Glycosylphosphatidylinositol-anchored and Secretory Isoforms of Mono-ADP-ribosyltransferases (1998)

glycosylphosphatidylinositol phosphatidylinositol-specific phospholipase C cytotoxic T lymphocytes lymphocyte function-associated molecule-1 poly(ADP-ribose) polymerase cholera toxin heat-labile enterotoxin of Escherichia coli pertussis toxin diphtheria toxin P. aeruginosa exotoxin A brefeldin A kilobase pair. Mono-ADP-ribosylation, a post-translational modification of proteins in which the ADP-ribose moiety of NAD is transferred to an acceptor amino acid, occurs in viruses, bacteria, and eukaryotic cells (1Moss J. Vaughan M. ADP-ribosylating Toxins and G Proteins: Insights into Signal Transduction. American Society for Microbiology, Washington, D. C.1990Google Scholar). The reaction is distinct from that catalyzed by poly(ADP-ribose) polymerase, a nuclear protein involved in DNA repair, cell differentiation, and the maintenance of chromatin structure (2de Murcia G. Schreiber V. Molinete M. Saulier B. Poch O. Masson M. Niedergang C. de Murcia J.M. Mol. Cell. Biochem. 1994; 138: 15-24Crossref PubMed Scopus (187) Google Scholar). Among mono-ADP-ribosyltransferases, the bacterial toxins, cholera toxin, pertussis toxin, diphtheria toxin, and Pseudomonas aeruginosa exotoxin A are the best characterized in molecular structure, function, and substrate specificity (reviewed in Ref. 1Moss J. Vaughan M. ADP-ribosylating Toxins and G Proteins: Insights into Signal Transduction. American Society for Microbiology, Washington, D. C.1990Google Scholar). Mono-ADP-ribosyltransferases from mammalian and avian cells have been cloned and characterized, and specific target proteins have been identified (3Zolkiewska A. Moss J. J. Biol. Chem. 1993; 268: 25273-25276Abstract Full Text PDF PubMed Google Scholar, 4Wang J. Nemoto E. Dennert G. J. Immunol. 1996; 156: 2819-2827PubMed Google Scholar). In lymphocytes, a glycosylphosphatidylinositol (GPI)1-anchored transferase appears to be involved in immune modulation, whereas other isoforms in lymphocytes (5Okazaki I.J. Kim H.-J. Moss J. J. Biol. Chem. 1996; 271: 22052-22057Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar) and chicken heterophil granules (6Tsuchiya M. Hara N. Yamada K. Osago H. Shimoyama M. J. Biol. Chem. 1994; 269: 27451-27457Abstract Full Text PDF PubMed Google Scholar) are membrane-associated but appear to be processed for secretion. Further, ADP-ribosyltransferases have been purified from brain, and data from several independent laboratories demonstrate that ADP-ribosylation is involved in neuronal function (7Duman R.S. Terwilliger R.Z. Nestler E.J. J. Neurochem. 1991; 57: 2124-2132Crossref PubMed Scopus (59) Google Scholar, 8Schuman E.M. Meffert M.K. Schulman H. Madison D.V. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 11958-11962Crossref PubMed Scopus (124) Google Scholar). Deduced amino acid sequences of the vertebrate ADP-ribosyltransferases have similarities to those of viral and bacterial toxin transferases (9Domenighini M. Rappuoli R. Mol. Microbiol. 1996; 21: 667-674Crossref PubMed Scopus (132) Google Scholar, 10Takada T. Iida K. Moss J. J. Biol. Chem. 1995; 270: 541-544Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar) in regions that form, in part, an active site cleft, consistent with a common mechanism of NAD binding and ADP-ribose transfer (9Domenighini M. Rappuoli R. Mol. Microbiol. 1996; 21: 667-674Crossref PubMed Scopus (132) Google Scholar). The majority of the eukaryotic enzymes are arginine-specific transferases. ADP-ribosylation of arginine appears to be a reversible process; free arginine can be regenerated in ADP-ribosylated proteins by ADP-ribosylarginine hydrolases (1Moss J. Vaughan M. ADP-ribosylating Toxins and G Proteins: Insights into Signal Transduction. American Society for Microbiology, Washington, D. C.1990Google Scholar). ADP-ribosylarginine hydrolase activity was detected in the soluble fraction of turkey erythrocytes, cultured mouse cells, and rat skeletal muscle with deduced amino acid sequences known for rat, mouse, and human brain ADP-ribosylarginine hydrolases (11Moss J. Stanley S.J. Nightingale M.S. Murtagh Jr., J.J. Monaco L. Mishima K. Chen H.