SII-SWORD/CoKE huggingface dataset:
Annexin A6 (ANX6)
Type: Family

The annexins (or lipocortins) are a family of proteins that bind to phospholipids in a calcium-dependent manner . The 12 annexins common to vertebrates are classified in the annexin A family and named as annexins A1-A13 (or ANXA1-ANXA13), leaving A12 unassigned in the official nomenclature. Annexins outside vertebrates are classified into families B (in invertebrates), C (in fungi and some groups of unicellular eukaryotes), D (in plants), and E (in protists) . Annexins are absent from yeasts and prokaryotes .

Most eukaryotic species have 1-20 annexin (ANX) genes. All annexins share a core domain made up of four similar repeats, each approximately 70 amino acids long . Each individual annexin repeat (sometimes referred to as endonexin folds) is folded into five α-helices, and in turn are wound into a right-handed super-helix; they usually contain a characteristic 'type 2' motif for binding calcium ions with the sequence 'GxGT-[38 residues]-D/E'. Animal and fungal annexins also have variable amino-terminal domains. The core domains of most vertebrate annexins have been analysed by X-ray crystallography, revealing conservation of their secondary and tertiary structures despite only 45-55% amino-acid identity among individual members. The four repeats pack into a structure that resembles a flattened disc, with a slightly convex surface on which the Ca2+ -binding loops are located and a concave surface at which the amino and carboxyl termini come into close apposition.

Annexins are traditionally thought of as calcium-dependent phospholipid-binding proteins, but recent work suggests a more complex set of functions. The family has been linked with inhibition of phospholipase activity, exocytosis and endocytosis, signal transduction, organisation of the extracellular matrix, resistance to reactive oxygen species and DNA replication .

This entry represents Type VI annexins that are found in various secretory cells, e.g. B- and T-cells (where it is found in greater concentrations in mature cells), and the lactation ducts of non-lactating human breasts. The observation that the protein is absent in lactating breasts suggests that it inhibits secretion. The type VI class may also play a part in the regulation of some calcium channels, and its presence may cause arrest of cell growth, before the DNA-replication stage, in cells growing at low serum concentrations. This annexin class is unusual in containing eight repeats of the conserved domain rather than the usual four. It is thus believed that the protein has arisen from a gene duplication event.
Nicotinic acetylcholine receptor (Nicotinic_acetylcholine_rcpt)
Type: Family

Nicotinic acetylcholine receptors are ligand-gated ion channels that mediate signal transduction at the post-synaptic membrane of cholinergic synapses, such as the neuromuscular junction . They belong to a family of neurotransmitter-gated receptors, including glycine, gamma-aminobutyric-acid (GABA), serotonin 5HT3 receptors. These are oligomeric transmembrane (TM) complexes (pentamers of 2 alpha and 1 beta, 1 gamma and 1 delta subunit) that contain a central channel, which transiently opens upon binding of a specific neurotransmitters. Their sequences are related and share the same topology: each has an extracellular, glycosylated N-terminal ligand-binding domain; 3 hydrophobic TM regions, which form the channel; a hydrophilic cytoplasmic domain; followed by a fourth putative TM region . The nicotinic receptor ligand binding domain is a specialised pocket of aromatic and hydrophobic residues formed at interfaces between protein subunits that changes conformation to convert agonist binding into gating of an intrinsic ion channel .

Neurotransmitter ligand-gated ion channels are transmembrane receptor-ion channel complexes that open transiently upon binding of specific ligands, allowing rapid transmission of signals at chemical synapses . Five of these ion channel receptor families have been shown to form a sequence-related superfamily:

Nicotinic acetylcholine receptor (AchR), an excitatory cation channel in vertebrates and invertebrates; in vertebrate motor endplates it is composed of alpha, beta, gamma and delta/epsilon subunits; in neurons it is composed of alpha and non-alpha (or beta) subunits .

Glycine receptor, an inhibitory chloride ion channel composed of alpha and beta subunits .

Gamma-aminobutyric acid (GABA) receptor, an inhibitory chloride ion channel; at least four types of subunits (alpha, beta, gamma and delta) are known .

