGCTTCG TCTCACGCAG CAACTCAATC  2086
 TGCAGCTCTA GCTCCAGGAT TCCGGCGCCT CCACTCCGTC CCCCGCGGGT CTGCTCTGTG  2146
 TGCCATGGAC GGCATTGTCC CAGATATAGC CGTTGGTACA AAGCGGGGAT CTGACGAGCT  2206
 TTTCTCTACT TGTGTCACTA ACGGACCGTT TATCATGAGC AGCAACTCGG CTTCTGCAGC  2266
 AAACGGAAAT GACAGCAAGA AGTTCAAAGG TGACAGCCGA AGTGCAGGCG TCCCCTCTAG  2326
 AGTGATCCAC ATCCGGAAGC TCCCCATCGA CGTCACGGAG GGGGAAGTCA TCTCCCTGGG  2386
 GCTGCCCTTT GGGAAGGTCA CCAACCTCCT GATGCTGAAG GGGAAAAACC AGGCCTTCAT  2446
 CGAGATGAAC ACGGAGGAGG CTGCCAATAC CATGGTGAAC TACTACACCT CGGTGACCCC  2506
 TGTGCTGCGC GGCCAGCCCA TCTACATCCA GTTCTCCAAC CACAAGGAGC TGAAGACCGA  2566
 CAGCTCTCCC AACCAGGCGC GGGCCCAGGC GGCCCTGCAG GCGGTGAACT CGGTCCAGTC  2626
 GGGGAACCTG GCCTTGGCTG CCTCGGCGGC GGCCGTGGAT GCAGGGATGG CGATGGCCGG  2686
 GCAGAGCCCC GTGCTCAGGA TCATCGTGGA GAACCTCTTC TACCCTGTGA CCCTGGATGT  2746
 GCTGCACCAG ATTTTCTCCA AGTTCGGCAC AGTGTTGAAG ATCATCACCT TCACCAAGAA  2806
 CAACCAGTTC CAGGCCCTGC TGCAGTATGC GGACCCCGTG AGCGCCCAGC ACGCCAAGCT  2866
 GTCGCTGGAC GGGCAGAACA TCTACAACGC CTGCTGCACG CTGCGCATCG ACTTTTCCAA  2926
 GCTCACCAGC CTCAACGTCA AGTACAACAA TGACAAGAGC CGTGACTACC TCGTGCCGAA  2986
 TTCTTTGGAT CC                                                      2998
 
           
           
             
               258 amino acids 
               amino acid 
               single 
               linear 
             
             
               protein 
             
             internal 
             150
 Ala Thr Gln Ala Ile Phe Glu Ile Leu Glu Lys Ser Trp Leu Pro Gln
  1               5                  10                  15
 Asn Cys Thr Leu Val Asp Met Lys Ile Glu Phe Gly Val Asp Val Thr
             20                  25                  30
 Thr Lys Glu Ile Val Leu Ala Asp Val Ile Asp Asn Asp Ser Trp Arg
         35                  40                  45
 Leu Trp Pro Ser Gly Asp Arg Ser Gln Gln Lys Asp Lys Gln Ser Tyr
     50                  55                  60
 Arg Asp Leu Lys Glu Val Thr Pro Glu Gly Leu Gln Met Val Lys Lys
 65                  70                  75                  80
 Asn Phe Glu Trp Val Ala Glu Arg Val Glu Leu Leu Leu Lys Ser Glu
                 85                  90                  95
 Ser Gln Cys Arg Val Val Val Leu Met Gly Ser Thr Ser Asp Leu Gly
             100                 105                 110
 His Cys Glu Lys Ile Lys Lys Ala Cys Gly Asn Phe Gly Ile Pro Cys
         115                 120                 125
 Glu Leu Arg Val Thr Ser Ala His Lys Gly Pro Asp Glu Thr Leu Arg
     130                 135                 140
 Ile Lys Ala Glu Tyr Glu Gly Asp Gly Ile Pro Thr Val Phe Val Ala
 145                 150                 155                 160
 Val Ala Gly Arg Ser Asn Gly Leu Gly Pro Val Met Ser Gly Asn Thr
                 165                 170                 175
 Ala Tyr Pro Val Ile Ser Cys Pro Pro Leu Thr Pro Asp Trp Gly Val
             180                 185                 190
 Gln Asp Val Trp Ser Ser Leu Arg Leu Pro Ser Gly Leu Gly Cys Ser
         195                 200                 205
 Thr Val Leu Ser Pro Glu Gly Ser Ala Gln Phe Ala Ala Gln Ile Phe
     210                 215                 220
 Gly Leu Ser Asn His Leu Val Trp Ser Lys Leu Arg Ala Ser Ile Leu
 225                 230                 235                 240
 Asn Thr Trp Ile Ser Leu Lys Gln Ala Asp Lys Lys Ile Arg Glu Cys
                 245                 250                 255
 Asn Leu
 