-C. Williamson K.C. Tsai S.-C. J. Biol. Chem. 1992; 267: 10481-10488Abstract Full Text PDF PubMed Google Scholar, 12Takada T. Iida K. Moss J. J. Biol. Chem. 1993; 268: 17837-17843Abstract Full Text PDF PubMed Google Scholar). ADP-ribosylation of cysteine was reported in bovine erythrocytes (13Saxty B.A. van Heyningen S. Biochem. J. 1995; 310: 931-937Crossref PubMed Scopus (22) Google Scholar), and an NAD:cysteine ADP-ribosyltransferase that modified Gαi was purified from human erythrocyte and platelet membranes (14Tanuma S. Kawashima K. Endo H. J. Biol. Chem. 1988; 263: 5485-5489Abstract Full Text PDF PubMed Google Scholar). Consistent with this, ADP-ribosylcysteine linkages were detected in rat liver plasma membranes (15Jacobson M.K. Loflin P.T. Aboul-Ela N. Mingmuang M. Moss J. Jacobson E.L. J. Biol. Chem. 1990; 265: 10825-10828Abstract Full Text PDF PubMed Google Scholar). ADP-ribosylation of cysteine can, however, occur nonenzymatically via the reaction of ADP-ribose, generated from NAD by NAD glycohydrolases, with cysteine to form an ADP-ribosylthiazolidine, a linkage distinct from the thioglycoside formed by pertussis toxin (PT)-catalyzed ADP-ribosylation of a cysteine in the heterotrimeric guanine nucleotide-binding (G) proteins (16McDonald L.J. Wainschel L.A. Oppenheimer N.J. Moss J. Biochemistry. 1992; 31: 11881-11887Crossref PubMed Scopus (42) Google Scholar). Nonenzymatic ADP-ribosylation of cysteine in proteins, however, yielded a product with the same chemical sensitivity as the linkage formed by PT (17McDonald L.J. Moss J. J. Biol. Chem. 1993; 268: 17878-17882Abstract Full Text PDF PubMed Google Scholar). Based on these data, the ADP-ribose-cysteine produced by the human erythrocyte enzyme may have been generated nonenzymatically from free ADP-ribose. Because nitric oxide (NO) induced the noncovalent binding of the entire NAD molecule to a cysteine of glyceraldehyde-3-phosphate dehydrogenase (18McDonald L.J. Moss J. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 6238-6241Crossref PubMed Scopus (176) Google Scholar), it is important to exclude NAD attachment to cysteine when assaying the radiolabeling of proteins with [32P]NAD. This review summarizes information on the avian and mammalian ADP-ribosyltransferases and the recent advances in understanding their role in cellular metabolism. The family of mammalian ADP-ribosyltransferases comprises five enzymes (ART1–5) based on similarities in their deduced amino acid sequences and conservation of gene structure (Fig. 1). ART1 was extensively purified from rabbit skeletal muscle as a 36-kDa protein (19Zolkiewska A. Nightingale M.S. Moss J. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 11352-11356Crossref PubMed Scopus (152) Google Scholar) and subsequently cloned from rabbit (19Zolkiewska A. Nightingale M.S. Moss J. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 11352-11356Crossref PubMed Scopus (152) Google Scholar) and human (20Okazaki I.J. Zolkiewska A. Nightingale M.S. Moss J. Biochemistry. 1994; 33: 12828-12836Crossref PubMed Scopus (80) Google Scholar) skeletal muscle and mouse lymphoma (Yac-1) cells (21Okazaki I.J. Kim H.-J. McElvaney G. Lesma E. Moss J. Blood. 1996; 88: 915-921Crossref PubMed Google Scholar). The human ART1 gene is on chromosome 11p15 (22Koch-Nolte F. Kuhl M. Haag F. Cetkovic-Cvrlje M. Leiter E.H. Thiele H.-G. Genomics. 1996; 36: 215-216Crossref PubMed Scopus (11) Google Scholar). The murine sequence is 75 and 77% identical to those of the rabbit and human muscle enzymes, respectively (21Okazaki I.J. Kim H.