SII-SWORD/CoKE huggingface dataset:
Phospholipase A2 (PLA2)
Type: Family

Phospholipase A2 (

) (PLA2 or PLA2G1B) is a small lipolytic enzyme that releases fatty acids from the second carbon group of glycerol. It is involved in a number of physiologically important cellular processes, such as the liberation of arachidonic acid from membrane phospholipids . It plays a pivotal role in the biosynthesis of prostaglandin and other mediators of inflammation. PLA2 has four to seven disulphide bonds and binds a calcium ion that is essential for activity. Within the active enzyme, the alpha amino group is involved in a conserved hydrogen-bonding network linking the N-terminal region to the active site. The side chains of two conserved residues, His and Asp, participate in the catalytic network.

Many PLA2's are widely distributed in snakes, lizards, bees, and mammals. In mammals, there are at least four forms: pancreatic, membrane-associated, as well as two less well characterised forms. The venom of most snakes contains multiple forms of PLA2 . Some of them are presynaptic neurotoxins, which inhibit neuromuscular transmission by blocking acetylcholine release from the nerve termini.

Some of the proteins in this family 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 [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: Api m 1.
Somatomedin B domain (Somatomedin_B_dom)
Type: Domain

Somatomedin B (SMB), a serum factor of unknown function, is a small cysteine-rich peptide, derived proteolytically from the N terminus of the cell-substrate adhesion protein vitronectin . Cys-rich somatomedin B-like domains are found in a number of proteins , including ectonucleotide pyrophosphatase/phosphodiesterase family member proteins (previously known as plasma-cell membrane glycoprotein) and placental protein 11 (also known as Poly(U)-specific endoribonuclease), which appears to possess amidolytic activity.

The SMB domain of vitronectin has been demonstrated to interact with both the urokinase receptor and the plasminogen activator inhibitor-1 (PAI-1) and the conserved cysteines of the NPP1 somatomedin B-like domain have been shown to mediate homodimerisation .

The SMB domain contains eight Cys residues, arranged into four disulphide bonds. It has been suggested that the active SMB domain may be permitted considerable disulphide bond heterogeneity or variability, provided that the Cys25-Cys31 disulphide bond is preserved. The three dimensional structure of the SMB domain is extremely compact and the disulphide bonds are packed in the centre of the domain forming a covalently bonded core . The structure of the SMB domain presents a new protein fold, with the only ordered secondary structure being a single-turn α-helix and a single-turn 3(10)-helix .
Mouse mammary tumour virus superantigen (MMTV_SAg)
Type: Family

The Mouse mammary tumor virus (MMTV) is a milk-transmitted type B retrovirus. The superantigen (SAg) is encoded in the long terminal repeat .
SET domain (SET_dom)
Type: Domain

The SET domain is a 130 to 140 amino acid, evolutionary well conserved sequence motif that was initially characterised in the Drosophila proteins Su(var)3-9, Enhancer-of-zeste and Trithorax. In addition to these chromosomal proteins modulating gene activities and/or chromatin structure, the SET domain is found in proteins of diverse functions ranging from yeast to mammals, but also including some bacteria and viruses .

The SET domains of mammalian SUV39H1 and 2 and fission yeast clr4 have been shown to be necessary for the methylation of lysine-9 in the histone H3 N terminus . However, this histone methyltransferase (HMTase) activity is probably restricted to a subset of SET domain proteins as it requires the combination of the SET domain with the adjacent cysteine-rich regions, one located N-terminally (pre-SET) and the other posterior to the SET domain (post-SET). Post- and pre- SET regions seem then to play a crucial role when it comes to substrate recognition and enzymatic activity .

