SII-SWORD/CoKE huggingface dataset:
Breast cancer type 2 susceptibility protein (BRCA2)
Type: Family

The breast cancer type 2 susceptibility protein (BRCA2) is a breast tumour suppressor involved in double-strand break repair and/or homologous recombination . BRCA2 gene expression is regulated in a cell-cycle dependent manner and peak expression of BRCA2 mRNA occurring in S phase, suggesting BRCA2 may participate in regulating cell proliferation. BRCA2, and related protein BRCA1, have transcriptional activation potential and the two proteins are associated with the activation of double-strand break repair and/or homologous recombination. The two proteins have been shown to coexist and colocalize in a biochemical complex. BRCA2 has a number of 39 amino acid repeats that are critical for binding to RAD51 (a key protein in DNA recombinational repair) and resistance to methyl methanesulphonate treatment . There are eight repeats in BRCA2 designated as BRC1 to BRC8. BRC1, BRC2, BRC3, BRC4, BRC7, and BRC8 have high sequence identity and bind to Rad51, whereas BRC5 and BRC6 are less well conserved and are unable to bind Rad51 . It has been suggested that BRCA2 plays a role in positioning Rad51 at the site of DNA repair or in removing Rad51 from DNA once repair has been completed.

Mutations in BRCA1 and BRCA2 have been linked to an elevated risk of young onset breast cancer and confer a high risk of the disease through a dominantly inherited fashion . BRCA2 mutations are typically microdeletions.

Homologues exist in plants: the BRCA2A and BRCA2B proteins from
Arabidopsis thaliana
are required for repair of breaks in double-stranded DNA and homologous recombination and in the prophase stage of meiosis are required for formation of RAD51 and DMC1 foci in males .
Frizzled/secreted frizzled-related protein (Frizzled/SFRP)
Type: Family

This entry includes both frizzled proteins and secreted frizzled-related proteins (SFRP).

Frizzleds are seven transmembrane-spanning proteins that constitute an unconventional class of G protein-coupled receptors . They have important regulatory roles during embryonic development .

Frizzleds expose their large N terminus on the extracellular side. The N-terminal, extracellular cysteine-rich domain (CRD) has been implicated as the Wnt binding domain and its structure has been solved . The cysteine-rich domain of Frizzled (Fz) is shared with other receptor tyrosine kinases that have roles in development including the muscle-specific receptor tyrosine kinase (MuSK), the neuronal specific kinase (NSK2), and ROR1 and ROR2. The cytoplasmic side of many Fz proteins has been shown to interact with the PDZ domains of PSD-95 family members and is thought to have a role in the assembly of signalling complexes. The conserved cytoplasmic motif of Fz, Lys-Thr-X-X-X-Trp, is required for activation of the beta-catenin pathway, and for membrane localisation and phosphorylation of Dsh.

In Drosophila melanogaster, the frizzled locus is involved in planar cell polarity, which is the coordination of the cytoskeleton of epidermal cells to produce a parallel array of cuticular hairs and bristles . In the wild-type wing, all hairs point towards the distal tip , whereas in Fz mutants, the orientation of individual hairs with respect both to their neighbours and to the organism as a whole is altered. In the developing wing, Fz function is required for cells to respond to the extracellular polarity signal as well as the proximal-distal transmission of an intracellular polarity signal.

In Caenorhabditis elegans, protein mom-5 is the equivalent of frizzled .

Three main signalling pathways are activated by agonist-activated Frizzled proteins: the Fz/beta-catenin pathway, the Fz/Ca2+ pathway and the Fz/PCP (planar cell polarity) pathway . The Wnt/beta-catenin pathway is the best studied signalling pathway involving Fz receptors. In the Wnt/beta-catenin pathway the first downstream cytoplasmic components activated by Fz signalling include Dishevelled (Dsh) and/or its regulatory kinases.