-J. McElvaney G. Lesma E. Moss J. Blood. 1996; 88: 915-921Crossref PubMed Google Scholar), consistent with considerable conservation of structure across species. The deduced amino acid sequence of ART1 possesses hydrophobic amino- and carboxyl-terminal signal peptides that are characteristic of GPI-linked proteins (19Zolkiewska A. Nightingale M.S. Moss J. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 11352-11356Crossref PubMed Scopus (152) Google Scholar, 20Okazaki I.J. Zolkiewska A. Nightingale M.S. Moss J. Biochemistry. 1994; 33: 12828-12836Crossref PubMed Scopus (80) Google Scholar, 23Ferguson M.A.J. Williams A.F. Annu. Rev. Biochem. 1988; 57: 285-320Crossref PubMed Scopus (953) Google Scholar). Rat mammary adenocarcinoma (NMU) cells, transformed with rabbit or mouse ART1 cDNAs, demonstrated membrane-associated transferase activity that was released into the medium by phosphatidylinositol-specific phospholipase C (PI-PLC), which cleaves the inositol phosphate-diacyl glycerol bond and solubilizes most GPI-anchored proteins. The transferase from transformed NMU cells and transferases partially purified from rabbit and human skeletal muscle reacted on immunoblot with antibodies that recognize the inositol 1,2-cyclic phosphate moiety that remains after cleavage of the GPI anchor with PI-PLC (20Okazaki I.J. Zolkiewska A. Nightingale M.S. Moss J. Biochemistry. 1994; 33: 12828-12836Crossref PubMed Scopus (80) Google Scholar), consistent with the presence of a GPI anchor on native transferases. In transformed NMU cells lacking the carboxyl-terminal signal peptide, required for attachment of the GPI anchor, transferase activity was found in the medium (20Okazaki I.J. Zolkiewska A. Nightingale M.S. Moss J. Biochemistry. 1994; 33: 12828-12836Crossref PubMed Scopus (80) Google Scholar). In C2C12 mouse myoblasts, GPI-anchored ART1 activity, which appeared with differentiation of myoblasts to myotubes, catalyzed the ADP-ribosylation of integrin α7 (3Zolkiewska A. Moss J. J. Biol. Chem. 1993; 268: 25273-25276Abstract Full Text PDF PubMed Google Scholar). Modification of integrin α7 did not block α7β1 heterodimer formation or its association with the cytoskeleton or laminin. Incubation of embryonic chick myoblasts in vitro withmeta-iodobenzylguanidine, an alternative substrate of NAD:arginine ADP-ribosyltransferases (24Banasik M. Komura H. Shimoyama M. Ueda K. J. Biol. Chem. 1992; 267: 1569-1575Abstract Full Text PDF PubMed Google Scholar), however, inhibited proliferation and differentiation of the myoblasts (25Kharadia S.V. Huiatt T.W. Huang H.-Y. Peterson J.E. Graves D.J. Exp. Cell Res. 1992; 201: 33-42Crossref PubMed Scopus (31) Google Scholar). ADP-ribose-integrin α7 was a substrate for extracellular phosphodiesterase activity that generated phosphoribosyl-integrin and 5′-AMP (26Zolkiewska A. Moss J. J. Biol. Chem. 1995; 270: 9227-9233Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar). Expression of skeletal muscle ART1 in parallel with integrin α7 during muscle cell development and ADP-ribosylation of integrin α7 are consistent with a regulatory role for this modification in myogenesis. ADP-ribosyltransferase activity with properties similar to those of the cloned ART1, was detected in mouse cytotoxic T lymphocytes (CTL) (27Wang J. Nemoto E. Kots A.Y. Kaslow H.R. Dennert G. J. Immunol. 1994; 153: 4048-4058PubMed Google Scholar). Incubation of CTL with 10 mm NAD resulted in ADP-ribosylation of membrane proteins and inhibition of CTL proliferation. A 35-kDa protein with ADP-ribosyltransferase activity was released by incubation of intact CTL with PI-PLC, with resulting partial loss of the inhibitory effect of NAD on CTL proliferation (27Wang J. Nemoto E. Kots A.Y. Kaslow H.R. Dennert G. J. Immunol. 