The structure of the SET domain and the two adjacent regions pre-SET and post-SET have been solved . The SET structure is all beta, but consists only in sets of few short strands composing no more than a couple of small sheets. Consequently the SET structure is mostly defined by turns and loops. An unusual feature is that the SET core is made up of two discontinual segments of the primary sequence forming an approximate L shape . Two of the most conserved motifs in the SET domain are constituted by (1) a stretch at the C-terminal containing a strictly conserved tyrosine residue and (2) a preceding loop inside which the C-terminal segment passes forming a knot-like structure, but not quite a true knot. These two regions have been proven to be essential for SAM binding and catalysis, particularly the invariant tyrosine where in all likelihood catalysis takes place .
Cysteine synthase/cystathionine beta-synthase, pyridoxal-phosphate attachment site (P-phosphate_BS)
Type: Binding_site

Cysteine synthase (

) (CSase) is the enzyme responsible for the formation of cysteine from O-acetyl-serine and hydrogen sulphide with the concomitant release of acetic acid . In bacteria such as Escherichia coli, two such forms of the enzyme are known (genes cysK and cysM). In plants there are also two forms, one located in the cytoplasm and the other in chloroplasts.

Cystathionine beta-synthase (

) catalyses the first irreversible step in homocysteine transulphuration, the conjugation of homocysteine and serine forming cystathionine. Like Csase it is a pyridoxal-phosphate dependent enzyme .

Both enzymes are evolutionary related. The pyridoxal-phosphate attaches to the lysine residue found in the N-terminal section of these enzymes; the sequence around the lysine residue is highly conserved.
Transcription factor STAT (STAT)
Type: Family

The STAT protein (Signal Transducers and Activators of Transcription) family contains transcription factors that are specifically activated to regulate gene transcription when cells encounter cytokines and growth factors, hence they act as signal transducers in the cytoplasm and transcription activators in the nucleus . Binding of these factors to cell-surface receptors leads to receptor autophosphorylation at a tyrosine, the phosphotyrosine being recognised by the STAT SH2 domain, which mediates the recruitment of STAT proteins from the cytosol and their association with the activated receptor. The STAT proteins are then activated by phosphorylation via members of the JAK family of protein kinases, causing them to dimerise and translocated to the nucleus, where they bind to specific promoter sequences in target genes. In mammals, STATs comprise a family of seven structurally and functionally related proteins: Stat1, Stat2, Stat3, Stat4, Stat5a and Stat5b, Stat6. STAT proteins play a critical role in regulating innate and acquired host immune responses. Dysregulation of at least two STAT signalling cascades (i.e. Stat3 and Stat5) is associated with cellular transformation.

Signalling through the JAK/STAT pathway is initiated when a cytokine binds to its corresponding receptor. This leads to conformational changes in the cytoplasmic portion of the receptor, initiating activation of receptor associated members of the JAK family of kinases. The JAKs, in turn, mediate phosphorylation at the specific receptor tyrosine residues, which then serve as docking sites for STATs and other signalling molecules. Once recruited to the receptor, STATs also become phosphorylated by JAKs, on a single tyrosine residue. Activated STATs dissociate from the receptor, dimerise, translocate to the nucleus and bind to members of the GAS (gamma activated site) family of enhancers.

The seven STAT proteins identified in mammals range in size from 750 and 850 amino acids. The chromosomal distribution of these STATs, as well as the identification of STATs in more primitive eukaryotes, suggest that this family arose from a single primordial gene. STATs share 6 structurally and functionally conserved domains including: an N-terminal domain (ND) that strengthens interactions between STAT dimers on adjacent DNA-binding sites; a coiled-coil STAT domain (CCD) that is implicated in protein-protein interactions; a DNA-binding domain (DBD) with an immunoglobulin-like fold similar to p53 tumour suppressor protein; an EF-hand-like linker domain connecting the DNA-binding and SH2 domains; an SH2 domain (

) that acts as a phosphorylation-dependent switch to control receptor recognition and DNA-binding; and a C-terminal transactivation domain . The crystal structure of the N terminus of Stat4 reveals a dimer. The interface of this dimer is formed by a ring-shaped element consisting of five short helices. Several studies suggest that this N-terminal dimerisation promotes cooperativity of binding to tandem GAS elements and with the transcriptional coactivator CBP/p300.
Nucleocapsid protein, coronavirus (Nucleocap_CoV)
Type: Family

The Nucleocapsid (N) protein is a highly immunogenic phosphoprotein also implicated in viral genome replication and in modulating cell signalling pathways. The N protein interacts with genomic and subgenomic RNA molecules. Together with the envelope protein M, it participates in genome condensation and packaging. The N protein is a highly immunogenic and abundantly expressed protein during infection, capable of inducing protective immune responses against SARS-CoV and SARS-CoV-2 .

