SII-SWORD/CoKE huggingface dataset:
Neutral amino acid SLC6 transporter (Neutral_aa_SLC6)
Type: Family

Solute carrier 6 (SLC6) transporters are part of the neurotransmitter:sodium symporters family. This entry represents a group of neutral amino acid SLC6 transporters that includes B0AT1 (SLC6A19), B0AT3 (SLC6A18), B0AT2 (SLC6A15), NTT4/XT1 (SLC6A17) and XTRP3/XT3 (SLC6A20) . B0AT1 (SLC6A19) catalyzes the secondary active transport of neutral amino acids across the apical membrane in the small intestine and kidney, whereas B0AT3 (SLC6A18) is found only in the kidney . Human B0AT3 is an inactive protein, which explains the absence of glycinuria in humans with homozygous nonsense mutations in B0AT3. Mouse B0AT3 requires collectrin both for trafficking of the transporter to the cell surface and for the catalytic activity .
Glucose transporter, type 1 (GLUT1) (Glu_transpt_1)
Type: Family

Facilitative sugar transport is mediated by members of the GLUT transporter family, which form an aqueous pore across the membrane through which sugars can move in a passive (i.e., energy-independent) manner. The GLUT family of glycosylated transmembrane proteins are predicted to span the membrane 12 times with both amino- and carboxyl-termini located in the cytosol. On the basis of sequence homology and structural similarity, three subclasses of sugar transporters have been defined: Class I (GLUTs 1-4) are glucose transporters; Class II (GLUTs 5, 7, 9 and 11) are fructose transporters; and Class III (GLUTs 6, 8, 10, 12 and HMIT1) are structurally atypical members of the GLUT family, which are poorly defined at present, indeed GLUT6 may only be a pseudo-gene .

This entry represents GLUT1 (also called HepG2), which is the most ubiquitously distributed of the glucose transporter isoform. It is highly expressed in foetal tissues and adult brain microvessels. It is thought to provide glucose transport in various cells that form barriers between body tissues and the blood supply. It is found in epithelial and endothelial barrier cells, such as those that constitute the blood-brain barrier, and also in the placenta.
Solute carrier family 12 member 1/2 (SLC12A1/SLC12A2)
Type: Family

The Na-K-Cl co-transporters are a family of integral membrane proteins that are ubiquitously expressed in animal tissues, serving a variety of
functions. In cells of Cl
-
absorptive and Cl
-
secretory epithelia, Na-K-Cl co-transport serves as the major Cl
-
entry pathway, and functions in concert with other membrane ion channels and pumps to carry out net transepithelial movement of salt. This vectorial transport of Cl
-
across epithelia is involved in the reabsorption of salt in the vertebrate kidney (which is crucial for urinary concentration), and in the secretion of salt in such tissues as the mammalian intestine and trachea. In addition, Na-K-Cl co-transport is known to play a role in cell volume regulation in most mammalian cell types. The proteins mediate the coupled, electroneutral transport of sodium, potassium and chloride ions across the plasma membrane of cells (with a stoichiometry of 1:1:2, respectively). Co-transport of all three ions is obligatory, since absence of one is sufficient to prevent ion movement. Their transport activity does not alter the cell's membrane potential, thus the driving force for the transport is determined solely by the chemical gradients of the three transported ions; hence, under normal physiological conditions, the direction will be inward.

Recent molecular studies have identified two distinct isoforms: one from Cl
-
secretory epithelia, NKCC1 (SLC12A2); and another, NKCC2 (SLC12A1), found specifically in the diluting segment of the vertebrate kidney, a Cl
-
absorptive epithelium . They show lowish amino acid sequence identity (~58%); nevertheless, they have rather similar hydropathy profiles, with hydrophilic N- and C-termini, flanking a central hydrophobic domain. Their N-termini show considerable variation, unlike the central domain (containing the 12 putative transmembrane (TM) domains) and their C-termini, which are well conserved (~70%). Both isoforms are known to be glycosylated and, consistent with this, consensus sites for N-linked glycosylation are located within the large hydrophilic loop between presumed TM domains 7 and 8. Sequence comparisons with other cloned ion co-transporters reveals that Na-K-Cl co-transporters belong to a superfamily of electroneutral cation-chloride
co-transporters, which includes the K-Cl co-transporter (

) and the thiazide-sensitive Na-Cl co-transporter. All share a similar predicted membrane topology of 12 TM regions in a central hydrophobic domain, together with hydrophilic N- and C-termini that are likely cytoplasmic. The structure from NKCC1 revealed that it forms a dimer; the first TM helices harbor the transport core and TM11-TM12 are lining the dimer interface. Helices from TM1 and TM6 break α-helical geometry halfway across the lipid bilayer where ion binding sites are organized around these discontinuous regions .