1994; 153: 4048-4058PubMed Google Scholar). Modification by the GPI-linked lymphocyte transferase of a 40-kDa membrane protein (p40) that complexes with the tyrosine kinase p56 resulted in inhibition of p56 action (4Wang J. Nemoto E. Dennert G. J. Immunol. 1996; 156: 2819-2827PubMed Google Scholar). It is noteworthy that T cell activation and lymphokine production can be mediated, in part, by signaling through GPI-anchored molecules (28Gunter K.C. Germain R.N. Kroczek R.A. Saito T. Yokoyama W.M. Chan C. Weiss A. Shevach E.M. Nature. 1987; 326: 505-507Crossref PubMed Scopus (133) Google Scholar,29Robinson P.J. Millrain M. Antoniou J. Simpson E. Mellor A.L. Nature. 1989; 342: 85-87Crossref PubMed Scopus (139) Google Scholar). Further, a GPI-linked transferase in CTL modified arginines in the extracellular domain of the lymphocyte function-associated molecule-1 (LFA-1), an adhesion molecule of the integrin family (30Nemoto E., Yu, Y. Dennert G. J. Immunol. 1996; 157: 3341-3349PubMed Google Scholar). ADP-ribosylation inhibited LFA-1-mediated generation of inositol phosphates and suppressed homotypic cell adhesion. As in C2C12 cells, in CTL, 5′-AMP was released from the modified LFA-1 by extracellular phosphodiesterases. ADP-ribosylation of integrins in muscle cells and CTL is consistent with the hypothesis that this modification alters cell-cell or cell-matrix interactions. ADP-ribosyltransferase activity was detected on the surface of human neutrophils, and the partial sequence of the cloned neutrophil transferase cDNA was identical to that encoding the human muscle transferase (31Allport J.R. Donnelly L.E. Kefalas P. Lo G. Numm A. Yadollahi-Farsani M. Rendell N.B. Murray S. Taylor G.W. MacDermot J. Br. J. Clin. Pharmacol. 1996; 42: 99-106Crossref PubMed Scopus (16) Google Scholar). Analysis of chemotaxis of intact neutrophils and actin polymerization in permeabilized cells in response toN-formyl-peptide (fMLP) without or with inhibitors of mono-ADP-ribosyltransferases (e.g. novobiocin, vitamin K1, vitamin K3, nicotinamide) or the alternative substrate, diethylamino(benzylidineamino)guanidine, demonstrated a close correlation among concentrations causing 50% inhibition (IC50) of ADP-ribosyltransferase activity, neutrophil chemotaxis, and actin polymerization (32Allport J.R. Donnelly L.E. Hayes B.P. Murray S. Rendell N.B. Ray K.P. MacDermot J. Br. J. Pharmacol. 1996; 118: 1111-1118Crossref PubMed Scopus (20) Google Scholar). The ADP-ribosyltransferase inhibitors did not, however, affect fMLP- or platelet-activating factor-induced increases in intracellular Ca2+ concentration (32Allport J.R. Donnelly L.E. Hayes B.P. Murray S. Rendell N.B. Ray K.P. MacDermot J. Br. J. Pharmacol. 1996; 118: 1111-1118Crossref PubMed Scopus (20) Google Scholar). The ART1 enzymes have significant amino acid sequence identity to the RT6 (ART2) family of rodent T cell alloantigens (10Takada T. Iida K. Moss J. J. Biol. Chem. 1995; 270: 541-544Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar,19Zolkiewska A. Nightingale M.S. Moss J. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 11352-11356Crossref PubMed Scopus (152) Google Scholar). In rats, RT6 and RT6 are alleles of a single gene that encodes for the corresponding alloantigens RT6.1 and RT6.2, respectively (33Koch-Nolte F. Haag F. Kastelein R. Bazan F. Immunol. Today. 1996; 17: 402-405Abstract Full Text PDF PubMed Scopus (34) Google Scholar). The expression of RT6 proteins appears in postthymic lymphocytes and is restricted to peripheral T cells and intestinal intraepithelial lymphocytes. RT6.1 and RT6.2 are 25–30-kDa GPI-anchored proteins that differ by only 10 amino acids. In the mouse, there are two functional copies of theRT6 gene (Rt6–1 and Rt6–2) located on chromosome 7. The deduced amino acid sequences of mouse Rt6–1 and Rt6–2 are 79% identical, whereas those of mouse Rt6–1 and rat RT6.2 proteins are 71% identical. In humans and chimpanzees, theART2 gene contains three premature stop codons corresponding to amino acids 47, 141, and 193 of the rat RT6 protein (33Koch-Nolte F. Haag F. Kastelein R. Bazan F. Immunol. Today. 