SII-SWORD/CoKE huggingface dataset:
Bestrophin (Bestrophin)
Type: Family

This entry represents the Bestrophin family that includes four paralogous genes in mammals (BEST1, BEST2, BEST3, BEST4) encoding integral membrane calcium (Ca2+)-activated chloride (Cl-) channels. In humans, they are widely distributed in various organs including the airways, colon, kidney, pancreas and central nervous system, but best known for their physiological roles in the eye. In particular, BEST1 that is genetically linked to a spectrum of retinal degenerative disorders collectively known as bestrophinopathies

Bestrophin is a 68kDa basolateral plasma membrane protein expressed in retinal pigment epithelial cells (RPE). It is encoded by the VMD2 gene, which is mutated in Best macular dystrophy, a disease characterised by a depressed light peak in the electrooculogram . VMD2 encodes a 585-amino acid protein with an approximate mass of 68kDa which has been designated bestrophin. Bestrophin shares homology with the Caenorhabditis elegans RFP gene family, named for the presence of a conserved arginine (R), phenylalanine (F), proline (P), amino acid sequence motif. Bestrophin is a plasma membrane protein, localised to the basolateral surface of RPE cells consistent with a role for bestrophin in the generation or regulation of the EOG light peak.

Bestrophin and other RFP family members represent a new class of calcium-activated chloride channels (CaCC) , indicating a direct role for bestrophin in generating the light peak . Bestrophins are also permeable to other monovalent anions including bicarbonate, bromine, iodine, thiocyanate an nitrate . Structural analysis revealed that N-terminal region of the proteins is highly conserved and sufficient for its CaCC activity. The C-terminal region has low sequence identity. The VMD2 gene underlying Best disease was shown to represent the first human member of the RFP-TM protein family. More than 97% of the disease-causing mutations are located in the N-terminal domain altering the electrophysiological properties of the channel .
Napin/ 2S seed storage protein/Conglutin (Napin/2SS/CON)
Type: Family

This entry represents a group of plant seed storage proteins, including Napin, 2S seed storage protein and Conglutin.

Napins are low-molecular weight, basic storage proteins synthesised in rape-seed embryos during seed maturation . Sequence comparisons have revealed that Napin belongs to a diverse protein family, which includes major allergens, trypsin inhibitors and natural anti-fungal proteins. Napin comprises 2 polypeptide chains (MW 9000 and 4000) held together by disulphide bonds. The protein is initially synthesised as a precursor of 178 residues, which is proteolytically cleaved to generate mature Napin chains, with 86 and 29 residues respectively .

Some of the proteins in this family are allergens, with cores that are very resistant to proteolytic digestion and to elevated temperatures of up to 100 degrees C . Allergies are hypersensitivity reactions of the immune system to specific substances called allergens (such as pollen, stings, drugs, or food) that, in most people, result in no symptoms. A nomenclature system has been established for antigens (allergens) that cause IgE-mediated atopic allergies in humans [WHO/IUIS Allergen Nomenclature Subcommittee King T.P., Hoffmann D., Loewenstein H., Marsh D.G., Platts-Mills T.A.E., Thomas W. Bull. World Health Organ. 72:797-806(1994)]. This nomenclature system is defined by a designation that is composed of the first three letters of the genus; a space; the first letter of the species name; a space and an arabic number. In the event that two species names have identical designations, they are discriminated from one another by adding one or more letters (as necessary) to each species designation.
Insect cuticle protein (Insect_cuticle)
Type: Family

Insect cuticle is composed of proteins and chitin. The cuticular proteins seem to be specific to the type of cuticle (flexible or stiff) that occur at stages of the insect development. The proteins found in the flexible cuticle of larva and pupa of different insects share a conserved C-terminal section such a region is also found in the soft endocuticle of adults insects as well as in other cuticular proteins including in arachnids . In addition, cuticular proteins share hydrophobic regions dominated by tetrapeptide repeats (A-A-P-A/V), which are presumed to be functionally important . Many insect cuticle proteins also include a 35-36 amino acid motif known as the R and R consensus. An extended form of this motif has been shown to bind chitin. It has no sequence similiarity to the cysteine-containing chitin-binding domain of chitinases and some peritrophic membrane proteins, suggesting that arthropods have two distinct classes of chitin-binding proteins, those with the chitin-binding domains found in lectins, chitinases and peritrophic membranes (cysCBD), and those with the type of chitin-binding domains found in cuticular proteins (non-cysCBD) .