Serotonin 5HT3 receptor, of which there are seven major types (5HT3-5HT7) .

Glutamate receptor, an excitatory cation channel of which at least three types have been described (kainate, N-methyl-D-aspartate (NMDA) and quisqualate) .

These receptors possess a pentameric structure (made up of varying subunits), surrounding a central pore. All known sequences of subunits from neurotransmitter-gated ion-channels are structurally related. They are composed of a large extracellular glycosylated N-terminal ligand-binding domain, followed by three hydrophobic transmembrane regions which form the ionic channel, followed by an intracellular region of variable length. A fourth hydrophobic region is found at the C-terminal of the sequence .
HMW kininogen (Kininogen)
Type: Family

The kininogens are multidomain proteins, belonging to the Type 3 cystatin family . It contains three tandemly repeated type 2-like cystatin domains of which only the second and third (D2 and D3) exhibit cysteine peptidase inhibitory activity, and which belong to MEROPS inhibitor family I25B.
Selectin superfamily (Selectin_superfamily)
Type: Family

Animal lectins display a wide variety of architectures. They are classified according to the carbohydrate-recognition domain (CRD) of which there are two main types, S-type and C-type.

C-type lectins

display a wide range of specificities. They require Ca
2+
for their activity. They are found predominantly but not exclusively in vertebrates.

They can be classified into a number of subgroups based on their function and structure:

Endocytic lectins -Membrane-bound receptors that mediate endocytosis of glycoproteins

Collectins -Represented by the soluble mannose-binding proteins of mammalian serum and liver

Selectins -Membrane-bound proteins involved in inflammation. There are three main divisions, CD62E, CD62 L and CD62P .

CD62E (also called E-selectin, ELAM-1 or LECAM-2), CD62L (also called L-selectin, LAM-1, LECAM-1, Leu-8, MEL-14 or TQ-1) and CD62P (also called P-selectin, granule membrane protein-140, GMP-140 or platelet activation dependent granule-external membrane protein, PADGEM) belong to this group. CD62E mediates leukocyte rolling on activated endothelium at inflammatory sites and may also support tumor cell adhesion during hematogenous metastasis, and play a role in angiogenesis. CD62L mediates lymphocyte homing to high endothelial venules of peripheral lymphoid tissue and leukocyte rolling on activated endothelium at inflammatory sites. Interaction of CD62P with PSGL-1 mediates tethering and rolling of leukocytes on the surface of activated endothelial cells, the first step in leukocyte extravasation and migration towards inflammations. CD62P mediates rolling of platelets on endothelial cells and CD62P-mediated interactions are also involved in platelet-mediated delivery of lymphocytes to high endothelial venules.

Members of the selectin superfamily have the same domain structure: an N-terminal lectin domain followed by an EGF repeat; a variable number (between 2 and 9) of complement regulatory elements; a single trans-membrane region; and a short cytoplasmic anchor. Some studies have found distinct carbohydrate structures on leukocytes that are adhered to by selectins, suggesting that selectins are involved in the selective trafficking of blood-borne components of the immune system.
Cytochrome P450, B-class (Cyt_P450_B)
Type: Family

This entry represents class B cytochrome P450 proteins, which are part of 3-component systems in bacteria, mitochondria and certain fungal enzymes.

Cytochrome P450 enzymes are a superfamily of haem-containing mono-oxygenases that are found in all kingdoms of life, and which show extraordinary diversity in their reaction chemistry. In mammals, these proteins are found primarily in microsomes of hepatocytes and other cell types, where they oxidise steroids, fatty acids and xenobiotics, and are important for the detoxification and clearance of various compounds, as well as for hormone synthesis and breakdown, cholesterol synthesis and vitamin D metabolism. In plants, these proteins are important for the biosynthesis of several compounds such as hormones, defensive compounds and fatty acids. In bacteria, they are important for several metabolic processes, such as the biosynthesis of antibiotic erythromycin in Saccharopolyspora erythraea (Streptomyces erythraeus).

