SII-SWORD/CoKE huggingface dataset:
GPCR, family 2, orphan receptor, GPR1/GPR3/GPR5 (GPR1/GPR3/GPR5)
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 secretin-like GPCRs include secretin , calcitonin , parathyroid hormone/parathyroid hormone-related peptides and vasoactive intestinal peptide , all of which activate adenylyl cyclase and the phosphatidyl-inositol-calcium pathway. These receptors contain seven transmembrane regions, in a manner reminiscent of the rhodopsins and other receptors believed to interact with G-proteins (however there is no significant sequence identity between these families, the secretin-like receptors thus bear their own unique '7TM' signature). Their N-terminal is probably located on the extracellular side of the membrane and potentially glycosylated. This N-terminal region contains a long conserved region which allows the binding of large peptidic ligand such as glucagon, secretin, VIP and PACAP; this region contains five conserved cysteines residues which could be involved in disulphide bond. The C-terminal region of these receptor is probably cytoplasmic. Every receptor gene in this family is encoded on multiple exons, and several of these genes are alternatively spliced to yield functionally distinct products.

Several 7TM receptors have been cloned but their endogenous ligands are unknown; these have been termed orphan receptors. GPR1 (formerly GPR56) was isolated from a human heart cDNA library using oligonucleotide primers corresponding to TM domains 4 and 7 of the secretin-like receptor family. The mRNA transcript is widely distributed throughout most tissues, the highest levels being found in thyroid, brain and heart. Within the brain, the hippocampus and hypothalamic nuclei express GPR1 in particularly high levels. This entry also include other orphan receptors, such as human adhesion G-protein coupled receptor G3 and G5 (AGRG3/5).
Protease-activated receptor (Protea_act_rcpt)
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 .

Thrombin is a coagulation protease that activates platelets, leukocytes, endothelial and mesenchymal cells at sites of vascular injury, acting partly through an unusual proteolytically activated GPCR . Gene knockout experiments have provided definitive evidence for a second thrombin receptor in mouse platelets and have suggested tissue-specific roles for different thrombin receptors. Because the physiological agonist at the receptor was originally unknown, it was provisionally named protease-activated receptor (PAR) . At least 4 PAR subtypes have now been characterised. Thus, the thrombin and PAR receptors constitute a fledgling receptor family that shares a novel proteolytic activation mechanism .
Tuberin (Tuberin)
Type: Family

Tuberous sclerosis (TSC) is an autosomal dominant disorder caused by a mutation in either the TSC1 or TSC2 tumour suppressor genes. The disease is characterised by hamartomas in one or more organs (including brain, skin, heart and kidney) giving rise to a broad phenotypic spectrum (including seizures, mental retardation, renal dysfunction and dermatological abnormalities. TSC2 encodes tuberin, a putative GTPase activating protein for rap1 and rab5. The TSC1 gene was recently identified and codes for hamartin, a novel protein with no significant similarity to tuberin or any other known vertebrate protein . Hamartin and tuberin have been shown to associate physically in vivo, their interaction being mediated by predicted coiled-coil domains. It is thought that hamartin and tuberin function in the same complex, rather than in separate pathways. Moreover, because oligomerisation of the hamartin C-terminal coiled coil domain is inhibited by the presence of tuberin, it is possible that tuberin acts as a chaperone, preventing hamartin self-aggregation .

Tuberin is a widely expressed 1784-amino-acid protein. Expression of the wild-type gene in TSC2 mutant tumour cells inhibits proliferation and tumorigenicity. This "suppressor" activity is encoded by a functional domain in the C terminus that shares similarity with the GTPase activating protein Rap1GAP . It is thought that tuberin functions as a Rab5GAP in vivo to negatively regulate Rab5-GTP activity in endocytosis . It also acts as a GTPase-activating protein (GAP) for the small GTPase RheB, a direct activator of the protein kinase activity of mTORC1 .
Rabaptin (Rabaptin)
Type: Family

Rabaptins interact with the GTP form of the small GTPase Rab5, a potent regulator of endocytic transport . Two rabaptins have been identified, rabaptin-5 and rabaptin-5beta. Both proteins bind to Rab5 and cooperate in endocytic membrane fusion .
Polycystic kidney disease type 2 protein (PKD_2)
Type: Family

Polycystic kidney diseases (PKD) are disorders characterised by large numbers of cysts distributed throughout grossly-enlarged kidneys. Cyst
development is associated with impairment of kidney function, and ultimately kidney failure and death . Most cases of autosomal dominant PKD result from mutations in the PKD1 gene that cause premature protein termination. A second gene for autosomal dominant polycystic kidney disease has been identified by positional cloning . The predicted 968-amino acid sequence of the PKD2 gene product (polycystin-2) contains 6 transmembrane domains, with intracellular N- and C-termini. Polycystin-2 shares some similarity with the family of voltage-activated calcium (and sodium) channels, and contains a potential calcium-binding domain .