Mutations in the gene encoding the renal-specific isoform of the Na-K-Cl co-transporter (NKCC2) give rise to Bartter's Syndrome Type 1, an inherited kidney disease characterised by hypokalaemia, metabolic alkalosis, salt-wasting and hypotension .
Beta-lactoglobulin (Blactoglobulin)
Type: Family

Beta-lactoglobulin (Blg) is the major protein component of milk from a wide range of species but not human. Glycodelin or PP14 protein is the human equivalent of Blg and is secreted into the endometrium. Blg binds a wide variety of hydrophobic ligands but its function remains unknown. The crystal structure of Blg has been solved , confirming membership of the lipocalin protein family.

This entry also includes human glycodelin. It has four glycoforms, namely glycodelin-S, -A, -F and -C have been identified in reproductive tissues that differ in glycosylation and biological activity. Glycodelin-A has contraceptive and immunosuppressive activities . Glycodelin-C stimulates binding of spermatozoa to the zona pellucida . Glycodelin-F inhibits spermatozoa-zona pellucida binding and significantly suppresses progesterone-induced acrosome reaction of spermatozoa . Glycodelin-S in seminal plasma maintains the uncapacitated state of human spermatozoa .

The lipocalins are a diverse, interesting, yet poorly understood family of proteins composed, in the main, of extracellular ligand-binding proteins displaying high specificity for small hydrophobic molecules . Functions of these proteins include transport of nutrients, control of cell regulation, pheromone transport, cryptic colouration and the enzymatic synthesis of prostaglandins.

The crystal structures of several lipocalins have been solved and show a novel 8-stranded anti-parallel β-barrel fold well conserved within the family. Sequence similarity within the family is at a much lower level and would seem to be restricted to conserved disulphides and 3 motifs, which form a juxtaposed cluster that may act as a common cell surface receptor site . By contrast, at the more variable end of the fold are found an internal ligand binding site and a putative surface for the formation of macromolecular complexes . The anti-parallel β-barrel fold is also exploited by the fatty acid-binding proteins (which function similarly by binding small hydrophobic molecules), by avidin and the closely related metalloprotease inhibitors, and by triabin. Similarity at the sequence level, however, is less obvious, being confined to a single short N-terminal motif. The lipocalin family can be subdivided into kernal and outlier sets. The kernal lipocalins form the largest self consistent group, comprising the subfamily of beta-lactoglobulins. The outlier lipocalins form several smaller distinct subgroups: the OBPs, the von Ebner's gland proteins, alpha-1-acid glycoproteins, tick histamine binding proteins and the nitrophorins.
Retinol binding protein/Purpurin (Retinol-bd/Purpurin)
Type: Family

Proteins in this family include plasma retinol binding protein (pRBP) and purpurin. They mediate retinol transport in blood plasma . Binding to RBP allows the hydrophobic vitamin to circulate in blood, but retinol dissociates from the protein prior to entering target cells .

Retinol circulates in the plasma without significant loss because it is bound to pRBP. This protein is synthesized primarily in the liver, where it requires the binding of retinol to trigger its secretion . In mammals, pRBP binds to transthyretin in the plasma, preventing the loss of pRBP through glomerular filtration . It has been suggested that a surface cell receptor would recognise the retinol-pRBP-transthyretin complex and, in that way, retinol would be delivered into the cell. However, such a protein remains to be identified. In fish, no transthyretin homologue has been found, though fish pRBP is capable of binding mammalian transthyretin . In Cyprinus carpio, pRBP is N-glycosylated and it has been suggested that pRBP filtration through kidney glomeruli may be reduced by a glycosylation-dependent increase in the molecular size and negative charge of the protein, since kidney filtration of anionic proteins is less than half that of neutral protein of the same size .