The cuticle protein signature has been found in locust cuticle proteins 7 (LM-7), 8 (LM-8), 19 (LM-19) and endocuticle structural glycoprotein ABD-4; Hyalophora cecropia (Cecropia moth) cuticle proteins 12 and 66; Drosophila melanogaster (Fruit fly) larval cuticles proteins I, II, III and IV (LCP1 to LCP4); drosophila pupal cuticle proteins PCP, EDG-78E and EDG-84E; Manduca sexta (Tobacco hawkmoth) cuticle protein LCP-14; Tenebrio molitor (Yellow mealworm) cuticle proteins ACP-20, A1A, A2B and A3A; and Araneus diadematus (Spider) cuticle proteins ACP 11.9, ACP 12.4, ACP 12.6, ACP 15.5 and ACP 15.7.
EamA domain (EamA_dom)
Type: Domain

EamA (named after the O-acetyl-serine/cysteine export gene in E. coli) domain is found in a wide range of proteins including the Erwinia chrysanthemi PecM protein, which is involved in pectinase, cellulase and blue pigment regulation, the Salmonella typhimurium PagO protein (function unknown), some eukaryotic members of the solute carrier family group 35 (SLC35) nucleoside-sugar transporters and the bacterial Probable 4-amino-4-deoxy-L-arabinose-phosphoundecaprenol flippase subunit ArnE. Many members of this group, found in all cellular organisms, are classed as drug/metabolite transporters and have no known function. They are predicted to be integral membrane proteins and many of the proteins contain two copies of this domain .
K/Cl co-transporter 1 (KCC1)
Type: Family

The K-Cl co-transporter (KCC) mediates the coupled movement of K
+
and Cl
-
ions across the plasma membrane of many animal cells. This transport is involved in the regulatory volume decrease in response to cell swelling in red blood cells, and has been proposed to play a role in the vectorial movement of Cl
-
across kidney epithelia. The transport process involves one for one electroneutral movement of K
+
together with Cl
-
, and, in all known mammalian cells, the net movement is outward .

Four isoforms of KCC have been identified: KCC1, KCC2, KCC3, and KCC4. They are predicted to have 12 transmembrane (TM) regions in a central hydrophobic domain, together with hydrophilic N- and C-termini that are likely cytoplasmic. Comparison of their sequences with those of other ion-tranporting membrane proteins reveals that they are part of a new superfamily of cation-chloride co-transporters, which includes the Na-Cl and Na-K-2Cl co-transporters. KCC1 and KCC3 are widely expressed in human tissues, while KCC2 is are expressed only in brain neurones, making it likely that this is the isoform responsible for maintaining low Cl
-
concentration in neurones .

KCC1, also known as solute carrier family 12 member 4 (SLC12A4), is widely expressed in human tissues, and when heterologously expressed,
possesses the functional characteristics of the well-studied red blood cell
K-Cl co-transporter, including stimulation by both swelling and
N-ethylmaleimide. Several splice variants have also been identified.

Proteins in this entry are predominantly found in chordates.
Shikimate kinase/Threonine synthase-like 1 (Shikimate_kinase/TSH1)
Type: Family

Shikimate kinase (

) catalyses the fifth step in the biosynthesis of aromatic amino acids from chorismate (the so-called shikimate pathway) . The enzyme catalyses the following reaction:

ATP + shikimate = ADP + shikimate-3-phosphate

The protein is found in bacteria (gene aroK or aroL), plants and fungi (where it is part of a multifunctional enzyme that catalyses five consecutive steps in this pathway). In 1994, the 3D structure of shikimate kinase was predicted to be very close to that of adenylate kinase, suggesting a functional similarity as well as an evolutionary relationship . This prediction has since been confirmed experimentally. The protein is reported to possess an α/β fold, consisting of a central sheet of five parallel β-strands flanked by α-helices. Such a topology is very similar to that of adenylate kinase .