1996; 17: 402-405Abstract Full Text PDF PubMed Scopus (34) Google Scholar) and appears not to be expressed. In humans, the role of ART2 may be assumed by related ADP-ribosyltransferases. In rats, the absence of RT6+ T cells is associated with lymphopenia and the development of an autoimmune-mediated diabetes (34Greiner D.L. Handler E.S. Nakano K. Mordes J.P. Rossini A.A. J. Immunol. 1986; 136: 148-151PubMed Google Scholar). can be in these by and of RT6+ lymphocytes D. Mordes J.P. D.L. D. N. Handler E.S. 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Immunol. 1996; 156: Google Scholar) or in NMU cells J. L.A. E. I.J. R. T. Mordes J.P. D.L. Rossini A.A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus (20) Google Scholar), catalyzed ADP-ribosylation of and the rat RT6 proteins, the mouse Rt6–1 was an with a of NAD activity J. L.A. E. I.J. R. T. Mordes J.P. D.L. Rossini A.A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus (20) Google Scholar). As in the rat, of mouse ART2 have been associated with it not been that of is related to activity or Because mouse ART2 is of ADP-ribosylating proteins, however, this activity may in similar to that in and were cloned from human N. F. A. S. G. G. 1996; PubMed Scopus (22) Google Scholar) and F. Haag F. R. Kuhl M. J. S. Bazan Thiele H.-G. Genomics. 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Chem. 1996; 271: 22052-22057Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar). deduced amino acid sequence similarities to other proteins in regions to be involved in activity and is identical to that of mouse ART1, identical to that of mouse and and identical to the human and proteins, ART1, NAD ADP-ribosyltransferase activity, and it catalyzed ADP-ribosylation of other proteins was The membrane-associated enzyme were not by Consistent with this, possesses a hydrophobic but not signal sequence and may be of an cDNA with and in from it was most and a in from and skeletal muscle (5Okazaki I.J. Kim H.-J. Moss J. J. Biol. Chem. 1996; 271: 22052-22057Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar). In three proteins and are whereas and are in and ART1, and are in lymphocytes. The of the ART1, and are similar (Fig. 1). The signal peptide, a the and the carboxyl-terminal signal sequence in the GPI-anchored transferases are in J. and J. In ART1 and but not a a amino is from the of the consistent with the presence of a domain in these proteins. distinct ADP-ribosyltransferases were purified from rat brain S. S. J. Neurochem. 1991; 57: PubMed Scopus Google Scholar), and in other ADP-ribosyltransferases were purified from rat H. H. S. J. Biochem. Cell Biol. 1995; PubMed Scopus (11) Google Scholar). The transferases from brain and to muscle and The in vitro modification of brain and G proteins for cell similar to those with the bacterial toxin ADP-ribosyltransferases. Rat brain ADP-ribosyltransferases modified E.J. Terwilliger R.Z. R.S. J. Neurochem. 1995; PubMed Scopus Google Scholar), ADP-ribosylation a protein involved in protein J. Vaughan M. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar), the protein kinase C substrate D. D.L. H. Biochem. Cell Biol. 1994; PubMed Scopus Google Scholar), and the protein P.J. K. H. 1993; PubMed Scopus Google Scholar), as as the protein C. Neurochem. 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A. 1994; 91: PubMed Scopus Google Scholar). protein and by activation of by guanine proteins J. Vaughan M. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar). ADP-ribosylation of was with of the M. A. M. G. L.J. Moss J. G. S. D. A. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: PubMed Scopus Google Scholar). The vertebrate NAD:arginine mono-ADP-ribosyltransferases and were identified and purified from turkey erythrocytes J. Vaughan M. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, J. Stanley S.J. J. Biol. Chem. Full Text PDF PubMed Google Scholar, Moss J. J. Biol. Chem. Full Text PDF PubMed Google Scholar, Jr., Moss J. Biochemistry. 1986; PubMed Scopus Google Scholar). A and were from the erythrocyte and transferases C and from the plasma membrane and In to in the transferases and distinct chicken ADP-ribosyltransferases and to heterophil granules were cloned from a cDNA (6Tsuchiya M. Hara N. Yamada K. Osago H. Shimoyama M. J. Biol. Chem. 1994; 269: 27451-27457Abstract Full Text PDF PubMed Google Scholar). The deduced amino acid sequence an signal but a carboxyl-terminal with and in granules and (Fig. the structure of the heterophil transferases that of which appeared to be the carboxyl-terminal signal (Fig. A transferase from a chicken cDNA a deduced sequence identical to those of the heterophil transferases T. S. 1995; PubMed Scopus Google Scholar). in of the heterophil transferase were identified M. Shimoyama M. Mol. Cell. Biochem. 1994; 138: PubMed Scopus Google Scholar) actin and a heterophil which is similar in amino acid sequence to the As with turkey transferase it was not demonstrated that in vitro catalyzed by the heterophil transferase occur in of identity of deduced amino acid the bacterial toxin ADP-ribosyltransferases regions of sequence that appear to form, in part, the site (9Domenighini M. Rappuoli R. Mol. Microbiol. 1996; 21: 667-674Crossref PubMed Scopus (132) Google Scholar). Based on and the of the bacterial and that of eukaryotic transferases appear to be of an a arginine or and an active site which is for activity, are located on two the (9Domenighini M. Rappuoli R. Mol. Microbiol. 1996; 21: 667-674Crossref PubMed Scopus (132) Google Scholar). of active have been for bacterial toxin transferases (9Domenighini M. Rappuoli R. Mol. Microbiol. 1996; 21: 667-674Crossref PubMed Scopus (132) Google Scholar). In the found in and the is formed by a a in and hydrophobic amino and the of the active site In of is important for NAD binding and ADP-ribose transfer to whereas in is involved in the binding of NAD but appears from the bond of NAD to affect ADP-ribose transfer D. Biochemistry. 1996; PubMed Scopus Google Scholar, M. F. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google Scholar). In of and a tyrosine on a is in the sequence by 10 amino acids from a tyrosine on an (9Domenighini M. Rappuoli R. Mol. Microbiol. 1996; 21: 667-674Crossref PubMed Scopus (132) Google Scholar, D. Biochemistry. 1996; PubMed Scopus Google Scholar). and have identified a active site and in and that is for enzyme activity (9Domenighini M. Rappuoli R. Mol. Microbiol. 1996; 21: 667-674Crossref PubMed Scopus (132) Google D. Biochemistry. 1996; PubMed Scopus Google Scholar, J. Biol. Chem. 1987; Full Text PDF PubMed Google Scholar). In of bacterial by and contains an located on a is identified by the sequence that is on the of the cleft, and contains the active site on a (9Domenighini M. Rappuoli R. Mol. Microbiol. 1996; 21: 667-674Crossref PubMed Scopus (132) Google Scholar). in of the or phosphate of NAD and a bond with the of which is located in van J. B. J. Mol. Biol. 1993; PubMed Scopus Google Scholar). of the active site of and not an role in (9Domenighini M. Rappuoli R. Mol. Microbiol. 1996; 21: 667-674Crossref PubMed Scopus (132) Google Scholar). In the of of and on that of of and of and is in close to the bond of NAD D. Biochemistry. 1996; PubMed Scopus Google Scholar). The regions of amino acid sequence among bacterial toxin transferases are in of the mammalian ADP-ribosyltransferases (10Takada T. Iida K. Moss J. J. Biol. Chem. 1995; 270: 541-544Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, F. D. S. Haag F. D. T. Kastelein R. Bazan F. Thiele H.