           
           
             
               1038 amino acids 
               amino acid 
               single 
               linear 
             
             151
 Ile Gln Arg Phe Gly Thr Ser Gly His Ile Met Asn Leu Gln Ala Gln
  1               5                  10                  15
 Pro Lys Ala Gln Asn Lys Arg Lys Arg Cys Leu Phe Gly Gly Gln Glu
             20                  25                  30
 Pro Ala Pro Lys Glu Gln Pro Pro Pro Leu Gln Pro Pro Gln Gln Ser
         35                  40                  45
 Ile Arg Val Lys Glu Glu Gln Tyr Leu Gly His Glu Gly Pro Gly Gly
     50                  55                  60
 Ala Val Ser Thr Ser Gln Pro Val Glu Leu Pro Pro Pro Ser Ser Leu
 65                  70                  75                  80
 Ala Leu Leu Asn Ser Val Val Tyr Gly Pro Glu Arg Thr Ser Ala Ala
                 85                  90                  95
 Met Leu Ser Gln Gln Val Ala Ser Val Lys Trp Pro Asn Ser Val Met
             100                 105                 110
 Ala Pro Gly Arg Gly Pro Glu Arg Gly Gly Gly Gly Gly Val Ser Asp
         115                 120                 125
 Ser Ser Trp Gln Gln Gln Pro Gly Gln Pro Pro Pro His Ser Thr Trp
     130                 135                 140
 Asn Cys His Ser Leu Ser Leu Tyr Ser Ala Thr Lys Gly Ser Pro His
 145                 150                 155                 160
 Pro Gly Val Gly Val Pro Thr Tyr Tyr Asn His Pro Glu Ala Leu Lys
                 165                 170                 175
 Arg Glu Lys Ala Gly Gly Pro Gln Leu Asp Arg Tyr Val Arg Pro Met
             180                 185                 190
 Met Pro Gln Lys Val Gln Leu Glu Val Gly Arg Pro Gln Ala Pro Leu
         195                 200                 205
 Asn Ser Phe His Ala Ala Lys Lys Pro Pro Asn Gln Ser Leu Pro Leu
     210                 215                 220
 Gln Pro Phe Gln Leu Ala Phe Gly His Gln Val Asn Arg Gln Val Phe
 225                 230                 235                 240
 Arg Gln Gly Pro Pro Pro Pro Asn Pro Val Ala Ala Phe Pro Pro Gln
                 245                 250                 255
 Lys Gln Gln Gln Gln Gln Gln Pro Gln Gln Gln Gln Gln Gln Gln Gln
             260                 265                 270
 Ala Ala Leu Pro Gln Met Pro Leu Phe Glu Asn Phe Tyr Ser Met Pro
         275                 280                 285
 Gln Gln Pro Ser Gln Gln Pro Gln Asp Phe Gly Leu Gln Pro Ala Gly
     290                 295                 300
 Pro Leu Gly Gln Ser His Leu Ala His His Ser Met Ala Pro Tyr Pro
 305                 310                 315                 320
 Phe Pro Pro Asn Pro Asp Met Asn Pro Glu Leu Arg Lys Ala Leu Leu
                 325                 330                 335
 Gln Asp Ser Ala Pro Gln Pro Ala Leu Pro Gln Val Gln Ile Pro Phe
             340                 345                 350
 Pro Arg Arg Ser Arg Arg Leu Ser Lys Glu Gly Ile Leu Pro Pro Ser
         355                 360                 365
 Ala Leu Asp Gly Ala Gly Thr Gln Pro Gly Gln Glu Ala Thr Gly Asn
     370                 375                 380
 Leu Phe Leu His His Trp Pro Leu Gln Gln Pro Pro Pro Gly Ser Leu
 385                 390                 395                 400
 Gly Gln Pro His Pro Glu Ala Leu Gly Phe Pro Leu Glu Leu Arg Glu
                 405                 410                 415
 Ser Gln Leu Leu Pro Asp Gly Glu Arg Leu Ala Pro Asn Gly Arg Glu
             420                 425                 430
 Arg Glu Ala Pro Ala Met Gly Ser Glu Glu Gly Met Arg Ala Val Ser
         435                 440                 445
 Thr Gly Asp Cys Gly Gln Val Leu Arg Gly Gly Val Ile Gln Ser Thr
     450                 455                 460
 Arg Arg Arg Arg Arg Ala Ser Gln Glu Ala Asn Leu Leu Thr Leu Ala
 465                 470                 475                 480
 Gln Lys Ala Val Glu Leu Ala Ser Leu Gln Asn Ala Lys Asp Gly Ser
                 485                 490                 495
 Gly Ser Glu Glu Lys Arg Lys Ser Val Leu Ala Ser Thr Thr Lys Cys
