SII-SWORD/CoKE huggingface dataset:
Voltage gated sodium channel, alpha-8 subunit (Na_channel_a8su)
Type: Family

Voltage-dependent sodium channels are transmembrane (TM) proteins responsible for the depolarising phase of the action potential in most
electrically excitable cells . They may exist in 3 states : the resting state, where the channel is closed; the activated state, where the channel is open; and the inactivated state, where the channel is closed and refractory to opening. Several different structurally and functionally distinct isoforms are found in mammals, coded for by a multigene family, these being responsible for the different types of sodium ion currents found in excitable tissues.

There are nine pore-forming alpha subunit of voltage-gated sodium channels consisting of four membrane-embedded homologous domains (I-IV), each consisting of six α-helical segments (S1-S6), three cytoplasmic loops connecting the domains, and a cytoplasmic C-terminal tail. The S6 segments of the four domains form the inner surface of the pore, while the S4 segments bear clusters of basic residues that constitute the channel's voltage sensors .

Sodium channel protein type 8 subunit alpha (SCN8A) encodes the voltage-gated Na+ channel alpha 8 subunit and is strongly expressed in Purkinje cells. Sodium currents are known to generate the rising phase and the prolonged plateau phase of cerebellar purkinje cell action potentials. Experiments in mice with mutated SCN8A subunits suggest its involvement in the persistent sodium current responsible for the prolonged plateau phase . SCN8A is abundantly expressed throughout the CNS and in the spinal cord. Mutations in this protein have been related to a number of neurological disorders, including paralysis, ataxia and dystonia .

This entry represents a conserved region found towards the N terminus of the protein, which defines the alpha 8 subunits and distinguishes them from other members of the voltage-gated Na+ channel superfamily. For entries containing other members of this superfamily see

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.
Neurotensin/neuromedin N (NeurotensiN)
Type: Family

Neurotensin is a 13-residue peptide transmitter, sharing significant similarity in its 6 C-terminal amino acid residues with several other neuropeptides, including neuromedin N (which is derived from the same precursor). This C-terminal region is responsible for the full biological activity, the N-terminal portion having a modulatory role.

Neurotensin is distributed throughout the central nervous system, with highest levels in the hypothalamus, amygdala and nucleus accumbens. It induces a variety of effects, including: analgesia, hypothermia and increased locomotor activity. It is also involved in regulation of dopamine pathways. In the periphery, neurotensin is found in endocrine cells of the small intestine, where it leads to secretion and smooth muscle contraction . The neurotensin/neuromedin N precursor can also be processed to produce large 125-138 amino acid peptides with the neurotensin or neuromedin N sequence at their C terminus. These large peptides appear to be less potent than their smaller counterparts, but are also less sensitive to degradation and may represent endogenous, long-lasting activators in a number of pathophysiological situations.
Tapasin (Tapasin)
Type: Family

Major histocompatibility complex (MHC) class I molecules present antigenic peptides to CD8 T cells. The majority of peptides found associated with class I molecules are derived from nuclear and cytosolic proteins, and they are generated largely by the proteasome complex. These peptides are transported from cytosol into the lumen of the endoplasmic reticulum (ER) by a peptide transporter, which is known as the transporter associated with antigen processing (TAP). TAP is a trimeric complex consisting of TAP1, TAP2 and tapasin (TAP-A). TAP1 and TAP2 are required for peptide transport. Tapasin, which actually serves as a docking site on the TAP complex specific for interaction with class I MHC molecules, is essential for peptide loading (up to four MHC class I-tapasin complexes have been found to bind to each TAP molecule). However, since the exact mechanisms of tapasin functions are still unknown, it has also been speculated that tapasin may regulate the MHC class I release from the ER rather than directly loading peptides onto MHC class I molecules .

In studies of the interaction between MHC class I and TAP, it was found that TAP1, but not TAP2, is required for the association of TAP with class I molecules. Because tapasin is essential for the association of MHC class I to TAP, tapasin may directly interact with TAP1. Thus the predicted order of interaction between different molecules in the TAP complex is TAP2 to TAP1, TAP1 to tapasin, and tapasin to MHC class I molecules. Thus, by these linked events, the translocation and loading of peptides rapidly and efficiently proceed in the same microenvironment .