There are secreted forms of Fz, known as soluble or secreted frizzled-related proteins (sFRPS), which function as modulators of Wnt signaling through direct interaction with Wnts . They consist of only the amino-terminal cysteine rich domain (CRD), but no transmembrane segments. These secreted forms may bind to Wnt proteins in solution and thereby change the activity of Wnts. Such as FRP/FrzB, which consist of the CRD only and can act as secreted antagonists of Wnt signalling.
Peptidase C26, gamma-glutamyl hydrolase (Pept_C26_g-glut_hydrolase)
Type: Family

Gamma-glutamyl hydrolase (GH) is a lysosomal and secreted glycoprotein that hydrolyses the gamma-glutamyl tail of antifolate and folate polyglutamates. Tumour cells that have high levels of GH are inherently resistant to classical antifolates, and further resistance can be acquired by elevations in GH following exposure to this class of anti-tumour agents. The highest level of expression in normal tissues occurs in the liver and kidney in humans. GH is a low-affinity (micromolar), high-turnover enzyme that has a cysteine at the active site. GH is being evaluated as an intracellular target for inhibition in order to enhance the therapeutic activity of antifolates and fluorouracil .

The 3-dimensional structure of GH shows a central eight-stranded β-sheet, which is sandwiched by three and five α-helices on each side (see . The fold resembles that of glutamine amidotransferases (GATase) of class I, which are characterised by a conserved Cys-His-Glu active site. The major differences consist of extensions in four loops and at the C terminus of GGH. The active site residues are well conserved and the catalytically essential cysteine, positioned at a nucleophile elbow, suggests that GGH is a cysteine peptidase.
Interleukin-12 beta (IL-12_beta)
Type: Family

This entry represents Interleukin-12 beta.

Interleukins are a group of cytokines that have important roles in cell growth, differentiation, and motility, and in the functioning of the immune system.

Interleukin-12 (also known as natural killer cell stimulatory factor, and cytotoxic lymphocyte maturation factor) is a 75kDa heterodimer composed of two genetically unrelated subunits - an alpha chain (p35 subunit) and a beta chain (p40 subunit). Production of the cytokine plays an important role in the generation of cell-mediated immunity against many infectious pathogens . The interluekin-12 beta chain also associates with interleukin-23 alpha to form interleukin-23 , a proinflammatory cytokine that is overexpressed in and around tumour tissues, where it induces local inflammation and promotes tumour development .
Interleukin-18 (IL-18)
Type: Family

Interleukins (IL) are a group of cytokines that play an important role in the immune system. They modulate inflammation and immunity by regulating growth, mobility and differentiation of lymphoid and other cells.

Interleukin-18 (IL-18) is a potent proinflammatory cytokine that induces interferon-gamma (IFN-gamma) production from Th1 cells, NK cells and activated macrophages, particularly in the presence of IL-12 . IL-18 also functions in developmental regulation of T-lymphocyte helper type I cells and in Fas-mediated cytotoxicity . Suppression of IL-18 activity is being investigated for treatment of chronic inflammatory diseases such as Crohn's disease and rheumatoid arthritis . It acts by inducing heterodimerization of the two subunits of its receptor, IL-18RAlpha and IL-18RBeta shows structural similarity to IL-1.

This entry represents interleukin-18.
Glucagon (Glucagon)
Type: Family

A number of polypeptidic hormones, mainly expressed in the intestine or the pancreas, belong to a group of structurally related peptides . Once such hormone, glucagon is widely distributed and produced in the alpha-cells of pancreatic islets . It affects glucose metabolism in the liver by inhibiting glycogen synthesis, stimulating glycogenolysis and enhancing gluconeogenesis. It also increases mobilisation of glucose, free fatty acids and ketone bodies, which are metabolites produced in excess in diabetes mellitus.

Glucagon is produced, like other peptide hormones, as part of a larger precursor (preproglucagon), which is cleaved to produce glucagon, glucagon-like protein I (GLP-1) and glucagon-like protein II (GLP-2) . GLP-1 and GLP-2 are key neuroendocrine signals for the gut-brain axis to control food intake and glucose homeostasis . The structure of glucagon itself is fully conserved in all known mammalian species .
Plasminogen activator inhibitor-2 (PAI-2)
Type: Family

Plasminogen activator inhibitor 2 (PAI-2; MEROPS identifier I04.007) is a serpin (SERine Proteinase INhibitor). Serpins belong to MEROPS inhibitor family I4 (clan ID) .