             500                 505                 510
 Gly Val Glu Phe Ser Glu Pro Ser Leu Ala Thr Lys Arg Ala Arg Glu
         515                 520                 525
 Asp Ser Gly Met Val Pro Leu Ile Ile Pro Val Ser Val Pro Val Arg
     530                 535                 540
 Thr Val Asp Pro Thr Glu Ala Ala Gln Ala Gly Gly Leu Asp Glu Asp
 545                 550                 555                 560
 Gly Lys Gly Leu Glu Gln Asn Pro Ala Glu His Lys Pro Ser Val Ile
                 565                 570                 575
 Val Thr Arg Arg Arg Ser Thr Arg Ile Pro Gly Thr Asp Ala Gln Ala
             580                 585                 590
 Gln Ala Glu Asp Met Asn Val Lys Leu Glu Gly Glu Pro Ser Val Arg
         595                 600                 605
 Lys Pro Lys Gln Arg Pro Arg Pro Glu Pro Leu Ile Ile Pro Thr Lys
     610                 615                 620
 Ala Gly Thr Phe Ile Ala Pro Pro Val Tyr Ser Asn Ile Thr Pro Tyr
 625                 630                 635                 640
 Gln Ser His Leu Arg Ser Pro Val Arg Leu Ala Asp His Pro Ser Glu
                 645                 650                 655
 Arg Ser Phe Glu Leu Pro Pro Tyr Thr Pro Pro Pro Ile Leu Ser Pro
             660                 665                 670
 Val Arg Glu Gly Ser Gly Leu Tyr Phe Asn Ala Ile Ile Ser Thr Ser
         675                 680                 685
 Thr Ile Pro Ala Pro Pro Pro Ile Thr Pro Lys Ser Ala His Arg Thr
     690                 695                 700
 Leu Leu Arg Thr Asn Ser Ala Glu Val Thr Pro Pro Val Leu Ser Val
 705                 710                 715                 720
 Met Gly Glu Ala Thr Pro Val Ser Ile Glu Pro Arg Ile Asn Val Gly
                 725                 730                 735
 Ser Arg Phe Gln Ala Glu Ile Pro Leu Met Arg Asp Arg Ala Leu Ala
             740                 745                 750
 Ala Ala Asp Pro His Lys Ala Asp Leu Val Trp Gln Pro Trp Glu Asp
         755                 760                 765
 Leu Glu Ser Ser Arg Glu Lys Gln Arg Gln Val Glu Asp Leu Leu Thr
     770                 775                 780
 Ala Ala Cys Ser Ser Ile Phe Pro Gly Ala Gly Thr Asn Gln Glu Leu
 785                 790                 795                 800
 Ala Leu His Cys Leu His Glu Ser Arg Gly Asp Ile Leu Glu Thr Leu
                 805                 810                 815
 Asn Lys Leu Leu Leu Lys Lys Pro Leu Arg Pro His Asn His Pro Leu
             820                 825                 830
 Ala Thr Tyr His Tyr Thr Gly Ser Asp Gln Trp Lys Met Ala Glu Arg
         835                 840                 845
 Lys Leu Phe Asn Lys Gly Ile Ala Ile Tyr Lys Lys Asp Phe Phe Leu
     850                 855                 860
 Val Gln Lys Leu Ile Gln Thr Lys Thr Val Ala Gln Cys Val Glu Phe
 865                 870                 875                 880
 Tyr Tyr Thr Tyr Lys Lys Gln Val Lys Ile Gly Arg Asn Gly Thr Leu
                 885                 890                 895
 Thr Phe Gly Asp Val Asp Thr Ser Asp Glu Lys Ser Ala Gln Glu Glu
             900                 905                 910
 Val Glu Val Asp Ile Lys Thr Ser Gln Lys Phe Pro Arg Val Pro Leu
         915                 920                 925
 Pro Arg Arg Glu Ser Pro Ser Glu Glu Arg Leu Glu Pro Lys Arg Glu
     930                 935                 940
 Val Lys Glu Pro Arg Lys Glu Gly Glu Glu Glu Val Pro Glu Ile Gln
 945                 950                 955                 960
 Glu Lys Glu Glu Gln Glu Glu Gly Arg Glu Arg Ser Arg Arg Ala Ala
                 965                 970                 975
 Ala Val Lys Ala Thr Gln Thr Leu Gln Ala Asn Glu Ser Ala Ser Asp
             980                 985                 990
 Ile Leu Ile Leu Arg Ser His Glu Ser Asn Ala Pro Gly Ser Ala Gly
         995                 1000                1005
 Gly Gln Ala Ser Glu Lys Pro Arg Glu Gly Thr Gly Lys Ser Arg Arg
     1010                1015                1020
 Ala Leu Pro Phe Ser Glu Lys Lys Lys Lys Lys Gln Lys Ala
 1025                1030                1035
 