The role of pRBP in retinol transport enables it to fulfill a number of physiological functions:1) it facilitates the transfer of insoluble retinol between tissues, principally transport from storage sites in the liver to peripheral tissues, 2) pRBP protects bound retinol from oxidation and tissues from the indiscriminate distribution of such a biologically active molecule, 3) the synthesis of pRBP regulates retinol release from the liver and mediates the specificity of its uptake by target cells, and 4) pRBP is believed to have an important role in the transfer of retinol from maternal circulation to the developing fetus in mammals .

Purpurin is a constituent of adherons, high molecular weight glycoprotein complexes that are released into the growth medium of cultured cells. Adherons mediate the adhesive interactions of many cell types, including those of embryonic chick neural retina. Purpurin promotes cell-adheron adhesion by interacting with a cell surface heparan sulphate proteoglycan. It also prolongs the survival of cultured neural retina cells . It is located almost exclusively in the neural cells of the retina , and it is synthesised in photoreceptor cells before incorporation into the extracellular matrix . The role of purpurin as a trophic factor, mediating both cell adhesion and survival, seems clear but it may also have a subsidiary role as a minor retinol transporter in the retina based on its retinol binding capacity . pRBP is also able to stimulate the adhesion of neural retina cells, although the serum protein is less active than purpurin .

Structural notes: This subgroup shares a common β-barrel fold with the parent group. See

for a detailed description.
von Ebner's gland protein/ Bos/Can allergen (von_Ebner_gland)
Type: Family

Von Ebner's gland protein (VEGP), a protein highly expressed by the small acinar von Ebner's salivary glands of the tongue, but not in the secretory duct, undertakes the selective binding of sapid chemicals and their transport to taste receptors in salivary secretions. VEGP can help to clear the bitter-tasting compound denatonium benzoate
in vivo
, suggesting a possible clearance function in taste reception, although it fails to bind other bitter compounds . VEGP is also secreted by the lachrymal gland into tear fluid, where, historically, it has been called tear prealbumin . Together with lysozyme and lactoferrin, VEGP forms 70-80% of total tear protein, although diseases affecting the lachrymal gland decrease this. Tear VEGP has been suggested to enhance the bactericial activity of lysozyme and to have an anti-microbial function, perhaps through transported compounds with anti-bacterial properties . VEGP has been shown to bind retinol , and can be co-extracted with fatty acids, particularly stearate and palmitate, phospholipids, glycolipids and fatty alcohols (including cholesterol) . VEGP may act as a transporter of lipids, synthesised in the dorsal, or meibomian, glands of the eyelid, to the thin film they form at the tear-fluid/air interface. Recently, two lipocalins, specifically expressed in the posterior and vomeronasal glands of the mouse nasal septum, have been identified and were suggested to act in the chemoreception of, as yet-unidentified, small lipophilic pheromones . One of these proteins was immunolocalised on the vomeronasal sensory epithelium, the site of primary pheromone reception, and the immunoreactivity was greatest during periods when contact between animals plays an important role in modulating behaviour. Canis familiaris (dog) allergen 1 (Can f1) is the major allergen present in dog dander and is produced by tongue epithelial tissue .
Alpha tubulin (Alpha_tubulin)
Type: Family

Microtubules are polymers of tubulin, a dimer of two 55kDa subunits, designated alpha and beta . Within the microtubule lattice, α-β heterodimers associate in a head-to-tail fashion, giving rise to microtubule polarity. Fluorescent labelling studies have suggested that tubulin is oriented in microtubules with beta-tubulin toward the plus end . For maximal rate and extent of polymerisation into microtubules, tubulin requires GTP. Two molecules of GTP are bound at different sites, termed N and E. At the E (Exchangeable) site, GTP is hydrolysed during incorporation into the microtubule. Close to the E site is an invariant region rich in glycine residues, which is found in both chains and is thought to control access of the nucleotide to its binding site .
Beta tubulin (Beta_tubulin)
Type: Family

Microtubules are polymers of tubulin, a dimer of two 55kDa subunits, designated alpha and beta . Within the microtubule lattice, α-β heterodimers associate in a head-to-tail fashion, giving rise to microtubule polarity. Fluorescent labelling studies have suggested that tubulin is oriented in microtubules with beta-tubulin toward the plus end . For maximal rate and extent of polymerisation into microtubules, tubulin requires GTP. Two molecules of GTP are bound at different sites, termed N and E. At the E (Exchangeable) site, GTP is hydrolysed during incorporation into the microtubule. Close to the E site is an invariant region rich in glycine residues, which is found in both chains and is thought to control access of the nucleotide to its binding site .

