SII-SWORD/CoKE huggingface dataset:
Acetaldehyde dehydrogenase, C-terminal (Acetylaldehyde_DH_C)
Type: Domain

This C-terminal domain is found in prokaryotic acetaldehyde dehydrogenases, it adopts a structure consisting of an α-β-α-β(3) core, which mediates dimerisation of the protein .

The acetaldehyde dehydrogenase family of bacterial enzymes catalyses the formation of acetyl-CoA from acetaldehyde in the 3-hydroxyphenylpropinoate degradation pathway. It occurs as a late step in the meta-cleavage pathways of a variety of compounds, including catechol, biphenyl, toluene, salicylate .
Phosphatidylinositol 3-/4-kinase (PI3/4_kinase)
Type: Family

This group of proteins is comprised entirely of PI3- and PI4-kinases.

Phosphatidylinositol 3-kinase (PI3-kinase) (

) is an enzyme that phosphorylates phosphoinositides on the 3-hydroxyl group of the inositol ring. The three products of PI3-kinase - PI-3-P, PI-3,4-P(2) and PI-3,4,5-P(3) function as secondary messengers in cell signalling. Phosphatidylinositol 4-kinase (PI4-kinase) (

) is an enzyme that acts on phosphatidylinositol (PI) in the first committed step in the production of the secondary messenger inositol-1'4'5'-trisphosphate. This domain is also present in a wide range of protein kinases, involved in diverse cellular functions, such as control of cell growth, regulation of cell cycle progression, a DNA damage checkpoint, recombination, and maintenance of telomere length. Despite significant homology to lipid kinases, no lipid kinase activity has been demonstrated for any of the PIK-related kinases .

The PI3- and PI4-kinases share a well conserved domain at their C-terminal section; this domain seems to be distantly related to the catalytic domain of protein kinases . The catalytic domain of PI3/PI4KK has the typical bilobal structure that is seen in other ATP-dependent kinases, divided into an N-lobe and a C-lobe (

) . The core of this domain is the most conserved region of the PI3Ks. The N-lobe contains a five-stranded antiparallel β-sheet core flanked by a helical hairpin on one side and a helix on the other. The C-lobe contains helices, which form a helical bundle together with the N--obe helix. The helical bundle is flanked by three β-strands and a helix. Three loops are related to kinase activity, the glycine-rich G-loop, the catalytic loop and the activation loop. The G-loop has been reported to bind to the phosphate group of nucleotides .
Integrin beta-2 superfamily (Integrin_b-2_sf)
Type: Homologous_superfamily

Integrins are the major metazoan receptors for cell adhesion to extracellular matrix proteins and, in vertebrates, also play important roles in certain cell-cell adhesions, make transmembrane connections to the cytoskeleton, and activate many intracellular signalling pathways . An integrin receptor is a heterodimer composed of alpha and beta subunits. Each subunit crosses the membrane once, with most of the polypeptide residing in the extracellular space, and has two short cytoplasmic domains. Some members of this family have EGF repeats at the C terminus and also have a VWA domain inserted within the integrin domain at the N-terminal.

Most integrins recognise relatively short peptide motifs and, in general, require an acidic amino acid to be present. Ligand specificity depends upon both the alpha and beta subunits . There are at least 18 types of alpha and 8 types of beta subunits recognised in humans . Each alpha subunit tends to associate only with one type of beta subunit, but there are exceptions to this rule . Each association of alpha and beta subunits has its binding specificity and signalling properties. Many integrins require activation on the cell surface before they can bind ligands. Integrins frequently intercommunicate, and binding at one integrin receptor activates or inhibits another.

Integrin Beta-2 is also referred to as ITGB2 and is known to interact with three different alpha integrin chains: ITGAL, ITGAM and ITGAX. These three integrin heterodimers are associated with leukocyte adhesion deficiency (LAD), which is characterised by recurrent bacterial infections. LFA-1 (ITGB2/ITGAL) is one of the most well studied of these integrins. Engagement of LFA-1 results in increased AP-1 dependent gene expression, which is mediated by the nuclear translocation of JAB1 . The ligand for LFA-1 is JAM-1, a member of the endothelial immunoglobulin superfamily. JAM-1 contributes to LFA-1 dependent transendothelial migration of leukocytes and LFA-1 mediated arrest of T cells . Studies of marginal zone (MZ) B cells also showed that LFA-1, together with alpha4beta1, is required for localisation of those cells in the splenic MZ and that these integrins are necessary for lymphoid tissue compartmentalization .
Aldose 1-epimerase (Aldose_1-epimerase)
Type: Family

Aldose 1-epimerase (

) (also known as mutarotase) participates in the Leloir pathway for galactose/glucose interconversion. It is the enzyme responsible for the anomeric interconversion of D-glucose and other aldoses between their alpha- and beta-forms. The sequence of mutarotase from two bacteria, Acinetobacter calcoaceticus and Streptococcus thermophilus is available . The best conserved region in the sequence of mutarotase is centered around a conserved histidine residue which may be involved in the catalytic mechanism.