           
           
             
               849 amino acids 
               amino acid 
               single 
               linear 
             
             152
 Ile Arg His Glu Val Ser Phe Leu Trp Asn Thr Glu Ala Ala Cys Pro
  1               5                  10                  15
 Ile Gln Thr Thr Thr Asp Thr Asp Gln Ala Cys Ser Ile Arg Asp Pro
             20                  25                  30
 Asn Ser Gly Phe Val Phe Asn Leu Asn Pro Leu Asn Ser Ser Gln Gly
         35                  40                  45
 Tyr Asn Val Ser Gly Ile Gly Lys Ile Phe Met Phe Asn Val Cys Gly
     50                  55                  60
 Thr Met Pro Val Cys Gly Thr Ile Leu Gly Lys Pro Ala Ser Gly Cys
 65                  70                  75                  80
 Glu Ala Glu Thr Gln Thr Glu Glu Leu Lys Asn Trp Lys Pro Ala Arg
                 85                  90                  95
 Pro Val Gly Ile Glu Lys Ser Leu Gln Leu Ser Thr Glu Gly Phe Ile
             100                 105                 110
 Thr Leu Thr Tyr Lys Gly Pro Leu Ser Ala Lys Gly Thr Ala Asp Ala
         115                 120                 125
 Phe Ile Val Arg Phe Val Cys Asn Asp Asp Val Tyr Ser Gly Pro Leu
     130                 135                 140
 Lys Phe Leu His Gln Asp Ile Asp Ser Gly Gln Gly Ile Arg Asn Thr
 145                 150                 155                 160
 Tyr Phe Glu Phe Glu Thr Ala Leu Ala Cys Val Pro Ser Pro Val Asp
                 165                 170                 175
 Cys Gln Val Thr Asp Leu Ala Gly Asn Glu Tyr Asp Leu Thr Gly Leu
             180                 185                 190
 Ser Thr Val Arg Lys Pro Trp Thr Ala Val Asp Thr Ser Val Asp Gly
         195                 200                 205
 Arg Lys Arg Thr Phe Tyr Leu Ser Val Cys Asn Pro Leu Pro Tyr Ile
     210                 215                 220
 Pro Gly Cys Gln Gly Ser Ala Val Gly Ser Cys Leu Val Ser Glu Gly
 225                 230                 235                 240
 Asn Ser Trp Asn Leu Gly Val Val Gln Met Ser Pro Gln Ala Ala Ala
                 245                 250                 255
 Asn Gly Ser Leu Ser Ile Met Tyr Val Asn Gly Asp Lys Cys Gly Asn
             260                 265                 270
 Gln Arg Phe Ser Thr Arg Ile Thr Phe Glu Cys Ala Gln Ile Ser Gly
         275                 280                 285
 Ser Pro Ala Phe Gln Leu Gln Asp Gly Cys Glu Tyr Val Phe Ile Trp
     290                 295                 300
 Arg Thr Val Glu Ala Cys Pro Val Val Arg Val Glu Gly Asp Asn Cys
 305                 310                 315                 320
 Glu Val Lys Asp Pro Arg His Gly Asn Leu Tyr Asp Leu Lys Pro Leu
                 325                 330                 335
 Gly Leu Asn Asp Thr Ile Val Ser Ala Gly Glu Tyr Thr Tyr Tyr Phe
             340                 345                 350
 Arg Val Cys Gly Lys Leu Ser Ser Asp Val Cys Pro Thr Ser Asp Lys
         355                 360                 365
 Ser Lys Val Val Ser Ser Cys Gln Glu Lys Arg Glu Pro Gln Gly Phe
     370                 375                 380
 His Lys Val Ala Gly Leu Leu Thr Gln Lys Leu Thr Tyr Glu Asn Gly
 385                 390                 395                 400
 Leu Leu Lys Met Asn Phe Thr Gly Gly Asp Thr Cys His Lys Val Tyr
                 405                 410                 415
 Gln Arg Ser Thr Ala Ile Phe Phe Tyr Cys Asp Arg Gly Thr Gln Arg