Coronavirus (CoV) nucleocapsid (N) proteins have 3 highly conserved domains. The N-terminal domain (NTD) (N1b), the C-terminal domain (CTD)(N2b) and the N3 region. The N1b and N2b domains from SARS CoV, infectious bronchitis virus (IBV), human CoV 229E and mouse hepatic virus (MHV) display similar topological organisations. N proteins form dimers, which are asymmetrically arranged into octamers via their N2b domains.

Domains N1b and N2b are linked by another domain N2a that contains an SR-rich region (rich in serine and arginine residues). A priming phosphorylation of specific serine residues by an as yet unknown kinase, triggers the subsequent phosphorylation by the host glycogen synthase kinase-3 (GSK-3) of several residues in the SR-rich region. This phosphorylation allows the N protein to associate with the RNA helicase DDX1 permitting template read-through, and enabling the transition from discontinuous transcription of subgenomic mRNAs (sgmRNAs) to continuous synthesis of longer sgmRNAs and genomic RNA (gRNA). Production of gRNA in the presence of N oligomers may promote the formation of ribonucleoprotein complexes, and the newly transcribed sgmRNA would guarantee efficient synthesis of structural proteins .

It has been shown that N proteins interact with nonstructural protein 3 (NSP3) and thus are recruited to the replication-transcription complexes (RTCs). In MHV, the N1b and N2a domains mediate the binding to NSP3 in a gRNA-independent manner. At the RTCs, the N protein is required for the stimulation of gRNA replication and sgmRNA transcription. It remains unclear, however, how and why the N protein orchestrates viral RNA synthesis. The cytoplasmic N-terminal ubiquitin-like domain of NSP3 and the SR-rich region of the N2a domain of the N protein may be important for this interaction. The direct association of N protein with RTCs is a critical step for MHV infection .

The entry represents the Coronavirus nucleocapsid protein.
Legume lectin domain (Legume_lectin_dom)
Type: Domain

Lectins are carbohydrate-binding proteins. Leguminous lectins form one of the largest lectin families and resemble each other in their physicochemical properties, though they differ in their carbohydrate specificities. They bind either glucose/mannose or galactose . Carbohydrate-binding activity depends on the simultaneous presence of both a calcium and a transition metal ion . The exact function of legume lectins is not known, but they may be involved in the attachment of nitrogen-fixing bacteria to legumes and in the protection against pathogens .

Some legume lectins are proteolytically processed to produce two chains, beta (which corresponds to the N-terminal) and alpha (C-terminal) . The lectin concanavalin A (conA) from jack bean is exceptional in that the two chains are transposed and ligated (by formation of a new peptide bond). The N terminus of mature conA thus corresponds to that of the alpha chain and the C terminus to the beta chain . Though the legume lectins monomer is structurally well conserved, their quaternary structures vary widely .
Glycoside hydrolase family 18, catalytic domain (Glyco_hydro18_cat)
Type: Domain

The glycosyl hydrolases family 18 (GH18)

is widely distributed in all kingdoms and contains hydrolytic enzymes with chitinase or endo-N-acetyl-beta-D-glucosaminidase (ENGase) activity as well as chitinase-like lectins (chi-lectins/proteins (CLPs). Chitinases (

) are hydrolytic enzymes that cleave the beta-1,4-bond releasing oligomeric, dimeric (chitobiose) or monomeric (N-actetylglucosamine, GlcNAc) products. ENGases (

) hydrolyze the beta-1,4 linkage in the chitobiose core of N-linked glycans from glycoproteins leaving one GlcNAc residue on the substrate. CLPs do not display chitinase activity but some of them have been reported to have specific functions and carbohydrate binding property . This family also includes glycoproteins from mammals, such as oviduct-specific glycoproteins.