Cytochrome P450 enzymes use haem to oxidise their substrates, using protons derived from NADH or NADPH to split the oxygen so a single atom can be added to a substrate. They also require electrons, which they receive from a variety of redox partners. In certain cases, cytochrome P450 can be fused to its redox partner to produce a bi-functional protein, such as with P450BM-3 from Bacillus megaterium , which has haem and flavin domains.

Organisms produce many different cytochrome P450 enzymes (at least 58 in humans), which together with alternative splicing can provide a wide array of enzymes with different substrate and tissue specificities. Individual cytochrome P450 proteins follow the nomenclature: CYP, followed by a number (family), then a letter (subfamily), and another number (protein); e.g. CYP3A4 is the fourth protein in family 3, subfamily A. In general, family members should share >40% identity, while subfamily members should share >55% identity.

Cytochrome P450 proteins can also be grouped by two different schemes. One scheme was based on a taxonomic split: class I (prokaryotic/mitochondrial) and class II (eukaryotic microsomes). The other scheme was based on the number of components in the system: class B (3-components) and class E (2-components). These classes merge to a certain degree. Most prokaryotes and mitochondria (and fungal CYP55) have 3-component systems (class I/class B) -a FAD-containing flavoprotein (NAD(P)H-dependent reductase), an iron-sulphur protein and P450. Most eukaryotic microsomes have 2-component systems (class II/class E) -NADPH:P450 reductase (FAD and FMN-containing flavoprotein) and P450. There are exceptions to this scheme, such as 1-component systems that resemble class E enzymes . The class E enzymes can be further subdivided into five sequence clusters, groups I-V, each of which may contain more than one cytochrome P450 family (eg, CYP1 and CYP2 are both found in group I). The divergence of the cytochrome P450 superfamily into B-and E-classes, and further divergence into stable clusters within the E-class, appears to be very ancient, occurring before the appearance of eukaryotes.
Peptidase C14 family (Pept_C14)
Type: Family

This group of sequences represent the p45 (45kDa) precursor of caspases, which can be processed to produce the active p20 (20kDa) and p10 (10kDa) subunits. Caspases (Cysteine-dependent ASPartyl-specific proteASE) are cysteine peptidases that belong to the MEROPS peptidase family C14 (caspase family, clan CD) based on the architecture of their catalytic dyad or triad . Caspases are tightly regulated proteins that require zymogen activation to become active, and once active can be regulated by caspase inhibitors. Activated caspases act as cysteine proteases, using the sulphydryl group of a cysteine side chain for catalysing peptide bond cleavage at aspartyl residues in their substrates. The catalytic cysteine and histidine residues are on the p20 subunit after cleavage of the p45 precursor.

Caspases are mainly involved in mediating cell death (apoptosis) . They have two main roles within the apoptosis cascade: as initiators that trigger the cell death process, and as effectors of the process itself. Caspase-mediated apoptosis follows two main pathways, one extrinsic and the other intrinsic or mitochondrial-mediated. The extrinsic pathway involves the stimulation of various TNF (tumour necrosis factor) cell surface receptors on cells targeted to die by various TNF cytokines that are produced by cells such as cytotoxic T cells. The activated receptor transmits the signal to the cytoplasm by recruiting FADD, which forms a death-inducing signalling complex (DISC) with caspase-8. The subsequent activation of caspase-8 initiates the apoptosis cascade involving caspases 3, 4, 6, 7, 9 and 10. The intrinsic pathway arises from signals that originate within the cell as a consequence of cellular stress or DNA damage. The stimulation or inhibition of different Bcl-2 family receptors results in the leakage of cytochrome c from the mitochondria, and the formation of an apoptosome composed of cytochrome c, Apaf1 and caspase-9. The subsequent activation of caspase-9 initiates the apoptosis cascade involving caspases 3 and 7, among others. At the end of the cascade, caspases act on a variety of signal transduction proteins, cytoskeletal and nuclear proteins, chromatin-modifying proteins, DNA repair proteins and endonucleases that destroy the cell by disintegrating its contents, including its DNA. The different caspases have different domain architectures depending upon where they fit into the apoptosis cascades, however they all carry the catalytic p10 and p20 subunits.

