SII-SWORD/CoKE huggingface dataset:
Proteinase inhibitor I15, leech antistasin (Prot_inh_I15_antistasin_leech)
Type: Family

This group of serine protease inhibitors belong to MEROPS inhibitor family I15, clan IO. They inhibit serine peptidases of the S1 family (

) and are characterised by a well conserved pattern of cysteine residues. This is a family of leech anti-coagulants.

Antistasin is a 15kDa protein found in the salivary glands of Haementeria officinalis (Mexican leech); it is an anticoagulant that functions by inhibiting factor Xa. The protein contains 119 residues, with an unusually high cysteine content (20 residues in all), and exhibits a 2-fold internal repeated structure. Four isoforms of antistasin have been identified in leech salivary gland extracts; partial sequence analysis indicates that these isoforms differ only by 1 or 2 amino acid residues .

Ghilanten is an anticoagulant-antimetastatic protein of Haementeria ghilianii (Amazon leech). Like antistasin, it contains 119 amino acids, with 20 cysteines, and a heparin-binding consensus motif at its C terminus. Arginine-34 is the residue involved in the active-site inhibition of trypsin and Factor Xa .

The 3D structure of antistasin has been determined to 1.9A resolution by X-ray crystallography . The structure reveals a novel protein fold comprising two similar domains, which can be divided into two similarly sized subdomains, with different relative orientations. Thus, the domain shapes differ, the N-terminal domain being wedge-shaped and the C-terminal domain flat . Docking studies suggest that it is differences in domain shape that enable the N-terminal domain to bind and inhibit factor Xa, rather than the C-terminal domain, despite very similar active sites. A putative exosite binding region is evident in the N-terminal domain (residues 15-17), which is likely to interact with a cluster of positively charged residues on the factor Xa surface (Arg222/Lys223/Lys224), explaining the specificity and inhibitory potency of antistasin towards factor Xa.
Autoimmune regulator, AIRE (AIRE)
Type: Family

AIRE (AutoImmune REgulator) is a transcription factor that plays an essential role to promote self-tolerance in the thymus by regulating the expression of a wide array of self-antigens that have the commonality of being tissue-restricted in their expression pattern in the periphery, called tissue restricted antigens (TRA) . Mutations cause a rare autosomal recessively inherited disease termed APECED. APECED, also called Autoimmune Polyglandular Syndrome type I (APS 1), is the only described autoimmune disease with established monogenic background, being localised outside the major histocompatibility complex region. It is characterised by the presence of two of the three major clinical entities, chronic mucocutaneus candidiasis, hypoparathyroidism and Addison's disease. Other immunologically mediated phenotypes, including insulin-dependent diabetes mellitus (IDDM), gonadal failure, chronic gastritis, vitiligo, autoimmune thyroid disease, enamel hypoplasia, and alopecia may also be present. Immunologically, APECED patients have deficient T cell responses towards Candida antigens, and clinical symptoms both within and outside the endocrine system, mainly as a result of autoimmunity against organ-specific autoantigens .

AIRE has a HSR/CARD domain involved in promoting AIRE to multimerise to itself, a SAND domain that appears to be involved in promoting a protein-protein interaction with a transcriptional repressive complex and two zinc fingers of the plant homodomain (PHD) type PHD1 and PHD2, of which PHD1 functions as a histone code reader .

AIRE has a dual subcellular location. It is not only expressed in multiple immunologically relevant tissues, such as the thymus, spleen, lymph nodes and bone marrow, but it has also been detected in various other tissues, such as kidney, testis, adrenal glands, liver and ovary, suggesting that APECED proteins might also have a function outside the immune system. However, AIRE is not expressed in the target organs of autoimmune destruction. At the subcellular level, AIRE can be found in the cell nucleus in a speckled pattern in domains resembling promyeolocytic leukaemia nuclear bodies, also known as ND10, nuclear dots or potential oncogenic domains associated with the AIRE homologous nuclear proteins Sp100, Sp140, and Lysp100.
Alpha giardin (Alpha_giardin)
Type: Family

Giardia lamblia (Giardia intestinalis) is a protozoan parasite of numerous mammals, including Homo sapiens . It belongs to the phylum Sarcomastigophora, and is amongst the most primitive eukaryotes identified to date. It is the main causative agent of global protozoan diarrhoea, and severe infection can cause giardiasis. G. lamblia exists as either trophozoites that live in the small intestine of the host and cause the disease symptoms, or cysts that are passed in the faeces of the host and infect the next host through contaminated water or food .