PAI-2 has antiapoptosis activity, probably related to its interaction with the proteasome subunit PSMbeta1 . PAI-2 might be an important factor in regulating cell death in TNF-mediated inflammatory processes . Its crystal structure has been reported .
Spermine synthase, animal (Spermine_synthase_animal)
Type: Family

The polyamines putrescine, spermidine and spermine represent a group of naturally occurring compounds exerting a bewildering number of biological effects. Their biosynthesis is accomplished by a concerted action of four different enzymes: ornithine decarboxylase, adenosylmethionine decarboxylase, spermidine synthase and spermine synthase. The development and introduction of specific inhibitors to the biosynthetic enzymes of the polyamines have revealed that an undisturbed synthesis of the polyamines is a prerequisite for animal cell proliferation to occur .
Neurotrophin-3 (Neurotrophin-3)
Type: Family

During the development of the vertebrate nervous system, many neurons become redundant (because they have died, failed to connect to target cells, etc.) and are eliminated. At the same time, developing neurons send out axon outgrowths that contact their target cells . Such cells control their degree of innervation (the number of axon connections) by the secretion of various specific neurotrophic factors that are essential for neuron survival. One of these is nerve growth factor (NGF or beta-NGF), a vertebrate protein that stimulates division and differentiation of sympathetic and embryonic sensory neurons . NGF is mostly found outside the central nervous system (CNS), but slight traces have been detected in adult CNS tissues, although a physiological role for this is unknown ; it has also been found in several snake venoms .

NGF is a protein of about 120 residues that is cleaved from a larger precursor molecule. It contains six cysteines all involved in intrachain disulphide bonds.

Neurotrophin-3 is a neurotrophic factor related to NGF and BDNF . NT-3 and its receptor TrkC are found in the spinal cord, and their expression is altered by voluntary exercise . In the brain, NT-3 and NT-4/5 may function synergistically with oleic acid to increase GAP-43 expression .
Aldehyde dehydrogenase domain (Aldehyde_DH_dom)
Type: Domain

Aldehyde dehydrogenases (

and

) are enzymes that oxidize a wide variety of aliphatic and aromatic aldehydes using NADP as a cofactor. In mammals at least four different forms of the enzyme are known : class-1 (or Ald C) a tetrameric cytosolic enzyme, class-2 (or Ald M) a tetrameric mitochondrial enzyme, class- 3 (or Ald D) a dimeric cytosolic enzyme, and class IV a microsomal enzyme. Aldehyde dehydrogenases have also been sequenced from fungal and bacterial species. A number of enzymes are known to be evolutionary related to aldehyde dehydrogenases. A glutamic acid and a cysteine residue have been implicated in the catalytic activity of mammalian aldehyde dehydrogenase. These residues are conserved in all the enzymes of this entry.

Some of the proteins in this entry are allergens. 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 . 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.

The allergens in this group of proteins include allergens with the following designations: Alt a 10 and Cla h 3.
Transforming growth factor-beta-related (TGF-beta-rel)
Type: Family

The transforming growth factor (TGF)-beta superfamily of cytokines is comprised of a number of structurally related, secreted polypeptides that regulate a multitude of cellular processes including proliferation, differentiation and neoplastic transformation . Family members include the activins/inhibins, bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs) and TGF-betas . These growth regulatory molecules induce ligand-mediated hetero-oligomerization of distinct type II and type I serine/threonine kinase receptors that transmit signals predominantly through receptor-activated Smad proteins but also induce Smad-independent pathways.
Growth differentiation factor-9, C-terminal (Growth_differentiation_fac-9_C)
Type: Domain

Growth differentiation factor-9 (GDF-9) is a cysteine knot-containing hormone oocyte-derived growth factor and a member of the transforming growth factor-beta (TGF-beta) superfamily that includes TGF-beta, activin, and bone morphogenetic proteins (BMPs) . GDF-9 is a growth factor secreted by oocytes in growing ovarian follicles. Recombinant GDF-9 enhances growth and differentiation of cultured ovarian follicles . GDF-9 signalling is mediated by the type I receptor ALK5 . Transgenic mice with deletion of the GDF-9 gene are characterised by the arrest of ovarian follicle development at the primary stage, Recombinant growth of GDF-9 enhances growth and differentiation of cultured early ovarian follicles .