Polycystin-2 is strongly expressed in ovary, foetal and adult kidney, testis, and small intestine. Polycystin-1 requires the presence of this protein for stable expression and is believed to interact with it via its C terminus. All mutations between exons 1 and 11 result in a truncated polycystin-2 that lacks a calcium-binding EF-hand domain and the cytoplasmic domains required for the interaction of polycystin-2 with polycystin-1 . PKD2, although clinically milder than PKD1, has a deleterious impact on life expectancy.
NADH:ubiquinone oxidoreductase, chain 2 (NADH_UbQ_OxRdtase_chain2)
Type: Family

This entry represents subunit 2 (ND2 or chain 2) from NADH:ubiquinone oxidoreductase (complex I). Defects in the ND2 gene are one of the causes of Leber's hereditary optic neuropathy, a maternally inherited disease resulting in acute bilateral blindness due to retinal degeneration, predominantly in young men . Cardiac conduction defects and neurological defects have also been described, resulting in optic nerve degeneration and cardiac dysrhythmia . The clinical manifestations of this disease are thought to be the product of an overall decrease in mitochondrial energy production, rather than the result of a defect in a specific mitochondrial enzyme . Further research has shown that a point mutation in ND2 is a potential risk factor for Alzheimer's disease .
NADH:ubiquinone oxidoreductase (NADH_UbQ_OxRdtase)
Type: Family

This entry contains members of the subunit families 4, 2 and 5 from complex I.
Cellulose synthase, subunit A (Cell_synth_A)
Type: Family

An operon encoding 4 proteins required for bacterial cellulose biosynthesis (bcs) in Acetobacter xylinus (Gluconacetobacter xylinus) has been isolated via genetic complementation with strains lacking cellulose synthase activity . Nucleotide sequence analysis showed the cellulose synthase operon to consist of 4 genes, designated bcsA, bcsB, bcsC and bcsD, all of which are required for maximal bacterial cellulose synthesis in A. xylinum.

The calculated molecular mass of the protein encoded by bcsA is 84.4kDa . Sequence analysis suggests that the gene product is an integral membrane protein with several transmembrane (TM) domains . It is postulated that the protein is anchored in the membrane at the N-terminal end by a single hydrophobic helix. Two potential N-glycosylation sites are predicted from sequence analysis, consistent with earlier observations that BcsA is a glycoprotein. The function of BcsA is unknown. The sequence shares a high degree of similarity with Escherichia coli YhjO.

Cellulose synthase catalyzes the beta-1,4 polymerisation of glucose residues in the formation of cellulose. In bacteria, the substrate is UDP-glucose. The synthase consists of two subunits (or domains in the frequent cases where it is encoded as a single polypeptide), the catalytic domain modelled here and the regulatory domain (

). The regulatory domain binds the allosteric activator cyclic di-GMP . The protein is membrane-associated and probably assembles into multimers such that the individual cellulose strands can self-assemble into multi-strand fibrils.
Cellulose synthase, subunit B (Cell_synth_B)
Type: Family

An operon encoding 4 proteins required for bacterial cellulose biosynthesis (bcs) in Acetobacter xylinus (Gluconacetobacter xylinus) has been isolated via genetic complementation with strains lacking cellulose synthase activity . Nucleotide sequence analysis showed the cellulose synthase operon to consist of 4 genes, designated bcsA, bcsB, bcsC and bcsD, all of which are required for maximal bacterial cellulose synthesis in A. xylinum.

The calculated molecular mass of the protein encoded by bcsB is 85.3kDa . BcsB encodes the catalytic subunit of cellulose synthase. The protein polymerises uridine 5'-diphosphate glucose to cellulose: UDP-glucose + (1,4-beta-D-glucosyl)(N) = UDP + (1,4-beta-D-glucosyl)(N+1). The enzyme is specifically activated by the nucleotide cyclic diguanylic acid. Sequence analysis suggests that BcsB contains several transmembrane (TM) domains, and shares a high degree of similarity with Escherichia coli YhjN.
Cellulose synthase, subunit C (Cell_synth_C)
Type: Family

An operon encoding 4 proteins required for bacterial cellulose biosynthesis (bcs) in Acetobacter xylinus (Gluconacetobacter xylinus) has been isolated via genetic complementation with strains lacking cellulose synthase activity . Nucleotide sequence analysis showed the cellulose synthase operon to consist of 4 genes, designated bcsA, bcsB, bcsC and bcsD, all of which are required for maximal bacterial cellulose synthesis in A. xylinum.