Tapasin is a type I transmembrane (TM) glycoprotein with a double lysine motif that is thought to be involved with mediating the retrieval of proteins back from the cis-Golgi, thus maintaining membrane proteins in the ER . It is encoded by an MHC-linked gene and is a member of the immunoglobulin superfamily. Binding to TAP is mediated by the C-terminal region, whereas its N-terminal 50 residues constitute the key element that converts the MHC class I molecules and TAP weak interactions into a stable complex .
Inward rectifier potassium channel 13 (KCNJ13)
Type: Family

Inward rectifier potassium channels are characterised by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. Inward rectifier potassium channel 13 (KCNJ13) has a very low single channel conductance, low sensitivity to block by external barium and cesium, and no dependence of its inward rectification properties on the internal blocking particle magnesium.
Fas receptor (Fas_rcpt)
Type: Family

Like all apoptotic cell death, T cell receptor (TCR)-mediated death can be divided into two phases: an inductive phase and an effector phase. The effector phase includes a sequence of steps that are common to apoptosis in many cell types, which, if not interrupted, will lead to cell death. The induction phase, which often requires the expression of new genes, consists of a set of signals that activate the effector phase. Outside the thymus, most, if not all, of the TCR-mediated apoptosis of mature T cells (sometimes referred to as activation-induced cell death (AICD)) is induced through the surface antigen Fas pathway: activation through the TCR induces expression of the Fas (CD95) ligand (FasL); the expression of FasL on either a neighbouring cell, or on the Fas-bearing cell, induces trimerisation of Fas, which then initiates a signal-transduction cascade, leading to apoptosis of the Fas-bearing cell. This commitment stage requires the activation of key death-inducing enzymes, termed caspases, which act by cleaving proteins that are essential for cell survival and proliferation .

Fas is also known to be essential in the death of hyperactivated peripheral CD4+ cells: in the absence of Fas, mature peripheral T cells do not die, but the activated cells continue to proliferate, producing cytokines that lead to grossly enlarged lymph nodes and spleen. Fas belongs to the tumour necrosis factor receptor (TNFR) family of cysteine-rich type I membrane receptors; its ligand (FasL) is expressed on activated lymphocytes, NK cells, platelets, certain immune-privileged cells and some tumour cells .

Defects in the Fas-FasL system are associated with various disease syndromes. Mice with non-functional Fas or FasL display characteristics of lympho-proliferative disorder, such as lymphadenopathy, splenomegaly, and elevated secretion of IgM and IgG. These mice also secrete anti-DNA autoantibodies and rheumatoid factor .
Pro-FMRFamide-related neuropeptide FF (NPFF)
Type: Family

Neuropeptide FF (together with neuropeptides AF and SF, which are derived from the same precursor) belongs to a family of neuropeptides containing an RF-amide motif at their C-termini . Neuropeptide FF is found at high concentrations in the posterior pituitary, spinal cord, hypothalamus and medulla, and is believed to be involved in pain modulation, opioid tolerance, cardiovascular regulation, memory and neuroendocrine regulation.
Potassium channel subfamily K member 15 (TASK5)
Type: Family

TASK is a member of the TWIK-related (two P-domain) K
+
channel family identified in human tissues . It is widely distributed, being particularly abundant in the pancreas and placenta, but it is also found in the brain, heart, lung and kidney. Its amino acid identity to TWIK-1 and TREK-1 is rather low, being about 25-28%. However, it is thought to share the same topology of four TM segments, with two P-domains. TASK is very sensitive to variations in extracellular pH in the physiological range, changing from fully-open to closed in approximately 0.5 pH units around pH 7.4. Thus, it may well be a biological sensor of external pH variations.

TASK-5 is expressed in the pancreas, liver, kidney, lung, ovary, testis and heart. It requires another as yet unidentified partner subunit to form functional channels in the plasma membrane, or it may form a channel in an intracellular organelle .
Lipocalin-interacting membrane receptor (LIMR)
Type: Family

Beyond its interaction with Lipocalin-1 (Lcn-1), the precise physiological function of lipocalin-1 interacting membrane receptor (LIMR) is unknown . LIMR can mediate the internalization of Lcn-1 in cultured cells, suggesting a role in cell signaling . It could be involved in the detoxification of the ligands bound to Lcn-1, either transferring the ligand into the cell, or acting as a detoxification protein itself . A member of this family in Drosophila, protein Lilipod, has been shown to have an important role in modulating bone morphogenetic protein (BMP) signaling .
Cyanate hydratase (Cyanase)
Type: Family

Cyanate hydratase or cyanase lyase catalyses the reaction of cyanate with bicarbonate to produce ammonia and carbon dioxide, allowing the host organisms to overcome the toxicity of environmental cyanate . The enzyme is also known as cyanate lyase and cyanate hydrolase.

The cyanate lyase monomer is composed of two domains: an N-terminal domain that shows structural similarity to the DNA-binding α-helix bundle motif, and a C-terminal domain that has an 'open fold' that shows no structural similarity to other proteins .