This entry represents the C-terminal domain of GDF-9.
Transforming growth factor beta-3 (TGFB3)
Type: Family

The transforming growth factors-beta (TGF-beta 1-5) constitute of a family of multi-functional cytokines that regulate cell growth and differentiation . Many cells synthesise TGF-beta, and essentially all have specific receptors for this peptide . TGF-beta regulates the actions of many other peptide growth factors and determines a positive or negative direction of their effects. The protein functions as a disulphide-linked homodimer. Its sequence is characterised by the presence of several C-terminal cysteine residues, which form interlocking disulphide links arranged in a knot-like topology. A similar cystine-knot arrangement has been noted in the structures of some enzyme inhibitors and neurotoxins that bind to voltage-gated Ca2+ channels, although the precise topology differs.

TGF-beta genes are expressed differentially, suggesting that the various TGF- beta species may have distinct physiological roles
in vivo
. Examination of TGF-beta 3 mRNA levels in adult murine tissues indicated that expression is predominant in brain, heart, adipose tissue and testis . TGF beta-3 mRNA is also observed in adult mouse lung and placenta. Research on rat foetal lung fibroblasts has shown that exposure to cortisol increases TGF-beta 3 mRNA expression in a time- and dose-dependent manner, suggesting that glucocorticoids may mediate their stimulatory effect on lung maturation by inducing TGF-beta 3 expression in foetal lung fibroblasts .

The three-dimensional structures of several members of the TGF-beta superfamily have been deduced. The crystal structure of TGF-beta 3 reveals a near identical central core to that of TGF-beta 2 . The principal differences are witnessed in the conformations of the N-terminal α-helix and in the β-sheet loops, which could account for the individual cellular responses, if these differences are recognised by the TGF-beta receptors.
Interleukin-1 receptor family (IL-1_rcpt_fam)
Type: Family

Interleukin-1 alpha and interleukin-1 beta (IL-1 alpha and IL-1 beta) are cytokines that participate in the regulation of immune responses, inflammatory reactions, and hematopoiesis . Two types of IL-1 receptor, each with three extracellular immunoglobulin (Ig)-like domains, limited sequence similarity (28%) and different pharmacological characteristics have been cloned from mouse and human cell lines: these have been termed type I and type II receptors . The receptors both exist in transmembrane (TM) and soluble forms: the soluble IL-1 receptor is thought to be post-translationally derived from cleavage of the extracellular portion of the membrane receptors. Both IL-1 receptors appear to be well conserved in evolution, and map to the same chromosomal location . The receptors can both bind all three forms of IL-1 (IL-1 alpha, IL-1 beta and interleukin-1 receptor antagonist, IL-1RA).

The crystal structure of the soluble extracellular part of type-I IL1R complexed with IL1RA has been determined . The receptor structure is characterised by three Ig-like domains, of which domains 1 and 2 are tightly linked, while domain 3 is completely separate and connected by a flexible linker.

This entry represents the interleukin-1 receptor family, which includes among others: interleukin-1 receptor type 1 (IL1R1), interleukin-1 receptor type 2 (IL1R2), interleukin-1 receptor accessory protein (IL1RAP), interleukin-18 receptor 1 and interleukin-18 receptor accessory protein.
CD2/SLAM family receptor (CD2/SLAM_rcpt)
Type: Family

The SLAM/CD2 family of receptors plays important roles in regulating multiple cellular interactions in the adaptive and innate immune systems .

Signalling lymphocyte activation molecule (SLAM) receptors are expressed in multiple cells of the immune system, including natural killer cells, T cells, and B cells . SLAM receptors interact with SH2 domain-containing, cytosolic adaptor proteins such as SAP, EAT-2, and SH2D1A, and mediate tyrosine phosphorylation events that contribute to immune cell activation. The finding that mutations in SAP are associated with an X-linked lymphoproliferative disorder suggests that signalling through SLAM receptors can influence the development and effector functions of immune cells.