Most species, excepting simple eukaryotes, express a variety of closely related alpha- and beta-isotypes. A third family member, gamma tubulin, has also been identified in a number of species .

British type familial amyloidosis is an autosomal dominant disease characterised by progressive dementia, spastic paralysis and ataxia. Amyloid deposits from the brain tissue of an individual who died with this disease have been characterised. Trypsin digestion and subsequent N-terminal sequence analysis yielded a number of short sequences, all of which are tryptic fragments of the C-termini of human alpha- and beta-tubulin . Consistent with the definition of amyloid, synthetic peptides based on the sequences of these fragments formed fibrils in vitro, suggesting that the C-termini of both alpha- and beta-tubulin are closely associated with the amyloid deposits of this type of amyloidosis .

This entry represents beta tubulin.
Gamma tubulin (Gamma_tubulin)
Type: Family

Gamma-tubulins constitute a ubiquitous and highly-conserved subfamily of the tubulin family. Gamma is a low abundance protein present within the cells in both various types of microtubule-organizing centers and cytoplasmic protein complexes. The protein recruits the alpha/beta-tubulin dimers that form the minus ends of microtubules and is found at microtubule organising centres (MTOC) such as the spindle poles or the centrosome, suggesting that it is involved in the microtubule nucleation . It exists in two main protein complexes: gamma-tubulin ring complexes (gamma-TuRCs) and the the gamma-tubulin small complex (gamma-TuSC) .
GPCR family 3, GABA-B receptor (GPCR3_GABA-B)
Type: Family

GPCR family 3 receptors (also known as family C) are structurally similar to other GPCRs, but do not show any significant sequence similarity and thus represent a distinct group. Structurally they are composed of four elements; an N-terminal signal sequence; a large hydrophilic extracellular agonist-binding region containing several conserved cysteine residues which could be involved in disulphide bonds; a shorter region containing seven transmembrane domains; and a C-terminal cytoplasmic domain of variable length . Family 3 members include the metabotropic glutamate receptors, the extracellular calcium-sensing receptors, the gamma-amino-butyric acid (GABA) type B receptors, and the vomeronasal type-2 receptors . As these receptors regulate many important physiological processes they are potentially promising targets for drug development.

GABA is the principal inhibitory neurotransmitter in the brain, and signals through ionotropic (type A and type C) and metabotropic (type B) receptor systems. The type B receptors have been cloned, and photoaffinity labelling experiments suggest that they correspond to two highly conserved receptor forms in the vertebrate nervous system . These receptors are involved in the fine tuning of inhibitory synaptic transmission . Presynaptic receptors inhibit neurotransmitter release by down-regulating high-voltage activated calcium channels, while postsynaptic receptors decrease neuronal excitability by activating a prominent inwardly rectifying potassium (Kir) conductance that underlies the late inhibitory postsynaptic potentials . The type B receptors negatively couple to adenylyl cyclase and show sequence similarity to the metabotropic receptors for the excitatory neurotransmitter L-glutamate. The physiological form of the B receptor is a heterodimer of the B1 and B2 subtypes, in which B1 seems to bind agonists, while B2 mediates coupling to G proteins .

This entry includes GPR156, a class C orphan GPCR that regulates hair cell orientation, which is important for capturing sound in the cochlea, balancing movements in vestibular organs and sensing water movements in the fish lateral line, and it also plays a role in lipid metabolism . Unlike GABR1/2, it lacks role the extracellular and exhibits constitutive activity .