Trophozoites exhibit antigenic variation to evade the host immune system, expressing a number of virulence factors to aid adherence and invasion of the small intestine endothelium . The molecular basis for its antigenic variation has been well characterised, and it is believed that its phenotypic heretogeneity arises from sexual reproduction . One of the major virulence factors of G. lamblia is giardin, an antigen expressed as several variants on the trophozoite surface . Alpha giardin is the predominant immunotypic giardin present, although beta and gamma giardin have also been identified .

This entry represents a family of alpha giardin proteins specific to Giardia. The biochemical properties of the subunit identify the protein as an annexin, a eukaryotic protein widely conserved amongst plants and animals. This protein associates with phosphatidyl serine-containing vesicles in a Ca2+-dependent manner, and has very low sequence similarity with human annexin XIX . This protein shows a fourfold cyclic configuration of five-helix bundles with repeats I/IV, and II/III each forming a module. The canonical membrane binding site of the annexins is located on the convex side of the molecule .
Ferric iron reductase (Fe_iron_reduct)
Type: Family

Iron is essential for growth in both bacteria and mammals. Controlling the amount of free iron in solution is often used as a tactic by hosts to limit invasion of pathogenic microbes; binding iron tightly within protein molecules can accomplish this. Such iron-protein complexes include haem in blood, lactoferrin in tears/saliva, and transferrin in blood plasma. Some bacteria express surface receptors to capture eukaryotic iron-binding compounds, while others have evolved siderophores (enterobactins) to scavenge iron from iron-binding host proteins .

The control of such siderophore gene expression in Escherichia coli is under the regulation of the negative repressor protein FUR . When complexed with Fe2+, it down-regulates the transcription not only of the siderophore genes, but also of the moieties that release Fe2+ ions bound to the hydrox-amate enterobactin proteins in the microbial cytoplasm . An example of the latter is FhuF from the Gram-negative microbes Yersinia pestis, Salmonella typhi, and E. coli . In conjunction with the siderophore system, this gene has been demonstrated to be essential for growth and virulence in pathogenic enterobacteria .

FhuF (Ferric siderophore reductase) is a member of the [2Fe-2S] ferric iron reductase family. However, in place of the symmetrical tetrahedral arrangement at the ferric iron binding site, an unusual Cys-Cys C-terminal group distorts the site in this protein . This property makes FhuF inherently unstable, and another set of regulatory genes, designated "suf", is thought to maintain its activity in the cytoplasm. FhuF, involved in the reduction of ferric iron in cytoplasmic ferrioxamine B , binds both the iron-loaded and the apo forms of ferrichrome .
Small ribosomal subunit protein mS29, metazoan-type (Ribosomal_mS29_met)
Type: Family

This entry represents the family of small ribosomal subunit mitochondrial protein mS29 which was originally described as death-associated-protein-3 (DAP-3). This protein was also known as MRPS29 in mammals and RSM23 in yeast. These proteins carry a P-loop DNA-binding motif, and induce apoptosis . mS29 has been shown to be a pro-apoptotic factor in the mitochondrial matrix and to be crucial for mitochondrial biogenesis.

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 .
T cell antigen CD28 (CD28)
Type: Family

Antigen (Ag) recognition by the T cell receptor (TCR) induces activation of T lymphocytes. However, TCR-mediated signals alone are insufficient for efficient T cell activation, and additional co-stimulatory signals are required. One of the most important surface molecules that delivers co-stimulatory signals for T cells is CD28. The human T lymphocyte Ag CD28 (Tp44) is a homodimeric 90kDa glycoprotein expressed on the surface of the majority of human peripheral T cells and lymphocytes. Stimulation of CD4+ T cells in the absence of CD28 co-signalling causes impaired proliferation, reduced cytokine production and altered generation of helper T cell subsets. Co-stimulation via CD28 promotes T cell viability, clonal expansion, cytokine production and effector functions, while also regulating apoptosis of activated T cells, suggesting its importance in regulating long-term T cell survival .