This entry also includes V-set and transmembrane domain-containing protein 5, a cell adhesion-like membrane protein of the central nervous system (CNS) which modulates both the position and complexity of central neurons by altering their membrane morphology and dynamics. It ia involved in the formation of neuronal dendrites and protrusions including dendritic filopodia. In synaptogenesis, regulates synapse formation by altering dendritic spine morphology and actin distribution .
T-cell surface antigen CD2 (CD2)
Type: Family

The CD2 adhesion molecule is a cell surface protein expressed by T cells and natural killer cells. CD2's extracellular domain contains immunoglobulin-like domains that are glycosylated at two sites and can mediate homodimerisation . Ligation of CD2 by CD58 in humans or CD48 in mice helps T cells adhere to antigen-presenting cells, and initiates signal transduction pathways that enhance signalling through the T cell receptor for antigen. CD2 knockout mice exhibit essentially normal immune function , and it is thought that CD2 is somewhat functionally redundant with other T cell co-stimulatory receptors such as CD28 .
E2F Family (E2F)
Type: Family

The E2F family of transcription factors plays a crucial role in the control of cell cycle and action of tumour suppressor proteins. This family consists of eight members and is divided into activators (E2F1-3) and repressors (E2F4-8) depending on cellular context, target gene and cofactors . The E2F proteins contain several evolutionarily conserved domains found in most members of the family. These domains include a DNA-binding domain, a dimerisation domain which determines interaction with the differentiation regulated transcription factor proteins (DP), a transactivation domain enriched in acidic amino acids, and a tumour suppressor protein association domain which is embedded within the transactivation domain . Classical E2Fs (E2F1-6) contain one DNA-binding domain which form heterodimers with DP proteins; atypical family members, E2F7 and E2F8, possess two DNA-binding domains, form homodimers or heterodimers, thus regulating transcription in a DP-independent manner .
Uracil DNA glycosylase family 2 (MUG/TDG)
Type: Family

G:U mismatches resulting from deamination of cytosine are the most common pro-mutagenic lesions occurring in DNA. Uracil is removed in a base-excision repair pathway by uracil DNA-glycosylase (UDG), which excises uracil from both single- and double-stranded DNA. The uracil DNA glycosylase family 2 consists of thymine DNA glycosylase (TDG) from eukaryotes and mismatch-specific uracil DNA glycosylase (MUG) from prokaryotes.

Thymine DNA glycosylases (TDG) in eukaryotic organisms are known for their double-stranded glycosylase activity on guanine/uracil (G/U) base pairs . In human TDG removes uracil and thymine from G:U and G:T mismatches in double-stranded DNA . In E. coli MUG is highly specific to G:U mismatches but also repairs G:T mismatches at high enzyme concentration. Structural studies of E. coli MUG reveal its structural homology to UDG despite low sequence identity. It has a specific uracil-binding pocket located in a DNA-binding groove and this specificity is likely the result of a multistep lesion recognition process .
Nuclear factor of activated T-cells 5, Rel homology domain, DNA-binding domain (NFAT5_RHD_DNA-bd)
Type: Domain

Nuclear factor of activated T-cells 5 (NFAT5) is a member of the nuclear factors of activated T cells (NFAT) of transcription factors. Proteins belonging to this family play a central role in inducible gene transcription during the immune response. This protein regulates gene expression induced by osmotic stress in mammalian cells. NFAT5, regulated by DDX5/DDX17, plays a role in the migratory capacity of breast cancer cells . Unlike monomeric members of this protein family, this protein exists as a homodimer and forms stable dimers with DNA elements. Five transcript variants encoding three different isoforms have been identified for this gene .

NFAT proteins appear to be regulated primarily at the level of their subcellular localisation . They are found exclusively in the cytoplasm of resting T cells, and consist of 2 components: a pre-existing cytoplasmic component that translocates into the nucleus on calcium mobilisation, and an inducible nuclear component comprising members of the activating protein-1 (AP-1) family of transcription factors. In response to antigen receptor signalling, the calcium-regulated phosphatase calcineurin acts directly to dephosphorylate NFAT proteins, causing their rapid translocation from the cytoplasm to the nucleus, where they cooperatively bind their target.

The Rel homology domain (RHD) is found in a family of eukaryotic transcription factors, which includes NF-kappaB, Dorsal, Relish, NFAT, among others. The RHD is composed of two structural domains: the N-terminal DNA binding domain that is similar to that found in P53, the C-terminal domain has an immunoglobulin-like fold (See

) that functions as a dimerisation domain. This entry represents the N-terminal DNA binding domain .