The N terminus of threonine synthase-like 1 from metazoan shares protein sequence similarity with shikimate kinase and is included in this entry. However, their functions may be different.
Anti-repression trans-activator protein, REV protein (REV_protein)
Type: Family

REV is a viral anti-repression trans-activator protein, which appears to act post-transcriptionally to relieve negative repression of GAG and ENV production. It is a phosphoprotein whose state of phosphorylation is mediated by a specific serine kinase activity present in the nucleus . REV accumulates in the nucleoli .
Ubiquitin-like domain (Ubiquitin-like_dom)
Type: Domain

Ubiquitin is expressed as three different precursors: a polymeric head-to-tail concatemer of identical units (polyubiquitin), and two N-terminal ubiquitin moieties, UbL40 and UbS27, that are fused to the ribosomal polypeptides L40 and S27, respectively. Specific endopeptidases cleave these precursor molecules to release ubiquitin moieties that are identical in sequence and contribute to the ubiquitin pool . Some organisms express additional ubiquitin fusion proteins . Furthermore, there are several ubiquitin-like proteins derived from ubiquitin .

This entry represents a domain characteristic of ubiquitin (Ub) and ubiquitin-like (Ubl) proteins such as SUMO and Nedd8 .

Ubiquitin is a protein of 76 amino acid residues, found in all eukaryotic cells and whose sequence is extremely well conserved from protozoan to vertebrates. Ubiquitin acts through its post-translational attachment (ubiquitinylation) to other proteins, where these modifications alter the function, location or trafficking of the protein, or targets it for destruction by the 26S proteasome .

Ubiquitin is a globular protein, the last four C-terminal residues (Leu-Arg-Gly-Gly) extending from the compact structure to form a 'tail', important for its function. The latter is mediated by the covalent conjugation of ubiquitin to target proteins, by an isopeptide linkage between the C-terminal glycine and the ε-amino group of lysine residues in the target proteins.
Intradiol ring-cleavage dioxygenase, C-terminal (Intradiol_dOase_C)
Type: Domain

This entry represents the C-terminal domain common to several intradiol ring-cleavage dioxygenases.

Dioxygenases catalyse the incorporation of both atoms of molecular oxygen into substrates using a variety of reaction mechanisms. Cleavage of aromatic rings is one of the most important functions of dioxygenases, which play key roles in the degradation of aromatic compounds. The substrates of ring-cleavage dioxygenases can be classified into two groups according to the mode of scission of the aromatic ring. Intradiol enzymes use a non-haem Fe(III) to cleave the aromatic ring between two hydroxyl groups (ortho-cleavage), whereas extradiol enzymes (

) use a non-haem Fe(II) to cleave the aromatic ring between a hydroxylated carbon and an adjacent non-hydroxylated carbon (meta-cleavage) . These two subfamilies differ in sequence, structural fold, iron ligands, and the orientation of second sphere active site amino acid residues.

Enzymes that belong to the intradiol family include catechol 1,2-dioxygenase (1,2-CTD) (

); protocatechuate 3,4-dioxygenase (3,4-PCD) (

); and chlorocatechol 1,2-dioxygenase (

) .
Vasopressin V1B receptor (Vprs_rcpt_V1B)
Type: Family

G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups . The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence . The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) . GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice . Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs .

The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices .

Vasopressin and oxytocin are members of the neurohypophyseal hormone family found in all mammalian species. They are present in high levels in the posterior pituitary. Vasopressin has an essential role in the control of the water content of the body, acting in the kidney to increase water and sodium absorption. In higher concentrations, vasopressin stimulates contraction of vascular smooth muscle, stimulates glycogen breakdown in the liver, induces platelet activation, and evokes release of corticotrophin from the anterior pituitary. Vasopressin and its analogues are used clinically to treat diabetes insipidus.

In the periphery, the V1A receptor is found in high levels in vascular smooth muscle, myometrium and the bladder where it mediates contraction. V1B receptors can be distinguished from V1A receptors by the low affinity of certain antagonists at the former. The receptors stimulate phosphoinositide metabolism and are found in the anterior pituitary.
ATP-dependent RNA helicase DEAD-box, conserved site (RNA-helicase_DEAD-box_CS)
Type: Conserved_site