The enzyme is active as a homodecamer of 17kDa subunits, and displays half-site binding of substrates or substrate analogues. The dimer structure reveals the C-terminal domains to be intertwined; the decamer is formed from a pentamer of these dimers. The active site of the enzyme is located between dimers and comprises residues from four adjacent subunits of the homodecamer.
GPCR family 2, Ig-hepta-like receptor (GPCR_2_Ig-hepta-like_rcpt)
Type: Family

Ig-Hepta/GPR116 is a member of the G protein-coupled receptor family. It has been named Ig-hepta due to the presence of two immunoglobulin-like repeats in its large extracellular domain. The receptor is expressed predominantly in the lung, this expression being strongly induce postnatally. Biochemical analysis indicates that Ig-hepta/GPR116 is heavily glycosylated and exists as a disulphide-linked dimer. The receptor appears to be localised in alveolar walls of the lungs and intercalated cells of the kidney collecting ducts, suggesting a role in regulation of acid-base balance . Ig-Hepta/GPR116 is likely to negatively regulate macrophage function and inflammation in the alveoli .

This entry also includes GPR110 and GPR115. Loss of GPR110 and GPR115 function does not result in detectable defects, indicating that genes of this GPCR group might function redundantly .

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.
Voltage-dependent calcium channel, L-type, beta-3 subunit (VDCC_L_b3su)
Type: Family

Ca2+ ions are unique in that they not only carry charge but they are also the most widely used of diffusible second messengers. Voltage-dependent Ca2+ channels (VDCC) are a family of molecules that allow cells to couple electrical activity to intracellular Ca2+ signalling. The opening and closing of these channels by depolarizing stimuli, such as action potentials, allows Ca2+ ions to enter neurons down a steep electrochemical gradient, producing transient intracellular Ca2+ signals. Many of the processes that occur in neurons, including transmitter release, gene transcription and metabolism are controlled by Ca2+ influx occurring simultaneously at different cellular locales. The pore is formed by the alpha-1 subunit which incorporates the conduction pore, the voltage sensor and gating apparatus, and the known sites of channel regulation by second messengers, drugs, and toxins . The activity of this pore is modulated by four tightly-coupled subunits: an intracellular beta subunit; a transmembrane gamma subunit; and a disulphide-linked complex of alpha-2 and delta subunits, which are proteolytically cleaved from the same gene product. Properties of the protein including gating voltage-dependence, G protein modulation and kinase susceptibility can be influenced by these subunits.

Voltage-gated calcium channels are classified as T, L, N, P, Q and R, and are distinguished by their sensitivity to pharmacological blocks, single-channel conductance kinetics, and voltage-dependence. On the basis of their voltage activation properties, the voltage-gated calcium classes can be further divided into two broad groups: the low (T-type) and high (L, N, P, Q and R-type) threshold-activated channels.

Co-expression of beta subunit mRNA with alpha-1 subunit mRNA in xenopus oocytes produces increased calcium currents, which are accompanied by a shift in the voltage-dependence of activation to more negative membrane potentials. Conversely, microinjection of antisense oligonucleotides to beta subunit mRNA produces decreased calcium currents and shifts voltage-dependent activation to more positive membrane potentials. There are four distinct beta subunits: beta-1, beta-2, beta-3 and beta-4; and the magnitude of the shift in the voltage-dependence of activation of change to membrane potentials varies with the particular subtype .

Beta-3 subunits are most abundant in the brain, but are also present in aorta, trachea, lung, heart, skeletal muscle and pancreatic islets, where they play a role in the regulation of insulin secretion . The beta-3
subunits regulate the activation (opening) and inactivation (closing) kinetics through phosphorylation and dephosphorylation. However, it is noted that no single channel is dependent on the beta-3 subunit.
Parvalbumin (Parvalbumin)
Type: Family

Fish allergies are common in Europe, particularly among male children and young adults. Children allergic to fish react variably to different species. Cod is among the most common offenders, while salmon is the one best tolerated. The allergy-eliciting protein has been isolated from the white muscle albumin. It is a parvalbumin, designated Allergen M. Parvalbumins are calcium (Ca)-binding proteins of low molecular weight. Like many other Ca-binding proteins, they belong to the EF-hand family characterised by helix-loop-helix (HLH) binding motifs (two helices pack together at an angle of ~90 degrees, separated by a loop region where calcium binds). In the parvalbumin HLH structural motif, calcium is coordinated through one carbonyl oxygen atom and the oxygen-containing side-chains of 5 amino acid residues, or 4 residues and a water molecule .

Initially, parvalbumins were detected in relatively high amounts in lower vertebrate white muscle, where they were thought to be important for fibre relaxation. They were subsequently found, although in lesser amounts, in the fast twitch skeletal muscles of higher vertebrates, as well as in a variety of non-muscle tissues, including testis, endocrine glands, skin and specific neurons. There are two distinct phylogenetic lineages: alpha and beta. Most muscles contain parvalbumin of only alpha or beta origin. Cod parvalbumin belongs to the beta-lineage and shares significant similarity with parvalbumin of other fish species .