             420                 425                 430
 Pro Val Phe Leu Lys Glu Thr Ser Asp Cys Ser Tyr Leu Phe Glu Trp
         435                 440                 445
 Arg Thr Gln Tyr Ala Cys Pro Pro Phe Asp Leu Thr Glu Cys Ser Phe
     450                 455                 460
 Lys Asp Gly Ala Gly Asn Ser Phe Asp Leu Ser Ser Leu Ser Arg Tyr
 465                 470                 475                 480
 Ser Asp Asn Trp Glu Ala Ile Thr Gly Thr Gly Asp Pro Glu His Tyr
                 485                 490                 495
 Leu Ile Asn Val Cys Lys Ser Leu Ala Pro Gln Ala Gly Thr Glu Pro
             500                 505                 510
 Cys Pro Pro Glu Ala Ala Ala Cys Leu Leu Gly Gly Ser Lys Pro Val
         515                 520                 525
 Asn Leu Gly Arg Val Arg Asp Gly Pro Gln Trp Arg Asp Gly Ile Ile
     530                 535                 540
 Val Leu Lys Tyr Val Asp Gly Asp Leu Cys Pro Asp Gly Ile Arg Lys
 545                 550                 555                 560
 Lys Ser Thr Thr Ile Arg Phe Thr Cys Ser Glu Ser Gln Val Asn Ser
                 565                 570                 575
 Arg Pro Met Phe Ile Ser Ala Val Glu Asp Cys Glu Tyr Thr Phe Ala
             580                 585                 590
 Trp Pro Thr Ala Thr Ala Cys Pro Met Lys Ser Asn Glu His Asp Asp
         595                 600                 605
 Cys Gln Val Thr Asn Pro Ser Thr Gly His Leu Phe Asp Leu Ser Ser
     610                 615                 620
 Leu Ser Gly Arg Ala Gly Phe Thr Ala Ala Tyr Ser Glu Lys Gly Leu
 625                 630                 635                 640
 Val Tyr Met Ser Ile Cys Gly Glu Asn Glu Asn Cys Pro Pro Gly Val
                 645                 650                 655
 Gly Ala Cys Phe Gly Gln Thr Arg Ile Ser Val Gly Lys Ala Asn Lys
             660                 665                 670
 Arg Leu Arg Tyr Val Asp Gln Val Leu Gln Leu Val Tyr Lys Asp Gly
         675                 680                 685
 Ser Pro Cys Pro Ser Lys Ser Gly Leu Ser Tyr Lys Ser Val Ile Ser
     690                 695                 700
 Phe Val Cys Arg Pro Glu Ala Gly Pro Thr Asn Arg Pro Met Leu Ile
 705                 710                 715                 720
 Ser Leu Asp Lys Gln Thr Cys Thr Leu Phe Phe Ser Trp His Thr Pro
                 725                 730                 735
 Leu Ala Cys Glu Gln Ala Thr Glu Cys Ser Val Arg Asn Gly Ser Ser
             740                 745                 750
 Ile Val Asp Leu Ser Pro Leu Ile His Arg Thr Gly Gly Tyr Glu Ala
         755                 760                 765
 Tyr Asp Glu Ser Glu Asp Asp Ala Ser Asp Thr Asn Pro Asp Phe Tyr
     770                 775                 780
 Ile Asn Ile Cys Gln Pro Leu Asn Pro Met His Gly Val Pro Cys Pro
 785                 790                 795                 800
 Ala Gly Ala Ala Val Cys Lys Val Pro Ile Asp Gly Pro Pro Ile Asp
                 805                 810                 815
 Ile Gly Arg Val Ala Gly Pro Pro Ile Leu Asn Pro Ile Ala Asn Glu
             820                 825                 830
 Ile Tyr Leu Asn Phe Glu Ser Ser Thr Pro Cys Gln Glu Phe Ser Cys
         835                 840                 845
 Lys
 
           
           
             
               852 amino acids 
               amino acid 
               single 
               linear 
             