A number of eukaryotic and prokaryotic proteins involved in ATP-dependent, nucleic-acid unwinding have been characterised on the basis of their structural similarity. All these proteins share a number of conserved sequence motifs. Some of them are specific to this family while others are shared by other ATP-binding proteins or by proteins belonging to the helicases `superfamily'. One of these motifs, called the 'D-E-A-D-box', represents a special version of the B motif of ATP-binding proteins. Proteins currently known to belong to this family include eukaryotic initiation factor eIF-4A; yeast PRP5, PRP28 and MSS116 splicing proteins, and proteins DHH1, DRS1, MAK5 and ROK1; mouse Pl10, Caenorhabditis elegans helicase glh-1; Drosophila Rm62 (p62), Me31B and Vasa; and Escherichia coli putative RNA helicases dbpA, deaD, rhlB and rhlE.
Small ribosomal subunit protein uS8 (Ribosomal_uS8)
Type: Family

This entry includes small ribosomal subunit protein uS8 from bacteria, archaea and eukaryotes (in yeast, these proteins are also known as S22 and in vertebrates S15A) . In Escherichia coli, uS8 is known to bind directly to 16S ribosomal RNA.

Ribosomes are the particles that catalyse mRNA-directed protein synthesis in all organisms. The codons of the mRNA are exposed on the ribosome to allow tRNA binding. This leads to the incorporation of amino acids into the growing polypeptide chain in accordance with the genetic information. Incoming amino acid monomers enter the ribosomal A site in the form of aminoacyl-tRNAs complexed with elongation factor Tu (EF-Tu) and GTP. The growing polypeptide chain, situated in the P site as peptidyl-tRNA, is then transferred to aminoacyl-tRNA and the new peptidyl-tRNA, extended by one residue, is translocated to the P site with the aid the elongation factor G (EF-G) and GTP as the deacylated tRNA is released from the ribosome through one or more exit sites . About 2/3 of the mass of the ribosome consists of RNA and 1/3 of protein. The proteins are named in accordance with the subunit of the ribosome which they belong to the small (S1 to S31) and the large (L1 to L44). Usually they decorate the rRNA cores of the subunits.

Many ribosomal proteins, particularly those of the large subunit, are composed of a globular, surfaced-exposed domain with long finger-like projections that extend into the rRNA core to stabilise its structure. Most of the proteins interact with multiple RNA elements, often from different domains. In the large subunit, about 1/3 of the 23S rRNA nucleotides are at least in van der Waal's contact with protein, and L22 interacts with all six domains of the 23S rRNA. Proteins S4 and S7, which initiate assembly of the 16S rRNA, are located at junctions of five and four RNA helices, respectively. In this way proteins serve to organise and stabilise the rRNA tertiary structure. While the crucial activities of decoding and peptide transfer are RNA based, proteins play an active role in functions that may have evolved to streamline the process of protein synthesis. In addition to their function in the ribosome, many ribosomal proteins have some function 'outside' the ribosome .
ATP/ADP-dependent (S)-NAD(P)H-hydrate dehydratase (CARKD)
Type: Domain

Hydration of NAD(P)H to NAD(P)HX, which inhibits several dehydrogenases, is corrected by an ATP-dependent dehydratase and an epimerase. The ATP-dependent dehydratase has been identified as the product of the vertebrate Carkd (carbohydrate kinase domain) gene . Variants of this enzyme leads to deficient NADHX repair mitochondrial dysfunction in humans, associated with a lethal neurometabolic disorder in early childhood . In E. coli, it is found as the C-terminal domain of a bifunctional enzyme (YjeF) that also includes the epimerase and uses ADP instead of ATP . These enzymes are widespread in eukaryotes, prokaryotes, and archaea.
Vinculin, conserved site (Vinculin_CS)
Type: Conserved_site

Vinculin is a eukaryotic protein that appears to be involved in the attachment of actin-based microfilaments to the plasma membrane . It also interacts with other structural proteins, such as talin and alpha-actinin. The protein is located on the cytoplasmic side of focal contacts or adhesion plaques. Vinculin is a large protein (~1000 residues) that contains an acidic N-terminal domain, separated from a smaller, basic C-terminal domain by a 50-residue proline-rich region . The central part of the N-terminal domain consists of a variable number of repeats of a 110-residue domain, one of which is lacking in nematode vinculin .
Serine/threonine dehydratase, pyridoxal-phosphate-binding site (Ser/Thr_deHydtase_PyrdxlP-BS)
Type: Binding_site