Ligands for CD28 and the structurally related CTLA-4 (CD152) are the molecules B7.1 (CD80) and B7.2 (CD86). B7.1 and B7.2 are expressed on professional antigen presenting cells (APCs) and their expression is up-regulated during an immune response. Ligation of CD28 by its natural ligands results in tyrosine phosphorylation at a YMNM motif within its cytoplasmic tail. The phosphorylated motif subsequently interacts with the Src homology 2 domain in the p85 regulatory subunit of P13K, activating the p110 catalytic subunit. One of the P13K-dependent downstream targets, resulting from the antibody cross-linking of CD28, is the phoshporylation and activation of Akt (or PKB). Constitutively active Akt is able to substitute for CD28 signals, and stimulates IL-2 production when introduced into mature CD28-deficient cells. Another molecule affected by CD28 stimulation is the proto-oncogene Vav, which acts as a guanine-nucleotide exchange factor for Rac and CDC42, allowing these molecules to switch from the inactive GDP-bound state to the active GTP-bound state .

Another interesting feature of CD28, is its ability to induce expression of PDE7, a cAMP phosphodiesterase, thus reducing cellular cAMP levels. cAMP has been reported to affect nearly every pathway important for lymphocyte activation, leading to inhibition of T cell proliferation. Specifically, increased intracellular cAMP has been implicated in the induction of T cell anergy, a non-responsive state that occurs after T cells are stimulated through TCR/CD3 in the absence of co-stimulation. This can have therapeutic implications, in that blockage of CD28 co-stimulation can be profoundly immunosuppressive, preventing induction of pathogenic T cell responses in autoimmune disease models, and allowing for prolonged acceptance of allografts in models of organ transplantation .

Finally, CD28 co-stimulation directly controls T cell cycle progression by down-regulating the cdk inhibitor p27kip1, which actually integrates mitogenic MEK and P13K-dependent signals from both TCR and CD28 .
Claudin-15 (Claudin15)
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-15 have been cloned. Claudin-15 shares ~25-45% overall similarity with other claudin family members at the amino acid level, displaying highest similarity to claudin-10.
Cytotoxic T-lymphocyte antigen 4 (CTLA4)
Type: Family

T cell-dependent immune processes require cell-surface interactions that mediate the initiation, modulation and the ultimate course of the response. The specificity of T cell recognition is determined by the engagement of the T cell receptor (TCR) on T cells with cognate peptide-MHC complexes presented by antigen presenting cells (APCs). Additional signals are required to sustain and enhance T cell activity, the most important of which is provided by the engagement of CD28 on T cells with its ligands B7-1 (CD80) and B7-2 (CD86). By contrast, the interaction of B7 isoforms with cytotoxic T lymphocyte-associated molecule-4 CTLA-4, a CD28 homologue receptor on T cells (31% identity), provides inhibitory signals required for down-regulation of the response, while it may also prevent T cell activation by weak TCR signals .

Unlike CD28, which is not expressed on resting T cells, CTLA-4 is not detected on the cell surface until 24 hours after activation. In fact, T cell activation leads to both increased CTLA4 gene expression and trafficking of CTLA4 protein to the cell surface. In addition, CTLA-4 exhibits an affinity for the B7 isoforms that is 10 to 100 times that for CD28. Covalent dimerisation of CTLA4 is required for its high binding avidity, but each monomeric subunit also contains a binding site for CD80 and CD86. It is likely that CTLA-4 directly competes with CD28 for binding B7 and also directs the assembly of inhibitory signalling complexes that lead to quiescence or anergy. Thus the balance between the opposing signals elicited by CD28 and CTLA-4 is central to the regulation of T cell responsiveness and homeostasis. One mechanism by which CTLA-4 may perform this function is by regulating cell-cycle progression; by contrast with CD28, which down-regulates the cell-cycle inhibitor p27kip1, CTLA-4 prevents this degradation .