Metabotropic glutamate receptor-like proteins (Grl) are similar in structure to GABA-B receptors and belong to the same receptor family .
GPCR family 3, gamma-aminobutyric acid receptor, type B1 (GPCR_3_GABA_rcpt_B1)
Type: Family

GPCR family 3 receptors (also known as family C) are structurally similar to other GPCRs, but do not show any significant sequence similarity and thus represent a distinct group. Structurally they are composed of four elements; an N-terminal signal sequence; a large hydrophilic extracellular agonist-binding region containing several conserved cysteine residues which could be involved in disulphide bonds; a shorter region containing seven transmembrane domains; and a C-terminal cytoplasmic domain of variable length . Family 3 members include the metabotropic glutamate receptors, the extracellular calcium-sensing receptors, the gamma-amino-butyric acid (GABA) type B receptors, and the vomeronasal type-2 receptors . As these receptors regulate many important physiological processes they are potentially promising targets for drug development.

GABA is the principal inhibitory neurotransmitter in the brain, and signals through ionotropic (type A and type C) and metabotropic (type B) receptor systems. The type B receptors have been cloned, and photoaffinity labelling experiments suggest that they correspond to two highly conserved receptor forms in the vertebrate nervous system . These receptors are involved in the fine tuning of inhibitory synaptic transmission . Presynaptic receptors inhibit neurotransmitter release by down-regulating high-voltage activated calcium channels, while postsynaptic receptors decrease neuronal excitability by activating a prominent inwardly rectifying potassium (Kir) conductance that underlies the late inhibitory postsynaptic potentials . The type B receptors negatively couple to adenylyl cyclase and show sequence similarity to the metabotropic receptors for the excitatory neurotransmitter L-glutamate. The physiological form of the B receptor may be a heterodimer of the B1 and B2 subtypes .

Neurophysiological and pharmacological studies point to a major role of the
GABA type B receptor in the epileptogenesis of absence seizures . Using in situ hybridisation, the gene encoding the human GABA type B1 receptor has been mapped to chromosome 6p21.3, in the vicinity of a susceptibility locus (EJM1) for idiopathic generalised epilepsies, identifying a candidate gene for inherited forms of epilepsy .

The metabotropic glutamate receptor-like protein E from Dictyostelium discoideum, which is probably a receptor for GABA and glutamate, is also included in this entry .
GPCR family 3, gamma-aminobutyric acid receptor, type B2 (GPCR_3_GABA_rcpt_B2)
Type: Family

GPCR family 3 receptors (also known as family C) are structurally similar to other GPCRs, but do not show any significant sequence similarity and thus represent a distinct group. Structurally they are composed of four elements; an N-terminal signal sequence; a large hydrophilic extracellular agonist-binding region containing several conserved cysteine residues which could be involved in disulphide bonds; a shorter region containing seven transmembrane domains; and a C-terminal cytoplasmic domain of variable length . Family 3 members include the metabotropic glutamate receptors, the extracellular calcium-sensing receptors, the gamma-amino-butyric acid (GABA) type B receptors, and the vomeronasal type-2 receptors . As these receptors regulate many important physiological processes they are potentially promising targets for drug development.

GABA is the principal inhibitory neurotransmitter in the brain, and signals through ionotropic (type A and type C) and metabotropic (type B) receptor systems. The type B receptors have been cloned, and photoaffinity labelling experiments suggest that they correspond to two highly conserved receptor forms in the vertebrate nervous system . These receptors are involved in the fine tuning of inhibitory synaptic transmission . Presynaptic receptors inhibit neurotransmitter release by down-regulating high-voltage activated calcium channels, while postsynaptic receptors decrease neuronal excitability by activating a prominent inwardly rectifying potassium (Kir) conductance that underlies the late inhibitory postsynaptic potentials . The type B receptors negatively couple to adenylyl cyclase and show sequence similarity to the metabotropic receptors for the excitatory neurotransmitter L-glutamate. The physiological form of the B receptor may be a heterodimer of the B1 and B2 subtypes .

A new subtype of the type B receptor (type B2) has been identified by EST database mining . Yeast two-hybrid screening has shown that the new subtype forms heterodimers with GABA subtype B1 via an interaction at their intracellular C-terminal tails. On expression with B2 in HEK293T cells, B1 is terminally glycosylated and expressed at the cell surface. Co-expression of the receptors produces a fully functional type B receptor at the cell surface; this receptor binds GABA with a high affinity equivalent to that of the endogenous brain receptor . Such results indicate that,
in vivo
, functional brain GABA(B) receptors may be heterodimers of the B1 and B2 subtypes.