The calculated molecular mass of the protein encoded by bcsC is 141.0kDa . The function of BcsC is unknown. The sequence shares a high degree of similarity with Escherichia coli YhjL.
Transcription initiation factor TFIID, subunit 10 (TAF10)
Type: Family

Transcription initiation factor TFIID is a multimeric protein complex that plays a central role in mediating promoter responses to various activators and repressors. The complex includes TATA binding protein (TBP) and various TBP-associated factors (TAFS). TFIID is a bona fide RNA polymerase II-specific TATA-binding protein-associated factor (TAF) and is essential for viability . This entry represents one of the TAFs, TAF10.

TFIID acts to nucleate the transcription complex, recruiting the rest of the factors through a direct interaction with TFIIB. The TBP subunit of TFIID is sufficient for TATA-element binding and TFIIB interaction, and can support basal transcription. The protein belongs to the TAF2H family.

TAF10 is part of other transcription regulatory multiprotein complexes (e.g., SAGA, TBP-free TAF-containing complex [TFTC], STAGA, and PCAF/GCN5). Several TAFs interact via histone-fold motifs. The histone fold (HFD) is the interaction motif involved in heterodimerization of the core histones and their assembly into nucleosome octamer. The minimal HFD contains three α-helices linked by two loops. The HFD is found in core histones, TAFs and many other transcription factors. Five HF-containing TAF pairs have been described in TFIID: TAF6-TAF9, TAF4-TAF12, TAF11-TAF13, TAF8-TAF10 and TAF3-TAF10 .
Claudin-6 (Claudin6)
Type: Family

Claudins form the paracellular tight junction seal in epithelial tissues. In humans, 24 claudins (claudin 1-24) have been identified. Their ability to polymerise and form strands is affected by the cell types . They can also form heteropolymers with each other within and between tight junction strands . Most of the claudins (claudin-12 being the exception) have a C-terminal PDZ-binding motif that can interact with other PDZ domain proteins, such as scaffolding protein, ZO-1, -2 and -3 . They also interact with non-tight junction proteins, such as cell adhesion proteins EpCam and tetraspanins and the signaling proteins, ephrin A and B and their receptors, EphA and EphB .

Claudin-6 was identified through searching expressed sequence tag (EST)
databases for sequences similar to claudin-1 and -2 . It was subsequently cloned and expressed in cells, where it was shown to concentrate at tight junctions. Human and mouse isoforms have been identified. Claudin-6 shares ~25-70% overall similarity with other claudin family members at the amino acid level, displaying highest similarity to claudin-9.
Claudin-16 (Claudin16)
Type: Family

Claudins form the paracellular tight junction seal in epithelial tissues. In humans, 24 claudins (claudin 1-24) have been identified. Their ability to polymerise and form strands is affected by the cell types . They can also form heteropolymers with each other within and between tight junction strands . Most of the claudins (claudin-12 being the exception) have a C-terminal PDZ-binding motif that can interact with other PDZ domain proteins, such as scaffolding protein, ZO-1, -2 and -3 . They also interact with non-tight junction proteins, such as cell adhesion proteins EpCam and tetraspanins and the signaling proteins, ephrin A and B and their receptors, EphA and EphB .

Claudin-16 was originally termed paracellin-1. It was re-classified as claudin-16 on the basis of its sequence similarity to the claudin family . Claudin-16 is involved in renal paracellular Mg2+ resorption and is required for selective paracellular conductance . Defects in the claudin-16 gene are associated with an autosomal recessive chronic interstitial nephritis with diffuse zonal fibrosis (CINF) .
Claudin-18 (Claudin18)
Type: Family

Claudins form the paracellular tight junction seal in epithelial tissues. In humans, 24 claudins (claudin 1-24) have been identified. Their ability to polymerise and form strands is affected by the cell types . They can also form heteropolymers with each other within and between tight junction strands . Most of the claudins (claudin-12 being the exception) have a C-terminal PDZ-binding motif that can interact with other PDZ domain proteins, such as scaffolding protein, ZO-1, -2 and -3 . They also interact with non-tight junction proteins, such as cell adhesion proteins EpCam and tetraspanins and the signaling proteins, ephrin A and B and their receptors, EphA and EphB .

Human and mouse isoforms of claudin-18 have been cloned. Claudin-18 shares ~22-40% overall similarity with other claudin family members at the amino acid level, displaying highest similarity to claudin-1.
Epithelial membrane protein EMP-1 (EMP_1)
Type: Family

The epithelial membrane proteins (EMP-1, -2 and -3), peripheral myelin protein 22 (PMP22), and lens fibre membrane intrinsic protein (LMIP) comprise a protein family on the basis of sequence and structural similarities . Each family member is a small hydrophobic membrane glycoprotein, ~160-170 amino acids in length, and shares a common predicted transmembrane (TM) topology of 4 TM domains, with intracellular N- and C-termini .