Pyridoxal phosphate is the active form of vitamin B6 (pyridoxine or pyridoxal). Pyridoxal 5'-phosphate (PLP) is a versatile catalyst, acting as a coenzyme in a multitude of reactions, including decarboxylation, deamination and transamination . PLP-dependent enzymes are primarily involved in the biosynthesis of amino acids and amino acid-derived metabolites, but they are also found in the biosynthetic pathways of amino sugars and in the synthesis or catabolism of neurotransmitters; pyridoxal phosphate can also inhibit DNA polymerases and several steroid receptors . Inadequate levels of pyridoxal phosphate in the brain can cause neurological dysfunction, particularly epilepsy .

PLP enzymes exist in their resting state as a Schiff base, the aldehyde group of PLP forming a linkage with the ε-amino group of an active site lysine residue on the enzyme. The α-amino group of the substrate displaces the lysine ε-amino group, in the process forming a new aldimine with the substrate. This aldimine is the common central intermediate for all PLP-catalysed reactions, enzymatic and non-enzymatic .

Serine and threonine dehydratases are functionally and structurally related pyridoxal-phosphate dependent enzymes. L-serine dehydratase (

) and D-serine dehydratase (

) catalyse the dehydratation of L-serine (respectively D-serine) into ammonia and pyruvate. Threonine dehydratase (

) (TDH) catalyses the dehydratation of threonine into alpha-ketobutarate and ammonia. In Escherichia coli and other microorganisms, two classes of TDH are known to exist. One is involved in the biosynthesis of isoleucine, the other in hydroxamino acid catabolism. Threonine synthase (

) is also a pyridoxal-phosphate enzyme, it catalyses the transformation of homoserine-phosphate into threonine. It has been shown that threonine synthase is distantly related to the serine/threonine dehydratases. In all these enzymes, the pyridoxal-phosphate group is attached to a lysine residue.
Viral ssDNA-binding protein (Viral_ssDNA-bd)
Type: Family

This entry includes the major DNA-binding protein (DBP, UL57 or ICP8) from Herpesviruses. DBP binds single-stranded DNA, and the region encompassing residues 368-902 contains the DNA-binding site . UL5, UL8 and UL52 genes encode an essential heterotrimeric DNA helicase-primase that is responsible for concomitant DNA unwinding and primer synthesis at the viral DNA replication fork. DBP may stimulate DNA unwinding and enable bypass of cisplatin damaged DNA by recruiting the helicase-primase to the DNA . DBP helps initiate DNA replication by binding to the origin-binding protein (UL9) . It also reorganizes the host nucleus leading to the formation of prereplicative sites and replication compartments .
HMG-I/HMG-Y, DNA-binding, conserved site (HMGI/Y_DNA-bd_CS)
Type: Conserved_site

High mobility group (HMG) proteins are a family of relatively low molecular weight non-histone components in chromatin . HMG-I and HMG-Y (HMGA) are proteins of about 100 amino acid residues which are produced by the alternative splicing of a single gene. HMG-I/Y proteins bind preferentially to the minor groove of AT-rich regions in double-stranded DNA in a non-sequence specific manner . It is suggested that these proteins could function in nucleosome phasing and in the 3' end processing of mRNA transcripts. They are also involved in the transcription regulation of genes containing, or in close proximity to, AT-rich regions. DNA-binding of these, and several related, proteins is effected by an 11-residue domain known as an AT-hook. Within known HMG-I/Y proteins are found three highly conserved regions, closely related to the consensus sequence TPKRPRGRPKK. A synthetic oligopeptide with this sequence specifically binds to substrate DNA in a manner reminiscent of intact HMG-I/Y proteins. Structure predictions suggest that the peptide has a secondary structure similar to the anti-tumour and anti-viral drugs netropsin and distamycin, and to the dye Hoechst 33258. These ligands, which also preferentially bind to AT-rich DNA, effectively compete with both the synthetic peptide and the HMG-I/Y proteins for DNA binding. The peptide also contains novel structural features such as a predicted Asx bend, or 'hook', at its N terminus, and laterally-projecting cationic Arg/Lys 'bristles', which may play a role in the binding of HMG-I/Y proteins. The predicted peptide structure, the AT-hook, is a previously undescribed DNA-binding motif .