Caspases can have roles other than in apoptosis, such as caspase-1 (interleukin-1 beta convertase) (

), which is involved in the inflammatory process. The activation of apoptosis can sometimes lead to caspase-1 activation, providing a link between apoptosis and inflammation, such as during the targeting of infected cells. Caspases may also be involved in cell differentiation .
IRS-type PTB domain (IRS_PTB)
Type: Domain

Insulin receptor substrate (IRS) molecules are mediators in insulin signaling and play a role in maintaining basic cellular functions such as growth and metabolism. They act as docking proteins between the insulin receptor and a complex network of intracellular signaling molecules containing Src homology 2 (SH2) domains. Four members (IRS-1, IRS-2, IRS-3, IRS-4) of this family have been identified that differ as to tissue distribution, subcellular localization, developmental expression, binding to the insulin receptor, and interaction with SH2 domain-containing proteins. IRS molecules have an N-terminal pleckstrin homology domain (

), followed by an IRS-like phosphotyrosine binding (PTB) domain which has a PH-like fold. These domains facilitate interaction with the activated tyrosine-phosphorylated insulin receptor. The PTB domain is situated towards the N terminus. Two arginines in this domain are responsible for hydrogen bonding phosphotyrosine residues on a Ac-LYASSNPApY-NH2 peptide in the juxtamembrane region of the insulin receptor. Further interactions via `bridged' water molecules are coordinated by residues an Asn and a Ser residue .

PTB domains function as adaptors or scaffolds to organise the signalling complexes involved in wide-ranging physiological processes including neural development, immunity, tissue homeostasis and cell growth. Due to structural differences, PTB domains are divided into three groups represented by phosphotyrosine-dependent IRS-like, phosphotyrosine-dependent Shc-like, and phosphotyrosine-independent Dab-like PTBs.

IRS-type PTB domain has an average length of about 100 amino acids. It binds to the insulin receptor through the Asn-Pro-Xaa-Tyr(P) motif found in many tyrosine-phosphorylated proteins. This domain is found in IRS/Dok/SNT proteins that are the major adapters for RTK and cytokine signaling. This domain binds both peptides and headgroups of phosphatidylinositides, utilizing two distinct binding motifs to mediate spatial organisation and localization within cells. The IRS-type PTB domain is found alone or in association with the PH domain . More recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains. This entry is part of the IRS-like subgroup .

The 3D structure of IRS-type PTB domain has been solved . It shares a folding pattern commonly referred to as the PH-domain "superfold". The core "superfold" consists of seven antiparallel β strands forming two orthogonal β sheets. This β sandwich is capped at the C terminus by an α helix. It contains a peptide binding pocket (formed by the β strand 5 and the C-terminal α helix) and a highly basic phospholipid binding "crown" (largely composed of residues from loop regions near the N terminus) .
Natriuretic peptide, C type (C_natriurtcpep)
Type: Family

Atrial natriuretic peptides (ANPs) are vertebrate hormones that play an important role in the control of cardiovascular homeostatis, and sodium and water balance in general . There are different NPs that vary in length but share a common core. All are processed from a single precursor.

A disulphide bond resident in the C-terminal section is required for full activity of atriopeptins. The family of NPs includes structurally-related peptides that elicit similar pharmacological spectra. Amongst these are brain natriuretic peptide (BNP); C-type natriuretic peptide (CNP); ventricular natriuretic peptide (VNP) ; and Dendroaspis angusticeps (Eastern green mamba) natriuretic peptide (DNP) .