Sequence comparison between human CTLA-4 and CD28 proteins suggests they are homologous, with the highest of degree of similarity being in the juxta- membrane and cytoplasmic regions. In addition, the cytoplasmic domains of human and murine CTLA-4 are identical, suggesting that this region has important functional properties .

Typically, activation of T cells by TCR-engaging peptide-MHC is dramatically enhanced by interaction of the CD28 co-stimulatory receptor with its ligands CD80 (B7-1) and CD86 (B7-2) on the APC surface. Interestingly, CTLA-4 is transported from intracellular stores toward the region of the cell surface receiving activation signals. This suggests that binding of CD28 to its ligand may occur primarily at the centre of the mature immunological synapse, and that CTLA-4 may be transported to this site under certain circumstances to block or reverse this effect.
Histamine H4 receptor (Histamine_H4_rcpt)
Type: Family

Histamine plays an important role in a variety of pathophysiological conditions. In allergic conditions, histamine is released from basophils and mast cells and is responsible for symptoms of allergic conditions of the skin and airways. In the gastric mucosa, gastric induced histamine release stimulates parietal cells to secrete gastric acid. In the central nervous system (CNS), histamine is synthesized in specific neurons that are localized in the posterior hypothalamus. These neurons are involved in a variety of important physiological functions, including the regulation of the sleep-wake cycle, cardiovascular control, regulation of the hypothalamic pituitary adrenal-axis, learning and memory .

Histamine exerts its biological effects by binding to and activating four distinct separate rhodopsin-like G protein-coupled receptors-histamine H1 receptor, histamine H2 receptor, histamine H3 receptor, and histamine H4 receptor. Each of the histamine receptors produce a functional response, but their mechanism differs. The H1 receptor couples to Gq/11 stimulating phospholipase C, whereas the H2 receptor interacts with Gs to activate adenylyl cyclase . The H3 and H4 receptors couple to Gi proteins to inhibit adenylyl cyclase, and to stimulate MAPK in the case of the H3 receptor .

This entry represents the histamine H4 receptor (HH4R or H4) it is expressed primarily in cells and tissues of the immune system, including peripheral blood leukocytes, bone marrow, spleen, and the thymus, but is also present in the lung, colon, epicanthus, bone marrow, spleen and liver , . As the H4 receptor is highly expressed in peripheral blood leukocytes and intestinal tissue, it makes the receptor a potential target in allergic and inflammatory diseases, particularly in the treatment of allergies and asthma . Activation of the H4 receptor can also enhance the activity of other chemoattractants, like chemokines on eosinophils and upregulate adhesion of molecules . Thus, H4 receptor stimulation could enhance the inflammatory activity seen in allergic rhinitis.
KiSS-1 peptide receptor (KiSS_1_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 .

The metastasis suppressor gene KiSS-1 encodes a number of RFamide-related peptides, the largest of which, metastin, contains 54 amino acids. An orphan G protein-coupled receptor, GPR54, has been identified as a receptor for these peptides . GPR54 is highly expressed in placenta, pituitary, pancreas and spinal cord. Binding of KiSS-1-encoded peptides to the receptor results in coupling to the Gq pathway, stimulating calcium mobilisation, phosphatidylinositol hydrolysis, arachidonic acid release, ERK and p38 MAP kinase phosphorylation and stress fibre formation. It also inhibits cell proliferation. The distribution of GPR54, together with the finding that administration of KiSS-1 peptides in rat stimulates oxytocin secretion, suggests a role in regulation of endocrine function.
Macrophage infectivity potentiator (INFPOTNTIATR)
Type: Family

Legionella pneumophila, the causative agent of Legionnaire's disease, is a facultative intracellular microbe that commonly infects human lung monocytes and macrophages and causes pneumonia . It is water-borne and highly virulent, relying on several specific pathogenic factors to invade and infect the alveolar tissue. However, once grown to stationary phase in culture, the pathogen spontaneously converts to an avirulent state .