             153
 Met Ala Arg Leu Ser Arg Pro Glu Arg Pro Asp Leu Val Phe Glu Glu
  1               5                  10                  15
 Glu Asp Leu Pro Tyr Glu Glu Glu Ile Met Arg Asn Gln Phe Ser Val
             20                  25                  30
 Lys Cys Trp Leu His Tyr Ile Glu Phe Lys Gln Gly Ala Pro Lys Pro
         35                  40                  45
 Arg Leu Asn Gln Leu Tyr Glu Arg Ala Leu Lys Leu Leu Pro Cys Ser
     50                  55                  60
 Tyr Lys Leu Trp Tyr Arg Tyr Leu Lys Ala Arg Arg Ala Gln Val Lys
 65                  70                  75                  80
 His Arg Cys Val Thr Asp Pro Ala Tyr Glu Asp Val Asn Asn Cys His
                 85                  90                  95
 Glu Arg Ala Phe Val Phe Met His Lys Met Pro Arg Leu Trp Leu Asp
             100                 105                 110
 Tyr Cys Gln Phe Leu Met Asp Gln Gly Arg Val Thr His Thr Arg Arg
         115                 120                 125
 Thr Phe Asp Arg Ala Leu Arg Ala Leu Pro Ile Thr Gln His Ser Arg
     130                 135                 140
 Ile Trp Pro Leu Tyr Leu Arg Phe Leu Arg Ser His Pro Leu Pro Glu
 145                 150                 155                 160
 Thr Ala Val Arg Gly Tyr Arg Arg Phe Leu Lys Leu Ser Pro Glu Ser
                 165                 170                 175
 Ala Glu Glu Tyr Ile Glu Tyr Leu Lys Ser Ser Asp Arg Leu Asp Glu
             180                 185                 190
 Ala Ala Gln Arg Leu Ala Thr Val Val Asn Asp Glu Arg Phe Val Ser
         195                 200                 205
 Lys Ala Gly Lys Ser Asn Tyr Gln Leu Trp His Glu Leu Cys Asp Leu
     210                 215                 220
 Ile Ser Gln Asn Pro Asp Lys Val Gln Ser Leu Asn Val Asp Ala Ile
 225                 230                 235                 240
 Ile Arg Gly Gly Leu Thr Arg Phe Thr Asp Gln Leu Gly Lys Leu Trp
                 245                 250                 255
 Cys Ser Leu Ala Asp Tyr Tyr Ile Arg Ser Gly His Phe Glu Lys Ala
             260                 265                 270
 Arg Asp Val Tyr Glu Glu Ala Ile Arg Thr Val Met Thr Val Arg Asp
         275                 280                 285
 Phe Thr Gln Val Phe Asp Ser Tyr Ala Gln Phe Glu Glu Ser Met Ile
     290                 295                 300
 Ala Ala Lys Met Glu Thr Ala Ser Glu Leu Gly Arg Glu Glu Glu Asp
 305                 310                 315                 320
 Asp Val Asp Leu Glu Leu Arg Leu Ala Arg Phe Glu Gln Leu Ile Ser
                 325                 330                 335
 Arg Arg Pro Leu Leu Leu Asn Ser Val Leu Leu Arg Gln Asn Pro His
             340                 345                 350
 His Val His Glu Trp His Lys Arg Val Ala Leu His Gln Gly Arg Pro
         355                 360                 365
 Arg Glu Ile Ile Asn Thr Tyr Thr Glu Ala Val Gln Thr Val Asp Pro
     370                 375                 380
 Phe Lys Ala Thr Gly Lys Pro His Thr Leu Trp Val Ala Phe Ala Lys
 385                 390                 395                 400
 Phe Tyr Glu Asp Asn Gly Gln Leu Asp Asp Ala Arg Val Ile Leu Glu
                 405                 410                 415
 Lys Ala Thr Lys Val Asn Phe Lys Gln Val Asp Asp Leu Ala Ser Val