This entry represents the catalytic domain of GH18s, which has a common (β/α)8 triosephosphate isomerase (TIM)-barrel structure that consists of a barrel-like framework made from eight internal parallel β-strands that are alternately connected by eight exterior α-helices. The active site motif DxxDxDxE is essential for the activity of the GH18 catalytic domain. .

O-Glycosyl hydrolases (

) are a widespread group of enzymes that hydrolyse the glycosidic bond between two or more carbohydrates, or between a carbohydrate and a non-carbohydrate moiety. A classification system for glycosyl hydrolases, based on sequence similarity, has led to the definition of 85 different families . This classification is available on the CAZy (CArbohydrate-Active EnZymes) website.
Vasopressin V1A receptor (Vprs_V1A_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 .

Vasopressin and oxytocin are members of the neurohypophyseal hormone family found in all mammalian species. They are present in high levels in the posterior pituitary. Vasopressin has an essential role in the control of the water content of the body, acting in the kidney to increase water and sodium absorption. In higher concentrations, vasopressin stimulates contraction of vascular smooth muscle, stimulates glycogen breakdown in the liver, induces platelet activation, and evokes release of corticotrophin from the anterior pituitary. Vasopressin and its analogues are used clinically to treat diabetes insipidus.

In the periphery, the V1A receptor is found in high levels in vascular smooth muscle, myometrium and the bladder where it mediates contraction. In the CNS, V1 sites are distributed widely and are found in lateral septal nucleus, hippocampus, superior collicular, substantia nigra and central grey matter. The receptors activate phosphoinositide metabolism through a pertussis-toxin-insensitive G-protein, probably of the Gq/G11 class.
Flavodoxin, conserved site (Flavodoxin_CS)
Type: Conserved_site

Flavodoxins are electron-transfer proteins that function in various electron transport systems. Flavodoxins bind one FMN molecule, which serves as a redox-active prosthetic group and are functionally interchangeable with ferredoxins. They have been isolated from prokaryotes, cyanobacteria, and some eukaryotic algae.

This entry represents a conserved site, indicative of the N-terminal region of Flavodoxin proteins that spans an FMN-binding site .

This conserved site is also found in Protoporphyrinogen IX dehydrogenase (quinone), encoded by the gene hemG in gamma-proteobacteria. Protoporphyrinogen IX dehydrogenase (quinone) is a member of a class of the long chain flavodoxin family, and was found to show protoporphyrinogen oxidase activity .
Acyl transferase domain superfamily (Ac_transferase_dom_sf)
Type: Homologous_superfamily

Enzymes like bacterial malonyl CoA-acly carrier protein transacylase (

) and eukaryotic fatty acid synthase (

) that are involved in fatty acid biosynthesis belong to this group . Also included are the polyketide synthases 6-methylsalicylic acid synthase (

), a multifunctional enzyme that involved in the biosynthesis of patulin and conidial green pigment synthase (

) and several non-reducing polyketide synthases.
2-C-methyl-D-erythritol 4-phosphate cytidylyltransferase (IspD)
Type: Family

2-C-methyl-D-erythritol 4-phosphate cytidylyltransferase (IspD) catalyses the formation of 4-diphosphocytidyl-2-C-methyl-D-erythritol from CTP and 2-C-methyl-D-erythritol 4-phosphate (MEP) in the deoxyxylulose pathway of isopentenyl diphosphate (IPP) biosynthesis . This mevalonate independent pathway that utilizes pyruvate and glyceraldehydes 3-phosphate as starting materials for production of IPP occurs in a variety of bacteria, archaea and plant cells, but is absent in mammals. The isoprenoid pathway is a well known target for anti-infective drug development . In about twenty percent of bacterial genomes, this protein occurs as IspDF, a bifunctional fusion protein.
Jacalin-like lectin domain (Jacalin-like_lectin_dom)
Type: Domain