C-type natriuretic peptide has vasorelaxant and cGMP-stimulating activities.
Natriuretic peptide, brain type (Natriuretic_peptide_brain)
Type: Family

Atrial natriuretic peptides (ANPs) are vertebrate hormones that play an important role in the control of
cardiovascular homeostatis, and sodium and water balance in general .
There are different NPs that vary in length but share a common core. All are processed from a single precursor.
A disulphide bond resident in the C-terminal section is required for full activity of atriopeptins. The family
of NPs includes structurally-related peptides that elicit similar pharmacological spectra. Amongst these are
Brain natriuretic peptide (BNP); C-type natriuretic peptide (CNP) ; Taipan natriuretic peptide (TNP) ; ventricular Natriuretic peptide (VNP) ; and Dendroaspis angusticeps (Eastern green mamba) natriuretic peptide (DNP) .
Peptidase S33 (Peptidase_S33)
Type: Family

Proteolytic enzymes that exploit serine in their catalytic activity are ubiquitous, being found in viruses, bacteria and eukaryotes . They include a wide range of peptidase activity, including exopeptidase, endopeptidase, oligopeptidase and omega-peptidase activity. Many families of serine protease have been identified, these being grouped into clans on the basis of structural similarity and other functional evidence . Structures are known for members of the clans and the structures indicate that some appear to be totally unrelated, suggesting different evolutionary origins for the serine peptidases .

Not withstanding their different evolutionary origins, there are similarities in the reaction mechanisms of several peptidases. Chymotrypsin, subtilisin and carboxypeptidase C have a catalytic triad of serine, aspartate and histidine in common: serine acts as a nucleophile, aspartate as an electrophile, and histidine as a base . The geometric orientations of the catalytic residues are similar between families, despite different protein folds . The linear arrangements of the catalytic residues commonly reflect clan relationships. For example the catalytic triad in the chymotrypsin clan (PA) is ordered HDS, but is ordered DHS in the subtilisin clan (SB) and SDH in the carboxypeptidase clan (SC) .

This entry represents a group of serine peptidase belonging to peptidase family S33 (clan SC). They include prolinases (Pro-Xaa dipeptidase,

), prolyl aminopeptidases (

), and L-amino acid amidases.
Cereal allergen/alpha-amylase inhibitor, rice type (Allergen/amylase_inhib_rice)
Type: Family

Seeds of cereals contain a variety of serine protease and alpha-amylase inhibitors. These inhibitors can be grouped into families based on structural similarities. Rice seed allergenic proteins (RA) have sequence homology to seed trypsin/alpha-amylase inhibitors. Some have serine peptidase activity or alpha-amylase, and a few are bifunctional. The proteins contain ~10 cysteine residues, all of which are involved in disulphide bond formation .

This majority of sequences in this family are from Oryza sativa (Rice), exceptions are from Hordeum vulgare (Barley) and Triticum aestivum (Wheat). The majority are annotated either as alpha-amylase inhibitors or seed allergens and all belong to the MEROPS inhibitor family I6, clan IJ. There is no direct evidence to suggest that they can inhibit serine peptidases belonging to MEROPS peptidase S1 , and studies on a closely related alpha-amylase inhibitor from Secale cereale (Rye) demonstrates no activity against trypsin, and illustrates the necessity of exercising caution in assigning function based on sequence comparisons .

The rice seed allergenic proteins are encoded by a multigene family consisting of at least four members. A conserved sequence similar to a motif identified in rice glutelin promoters was observed in the 5' region of the two genes. RA genes are specifically expressed in ripening seeds and they accumulate maximally 15-20 days after flowering .
Venom allergen 5-like (V5_allergen-like)
Type: Family

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 [WHO/IUIS Allergen Nomenclature Subcommittee King T.P., Hoffmann D., Loewenstein H., Marsh D.G., Platts-Mills T.A.E., Thomas W. Bull. World Health Organ. 72:797-806(1994)]. 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 family include allergens with the following designations: Dol m 5, Pol d 5, Pol e 5, Pol f 5, Sol i 3, Sol r 3, Ves c 5,Ves f 5, Ves g 5, Ves m 5, Ves p 5, Ves s 5, Ves v 5, Ves vi 5 and Vesp m 5.

Venom allergen 5 (Ves 5) is a major allergen of vespid wasp venom . Regions of conservation have been identified that are shared both by a family of proteins from human, mouse and rat testis, and by a class of pathogenesis-related proteins from Nicotiana tabacum (Common tobacco) and Solanum lycopersicum (Tomato) (Lycopersicon esculentum) leaves. Ves 5 also shares similarity with the Solenopsis invicta (Red imported fire ant) 3 allergen .