             420                 425                 430
 Trp Cys Gln Cys Gly Glu Leu Glu Leu Arg His Glu Asn Tyr Asp Glu
         435                 440                 445
 Ala Leu Arg Leu Leu Arg Lys Ala Thr Ala Leu Pro Ala Arg Arg Ala
     450                 455                 460
 Glu Tyr Phe Asp Gly Ser Glu Pro Val Gln Asn Arg Val Tyr Lys Ser
 465                 470                 475                 480
 Leu Lys Val Trp Ser Met Leu Ala Asp Leu Glu Glu Ser Leu Gly Thr
                 485                 490                 495
 Phe Gln Ser Thr Lys Ala Val Tyr Asp Arg Ile Leu Asp Leu Arg Ile
             500                 505                 510
 Ala Thr Pro Gln Ile Val Ile Asn Tyr Ala Met Phe Leu Glu Glu His
         515                 520                 525
 Lys Tyr Phe Glu Glu Ser Phe Lys Ala Tyr Glu Arg Gly Ile Ser Leu
     530                 535                 540
 Phe Lys Trp Pro Asn Val Ser Asp Ile Trp Ser Thr Tyr Leu Thr Lys
 545                 550                 555                 560
 Phe Ile Ala Arg Tyr Gly Gly Arg Lys Leu Glu Arg Ala Arg Asp Leu
                 565                 570                 575
 Phe Glu Gln Ala Leu Asp Gly Cys Pro Pro Lys Tyr Ala Lys Thr Leu
             580                 585                 590
 Tyr Leu Leu Tyr Ala Gln Leu Glu Glu Glu Trp Gly Leu Ala Arg His
         595                 600                 605
 Ala Met Ala Val Tyr Glu Arg Ala Thr Arg Ala Val Glu Pro Ala Gln
     610                 615                 620
 Gln Tyr Asp Met Phe Asn Ile Tyr Ile Lys Arg Ala Ala Glu Ile Tyr
 625                 630                 635                 640
 Gly Val Thr His Thr Arg Gly Ile Tyr Gln Lys Ala Ile Glu Val Leu
                 645                 650                 655
 Ser Asp Glu His Ala Arg Glu Met Cys Leu Arg Phe Ala Asp Met Glu
             660                 665                 670
 Cys Lys Leu Gly Glu Ile Asp Arg Ala Arg Ala Ile Tyr Ser Phe Cys
         675                 680                 685
 Ser Gln Ile Cys Asp Pro Arg Thr Thr Gly Ala Phe Trp Gln Thr Trp
     690                 695                 700
 Lys Asp Phe Glu Val Arg His Gly Asn Glu Asp Thr Ile Lys Glu Met
 705                 710                 715                 720
 Leu Arg Ile Arg Arg Ser Val Gln Ala Thr Tyr Asn Thr Gln Val Asn
                 725                 730                 735
 Phe Met Ala Ser Gln Met Leu Lys Val Ser Gly Ser Ala Thr Gly Thr
             740                 745                 750
 Val Ser Asp Leu Ala Pro Gly Gln Ser Gly Met Asp Asp Met Lys Leu
         755                 760                 765
 Leu Glu Gln Arg Ala Glu Gln Leu Ala Ala Glu Ala Glu Arg Asp Gln
     770                 775                 780
 Pro Leu Arg Ala Gln Ser Lys Ile Leu Phe Val Arg Ser Asp Ala Ser
 785                 790                 795                 800
 Arg Glu Glu Leu Ala Glu Leu Ala Gln Gln Val Asn Pro Glu Glu Ile
                 805                 810                 815
 Gln Leu Gly Glu Asp Glu Asp Glu Asp Glu Met Asp Leu Glu Pro Asn
             820                 825                 830
 Glu Val Arg Leu Glu Gln Gln Ser Val Pro Ala Ala Val Phe Gly Ser
         835                 840                 845
 Leu Lys Glu Asp
     850
 