The jacalin-like mannose-binding lectin domain has a β-prism fold consisting of three 4-stranded β-sheets, with an internal pseudo 3-fold symmetry. Some proteins with this domain stimulate distinct T- and B- cell functions, such as the plant lectin jacalin, which binds to the T-antigen and acts as an agglutinin. The domain can occur in tandem-repeat arrangements with up to six copies, and in architectures combined with a variety of other functional domains. While the family was initially named after an abundant protein found in the jackfruit seed, taxonomic distribution is not restricted to plants. The domain is also found in the salt-stress induced protein from rice and an animal prostatic spermine-binding protein. Proteins containing this domain include:

Jacalin, a tetrameric plant seed lectin and agglutinin from Artocarpus heterophyllus (jackfruit), which is specific for galactose .

Artocarpin, a tetrameric plant seed lectin from A. heterophyllus .

Lectin MPA, a tetrameric plant seed lectin and agglutinin from Maclura pomifera (Osage orange), .

Heltuba lectin, a plant seed lectin and agglutinin from Helianthus tuberosus (Jerusalem artichoke) .

Agglutinin from Calystegia sepium (Hedge bindweed) .

Griffithsin, an anti-viral lectin from red algae (Griffithsia species) .
CD44 antigen (CD44_antigen)
Type: Family

CD44, also known as the hyaluronan receptor , is a polymorphic cell-surface glycoprotein synthesised in a variety of cells. The protein interacts with actin-based cytoskeletons, and co-localises with ERM proteins (ezrin, radixin and moesin) at actin filament- plasma membrane interaction sites. CD44 may be involved in cell migration, adhesion and differentiation in normal cells, as well as in metastasis in cancer cells. It is a receptor for extracellular materials, such as soluble or cell-bound hyaluronic acid, collagen, fibronectin and serglycin. The protein has a single membrane-spanning domain and has a heavily glycosylated extracellular domain; its cytoplasmic domain is reportedly associated with an ankyrin-like protein .

Some of the proteins in this group are responsible for the molecular basis of the blood group antigens, surface markers on the outside of the red blood cell membrane. Most of these markers are proteins, but some are carbohydrates attached to lipids or proteins [Reid M.E., Lomas-Francis C. The Blood Group Antigen FactsBook Academic Press, London / San Diego, (1997)]. CD44 antigen (Phagocytic glycoprotein I) belongs to the Indian blood group system and is associated with In(a/b) antigen.
S-phase kinase-associated protein 1-like (SKP1-like)
Type: Family

This entry includes SKP1 and SKP1-like protein, elongin-C (also known as TCEB1). SKP1 is part of the E3 ubiquitin ligase complexes. Elongin-C has dual functions, works as a component of RNA polymerase II (Pol II) transcription elongation factor and as the substrate recognition subunit of a Cullin-RING E3 ubiquitin ligase .

Mammlian S-phase kinase-associated protein 1 (SKP1) is an essential component of the SCF (SKP1-CUL1-F-box protein) ubiquitin ligase complex, which mediates the ubiquitination of proteins involved in cell cycle progression, signal transduction and transcription . It is also part of the ubiquitin E3 ligase complex (Skp1-Pam-Fbxo45) that controls the core epithelial-to-mesenchymal transition-inducing transcription factors . Budding yeast Skp1 is a kinetochore protein found in several complexes, including the SCF ubiquitin ligase complex, the CBF3 complex that binds centromeric DNA , and the RAVE complex that regulates assembly of the V-ATPase .
RNA-splicing ligase, RtcB (RtcB)
Type: Family

RctB is a RNA ligase that mediates the joining of broken tRNA-like stem-loop structures in case of tRNA damage. It probably participates to tRNA restriction-repair by ligating broken tRNA-like stem-loop structures with 2',3'-cyclic phosphate and 5'-OH ends to form a splice junction with a 2'-OH, 3',5'-phosphodiester . In worms, this protein has as a neuroprotective role in the age-dependent degeneration of dopamine neurons .