-G. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar). In of the mouse on a on a by an and the active site on a are in the in a similar to that found in the structure of the bacterial toxins, in and PT (9Domenighini M. Rappuoli R. Mol. Microbiol. 1996; 21: 667-674Crossref PubMed Scopus (132) Google Scholar, F. D. S. Haag F. D. T. Kastelein R. Bazan F. Thiele H.-G. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar). In the of deduced amino acid sequences of ART1, and a arginine and similar to those in and PT appear to be of rabbit ART1 with of its with did not activity (10Takada T. Iida K. Moss J. J. Biol. Chem. 1995; 270: 541-544Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar). A mouse ART1 protein from which the amino acids were NAD but not activity H.-J. I.J. T. Moss J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The transferase to of rabbit but possesses which is consistent with the hypothesis the transferase is similar to not and that as in the may a role in active site and NAD Based on (10Takada T. Iida K. Moss J. J. Biol. Chem. 1995; 270: 541-544Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar) and amino acid sequence the in ART1 and is to be to and of and In the mouse ART2 sequences (Rt6–1 and in is by in the rat ART2 sequences and F. D. S. Haag F. D. T. Kastelein R. Bazan F. Thiele H.-G. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar). of of the rat ART2 which possesses NAD activity, with resulted in the generation of an arginine-specific ADP-ribosyltransferase and activity, with effect on NAD binding or NAD activity T. S. T. 1996; PubMed Scopus (16) Google Scholar, N. M. Shimoyama M. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus (34) Google Scholar). of a the rat ART2 protein activity the mouse ART2 or ART1 transferases. the in the appears to be for arginine-specific The deduced amino acid sequences of human poly(ADP-ribose) polymerase (9Domenighini M. Rappuoli R. Mol. Microbiol. 1996; 21: 667-674Crossref PubMed Scopus (132) Google Scholar, M. H. T. H. M. ADP-ribosylation Google Scholar) and appear to have regions of that with and structure of the chicken A. Murcia J. de Murcia G. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google Scholar) and of human M. H. T. H. M. ADP-ribosylation Google Scholar, C. E. S. de Murcia G. Murcia J. 1996; PubMed Scopus (22) Google Scholar) demonstrated that which is for ADP-ribose is in a similar to that found in the bacterial data are consistent with the hypothesis that several of the bacterial toxin and vertebrate transferases a common mechanism of NAD binding and ADP-ribose transfer and that in may in substrate proteins. ADP-ribosyltransferase activity been detected in turkey erythrocytes, rabbit skeletal and mouse The mammalian proteins appear to be in a In muscle cells and lymphocytes, GPI-linked enzymes consistent with a role in of cell-cell or cell-matrix (Fig. In lymphocytes, the GPI-anchored ART1 and ART2 transferases are associated with of immune function, which is and an of active A of the ADP-ribosyltransferases and the heterophil a carboxyl-terminal signal sequence and may not be have an signal sequence and have been found in chicken heterophil these proteins may be (Fig. intracellular ADP-ribosylation in eukaryotic cells been K.C. Moss J. ADP-ribosylating Toxins and G Proteins: Insights into Signal Transduction. American Society for Microbiology, Washington, D. Scholar) based on the presence of NAD:arginine ADP-ribosyltransferases and ADP-ribosylarginine which ADP-ribose, free arginine (Fig. modified by GPI-anchored transferases are processed by extracellular and (Fig. three of transferases may and Vaughan for and review of the