           
           
             
               693 amino acids 
               amino acid 
               single 
               linear 
             
             154
 Met Phe Ser Ala Leu Lys Lys Leu Val Gly Ser Asp Gln Ala Pro Gly
  1               5                  10                  15
 Arg Asp Lys Asn Ile Pro Ala Gly Leu Gln Ser Met Asn Gln Ala Leu
             20                  25                  30
 Gln Arg Arg Phe Ala Lys Gly Val Gln Tyr Asn Met Lys Ile Val Ile
         35                  40                  45
 Arg Gly Asp Arg Asn Thr Gly Lys Thr Ala Leu Trp His Arg Leu Gln
     50                  55                  60
 Gly Arg Pro Phe Val Glu Glu Tyr Ile Pro Thr Gln Glu Ile Gln Val
 65                  70                  75                  80
 Thr Ser Ile His Trp Ser Tyr Lys Thr Thr Asp Asp Ile Val Lys Val
                 85                  90                  95
 Glu Val Trp Asp Val Val Asp Lys Gly Lys Cys Lys Lys Arg Gly Asp
             100                 105                 110
 Gly Leu Lys Met Glu Asn Asp Pro Gln Glu Xaa Glu Ser Glu Met Ala
         115                 120                 125
 Leu Asp Ala Glu Phe Leu Asp Val Tyr Lys Asn Cys Asn Gly Val Val
     130                 135                 140
 Met Met Phe Asp Ile Thr Lys Gln Trp Thr Phe Asn Tyr Ile Leu Arg
 145                 150                 155                 160
 Glu Leu Pro Lys Val Pro Thr His Val Pro Val Cys Val Leu Gly Asn
                 165                 170                 175
 Tyr Arg Asp Met Gly Glu His Arg Val Ile Leu Pro Asp Asp Val Arg
             180                 185                 190
 Asp Phe Ile Asp Asn Leu Asp Arg Pro Pro Gly Ser Ser Tyr Phe Arg
         195                 200                 205
 Tyr Ala Glu Ser Ser Met Lys Asn Ser Phe Gly Leu Lys Tyr Leu His
     210                 215                 220
 Lys Phe Phe Asn Ile Pro Phe Leu Gln Leu Gln Arg Glu Thr Leu Leu
 225                 230                 235                 240
 Arg Gln Leu Glu Thr Asn Gln Leu Asp Met Asp Ala Thr Leu Glu Glu
                 245                 250                 255
 Leu Ser Val Gln Gln Glu Thr Glu Asp Gln Asn Tyr Gly Ile Phe Leu
             260                 265                 270
 Glu Met Met Glu Ala Arg Ser Arg Gly His Ala Ser Pro Leu Ala Ala
         275                 280                 285
 Asn Gly Gln Ser Pro Ser Pro Gly Ser Gln Ser Pro Val Leu Pro Ala
     290                 295                 300
 Pro Ala Val Ser Thr Gly Ser Ser Ser Pro Gly Thr Pro Gln Pro Ala
 305                 310                 315                 320
 Pro Gln Leu Pro Leu Asn Ala Ala Pro Pro Ser Ser Val Pro Pro Val
                 325                 330                 335
 Pro Pro Ser Glu Ala Leu Pro Pro Pro Ala Cys Pro Ser Ala Pro Ala
             340                 345                 350
 Pro Arg Arg Ser Ile Ile Ser Arg Leu Phe Gly Thr Ser Pro Ala Thr
         355                 360                 365
 Glu Ala Ala Pro Pro Pro Pro Glu Pro Val Pro Ala Ala Gln Gly Pro
     370                 375                 380
 Ala Thr Val Gln Ser Val Glu Asp Phe Val Pro Asp Asp Arg Leu Asp
 385                 390                 395                 400
 Arg Ser Phe Leu Glu Asp Thr Thr Pro Ala Arg Asp Glu Lys Lys Val
                 405                 410                 415
 Gly Ala Lys Ala Ala Gln Gln Asp Ser Asp Ser Asp Gly Glu Ala Leu
             420                 425                 430
 Gly Gly Asn Pro Met Val Ala Gly Phe Gln Asp Asp Val Asp Leu Glu
         435                 440                 445
 Asp Gln Pro Arg Gly Ser Pro Pro Leu Pro Ala Gly Pro Val Pro Ser
     450                 455                 460
 Gln Asp Ile Thr Leu Ser Ser Glu Glu Glu Ala Glu Val Ala Ala Pro
 465                 470                 475                 480
 Thr Lys Gly Pro Ala Pro Ala Pro Gln Gln Cys Ser Glu Pro Glu Thr
                 485                 490                 495
 Lys Trp Ser Ser Ile Pro Ala Ser Lys Pro Arg Arg Gly Thr Ala Pro
             500                 505                 510
 Thr Arg Thr Ala Ala Pro Pro Trp Pro Gly Gly Val Ser Val Arg Thr
         515                 520                 525
 Gly Pro Glu Lys Arg Ser Ser Thr Arg Pro Pro Ala Glu Met Glu Pro
     530                 535                 540
 Gly Lys Gly Glu Gln Ala Ser Ser Ser Glu Ser Asp Pro Glu Gly Pro
 545                 550                 555                 560
 Ile Ala Ala Gln Met Leu Ser Phe Val Met Asp Asp Pro Asp Phe Glu
                 565                 570                 575
 Ser Glu Gly Ser Asp Thr Gln Arg Arg Ala Asp Asp Phe Pro Val Arg
             580                 585                 590
 Asp Asp Pro Ser Asp Val Thr Asp Glu Asp Glu Gly Pro Ala Glu Pro
         595                 600                 605
 Pro Pro Pro Pro Lys Leu Pro Leu Pro Ala Phe Arg Leu Lys Asn Asp
     610                 615                 620
 Ser Asp Leu Phe Gly Leu Gly Leu Glu Glu Ala Gly Pro Lys Glu Ser
 625                 630                 635                 640
 Ser Glu Glu Gly Lys Glu Gly Lys Thr Pro Ser Lys Glu Lys Lys Lys
                 645                 650                 655
 Lys Thr Lys Ser Phe Ser Arg Val Leu Leu Glu Arg Pro Arg Ala His
             660                 665                 670
 Arg Phe Ser Thr Arg Val Gly Tyr Gln Val Ser Val Pro Asn Ser Pro
         675                 680                 685
 Tyr Ser Glu Ser Tyr
     690