Allergen M contains 113 residues, is a homogenous acidic protein and belongs to a group of muscle sarcoplasmic proteins. It carries the major allergenic determinants associated with cod sensitivity, which is dependent directly on the linear structure rather than on the molecular conformation. The allergenic activity of allergen M resides in particular epitopes found in three loops: AB (~13-33), CD (~48-64) and EF (~80-103). It has an N-acetyl terminal amino acid residue and includes 1 residue of glucose attached to the conserved N-terminal cysteine, and 1 residue each of tyrosine, tryptophan and arginine -the arginine is believed to play a key role in maintaining the tertiary structure. Mutation of the last conserved coordinating residue of the Ca-binding loop (E101D-motif 4) has also been shown to have a significant impact on the ability of the mutant to obtain the sevenfold coordination preferred by Ca2+.
Cytoplasmic FMR1-interacting (Cytoplasmic_FMR1-int)
Type: Family

This entry includes cytoplasmic fragile X messenger ribonucleoprotein 1-interacting proteins from humans and their homologues, such as Sra-1 (specifically Rac1-associated protein 1) from Drosophila and PIROGI from Arabidopsis.

In humans, there are two members, CYFIP1 and CYFIP2. They both interact with FMRP (Fragile X messenger ribonucleoprotein 1), which is responsible for pathologic manifestations in the Fragile X Syndrome. CYFIP1 interacts with the small GTPase Rac1 . CYFIP1 represses cap-dependent translation of mRNA by interacting with the initiation factor eIF4E . CYFIP1 and CYFIP2 are part of the Wiskott-Aldrich syndrome protein-family verprolin-homologous protein (WAVE) complex that regulates actin polymerization at synapses .

Drosophila Sra-1 interacts with the Kette and Wasp. It is required for neuronal and bristle development in Drosophila .
CD34 antigen (CD34)
Type: Family

The CD34 group of monoclonal antibodies recognises CD34 (also termed CD34 antigen), a 105-120kDa cell surface glycoprotein, which is selectively expressed by human myeloid and lymphoid progenitor cells, including the haemopoietic stem cell. The protein is also expressed on vascular endothelial cells. Here, it is concentrated on the surface of the inter-digitating processes, suggesting a possible involvement in cell interactions or adhesion, by mediating the attachment of stem cells to the bone marrow extracellular matrix, or directly to stromal cells. The restricted pattern of expression of CD34 in haemopoiesis suggests that it may have a significant function in the earliest stages of blood cell differentiation in the bone marrow .

CD34 is a phosphoprotein shown to be activated by protein kinase C (PKC) in a developmental stage-specific manner. Analysis of the human CD34 sequence reveals that the protein appears to be a type I transmembrane (TM) molecule. The predicted internal portion of the protein appears to retain basic amino acid residues adjacent to Ser residues, presenting at least two potential target sites for PKC phosphorylation. In addition, there are two other consensus motifs that correspond to potential target sites for Ca+/calmodulin-dependent kinase and/or protease activated kinase I .

The protein is not strongly similar to other known proteins, but some weak similarities do exist: e.g., to the S+T region (a region rich in potential O-linked carbohydrate attachment sites), the TM domain and cytoplasmic domain of cell surface proteins such as leukosialin, a major sialoglyco-protein of rat and human leukocytes; to the N-terminal glycosylated region of CD45 (the leukocyte common antigen); and to groups of interrelated proteins involved in cell adhesion or the regulation of complement.

A homologue of human CD34 is expressed in mouse. The amino acid sequences only diverge significantly at their N-termini, which are predicted to be highly glycosylated and whose functions are probably modulated by carbohydrate. The observed pattern of expression of the murine CD34 gene is consistent with that of the human antigen. That CD34 is also highly expressed outside haematopoiesis, by vascular endothelial cells and by fibroblasts in differentiated tissue, suggests a role common to a variety of cell types. Concentration of CD34 on the interdigitating membrane projections of adjacent capillary endothelial cells has strengthened the idea that it functions in the control of events leading to cell-cell or cell-matrix adhesion, which role could be modulated by variation in its levels of glycosylation. The conservation between the human and mouse cysteine-rich domain in the extracellular part of the protein, and the exceptionally high conservation of the cytoplasmic domain, imply that the protein is more than a carrier for either carbohydrate or negatively charged terminal sialic acid residues (a role postulated for leukosialin/sialophorin). The highly conserved domain may serve to provide an internal signal of external contact with a ligand.