EMP-1, previously termed tumour-associated membrane protein (TMP), was originally isolated from a mouse brain tumour . Human, rat and rabbit isoforms have also been identified. EMP-1 is expressed in a wide range of tissues, including heart, placenta, lung, skeletal muscle, kidney and small intestine . A role for the protein in the control of cell growth has been suggested . EMP-1 is expressed at high levels in proliferating cells, and at reduced levels in cells undergoing growth arrest . In contrast, PMP22, which is co-expressed with EMP-1 in a range of tissues, displays an inverse pattern of regulation, with high levels of expression in cultured cells undergoing growth arrest . It has therefore been proposed that these proteins may have reciprocal functions in the control of cell quiescence and proliferation.
Epithelial membrane protein 2 (EMP-2)
Type: Family

The epithelial membrane proteins (EMP-1, -2 and -3), peripheral myelin protein 22 (PMP22), and lens fibre membrane intrinsic protein (LMIP) comprise a protein family on the basis of sequence and structural similarities . Each family member is a small hydrophobic membrane glycoprotein, ~160-170 amino acids in length, and shares a common predicted transmembrane (TM) topology of 4 TM domains, with intracellular N- and C-termini .

A role for the EMP family members in the control of cell growth has been suggested . EMP-1 is expressed at high levels in proliferating cells, and at reduced levels in cells undergoing growth arrest . In contrast, PMP22, which is co-expressed with EMP-1 in a range of tissues, displays an inverse pattern of regulation, with high levels of expression in cultured cells undergoing growth arrest . It has therefore been proposed that these proteins may have reciprocal functions in the control of cell quiescence and proliferation.

EMP-2, previously termed XMP, was identified by expressed sequence tag (EST) database searching, pursuing sequences similar to EMP-1 . Mus musculus (Mouse) and Homo sapiens (Human) isoforms have been cloned. EMP-2 is expressed in a range of tissues, including ovary, heart, lung and intestine. Although its function has not been elucidated, it has been postulated that EMP-2 may be involved in the regulation of cell proliferation on the basis of its sequence similarity to EMP-1 .
Epithelial membrane protein EMP-3 (EMP_3)
Type: Family

The epithelial membrane proteins (EMP-1, -2 and -3), peripheral myelin protein 22 (PMP22), and lens fibre membrane intrinsic protein (LMIP) comprise a protein family on the basis of sequence and structural similarities . Each family member is a small hydrophobic membrane glycoprotein, ~160-170 amino acids in length, and shares a common predicted transmembrane (TM) topology of 4 TM domains, with intracellular N- and C-termini .

A role for the EMP family members in the control of cell growth has been suggested . EMP-1 is expressed at high levels in proliferating cells, and at reduced levels in cells undergoing growth arrest . In contrast, PMP22, which is co-expressed with EMP-1 in a range of tissues, displays an inverse pattern of regulation, with high levels of expression in cultured cells undergoing growth arrest . It has therefore been proposed that these proteins may have reciprocal functions in the control of cell quiescence and proliferation.

EMP-3, previously termed YMP, was identified by expressed sequence tag (EST) database searching, pursuing sequences similar to EMP-1 . Mouse, human and rat isoforms have been cloned. EMP-3 is expressed in a range of tissues, including peripheral blood leukocytes, ovary and intestine. Although its function has not been elucidated, it has been postulated that EMP-3 may be involved in the regulation of cell proliferation on the basis of its sequence similarity to EMP-1 .
Lens fibre membrane intrinsic protein (LMIP)
Type: Family

The epithelial membrane proteins (EMP-1, -2 and -3), peripheral myelin protein 22 (PMP22), and lens fibre membrane intrinsic protein (LMIP) comprise a protein family on the basis of sequence and structural similarities . Each family member is a small hydrophobic membrane glycoprotein, ~160-170 amino acids in length, and shares a common predicted transmembrane (TM) topology of 4 TM domains, with intracellular N- and C-termini .

LMIP, previously termed MP17, MP18, MP19 and MP20, is expressed at extremely high levels in the mammalian eye lens, where it is localised to the thicker (16-17nm) cell membrane junctions . Although its function has not been elucidated, it has been shown to co-localise with connexin-46, suggesting that it may be involved in the organisation of junctional plaques . A role for LMIP in signal transduction has also been proposed, as it is phosphorylated by cAMP-dependent kinase and binds calmodulin .