This entry includes galactose mutarotases/aldose-1-epimerases mainly from bacteria, plants and animals . In animals, beta-D-galactose is metabolized in the liver into glucose 1-phosphate, the primary metabolic fuel, by the action of four enzymes that constitute the Leloir pathway: GALM, GALK1 (galactokinase), GALT (galactose-1-phosphate uridylyltransferase) and GALE (UDP-galactose-4'-epimerase). A biallelic GALM variant has been identified as causing a novel type of galactosemia .
TATA-Box binding protein-like 1 (TBP-like)
Type: Family

This entry refers to TATA box-binding protein-like 1 proteins also known as TBP-like 1.

TATA-Box binding protein (TBP) is a general factor that plays a central role in the activation of eukaryotic genes transcribed by RNA polymerase II . TBP binds specifically to the TATA-box promoter element, which lies close to the position of transcription initiation.

TBP-like factors (TLF; also called TLP, TRF, TRP) are found in most metazoans. TLFs and TBPs have well-conserved core domains; however, they only share about 60% similarity. TLFs, like TBPs, interact with TFIIA and TFIIB, which are part of the basal transcription machinery. Yet, in contrast to TBPs, TLFs seem not to interact with the TATA-box and even have a negative effect on the transcription of TATA-containing promoters. Recent results indicate that TLFs are involved in the transcription via TATA-less promoters .
Bone morphogenetic protein 1/tolloid-like protein (BMP_1/tolloid-like)
Type: Family

This entry includes metalloproteases that serve as activators of a broader subset of the TGFbeta superfamily of proteins and are involved in the morphogenetic processes . Members of this family are bone morphogenetic protein 1 (BMP1), tolloid-like protein1/2 from mammals, dorsal-ventral patterning protein tolloid from Drosophila melanogaster, Zinc metalloproteinase nas-39 from Caenorhabditis elegans and others.
MDM4 (MDM4)
Type: Family

MDM4, also known as MDMX, is a MDM2-related protein that has been shown to inhibit p53, although not as well as MDM2 .
CD8 alpha subunit (CD8_asu)
Type: Family

The CD8 alpha subunit is a component of the CD8 α-β heterodimer and is additionally found as a homodimeric complex . Both of these species assist in the recognition of MHC class I-peptide complexes by the α-β T cell receptor (TCR). CD8 binds to constant regions of the peptide-MHC complex and augments antigen-specific interactions that are formed by the TCR . Additionally, CD8 is directly coupled to TCR signalling by virtue of its interactions with the p56Lck kinase , as well as other proteins. CD8 expression is limited to and one of the defining characteristics of cytolytic T cells.
Calcitonin gene-related peptide (Calcitonin_gene-rel_peptide)
Type: Family

The calcitonin (CT) gene is alternatively expressed in a tissue-specific manner, producing either the calcium regulatory hormone CT in the thyroid, or the neuropeptide calcitonin gene related peptide (CGRP) in the brain . In medullary carcinoma of the thyroid, both peptides are produced .

The calcitonin regulatory hormone is a peptide of 32 residues that causes a rapid but short-lived drop in calcium and phosphate levels in the blood by promoting the incorporation of these ions in the bones . The structure of Oncorhynchus sp. (Salmon) calcitonin has been studied by 2D NMR in SDS micelles . The main conformational feature of the hormone is an α-helix from residues 6-22, which includes an amphipathic segment. Two cysteine residues (at positions 1 and 7) form an N-terminal loop, and a C-terminal decapeptide forms a loop that folds back towards the helix .

CGRP is a 37-residue peptide produced by alternative splicing of the CT gene. CGRP induces vasodilation in various vessels, including those of the coronary, cerebral and systemic vasculature. A neurotransmitter or neuro-modulator role is suggested by its abundance in the CNS . The structure of human CGRP has been determined by 1H NMR . The main conformational feature of the hormone is an N-terminal disulphide-bonded loop (residues 2-7), leading into a well-defined α-helix between residues 8 and 18; thereafter, the structure is predominantly disordered, although there are indications of a preference for a turn-type conformation between residues 19 and 21 .

This entry represents the full-length propeptide (procalcitonin gene-related peptide or proCGRP) before cleavage into the calcitonin peptide.
Syntrophin (Syntrophin)
Type: Family

The syntrophin family are intracellular membrane-associated proteins that interact with both ion channels and signalling proteins. As such, syntrophins appear to be important for linking ion channels to intracellular signalling pathways. Syntrophins are concentrated at postsynaptic sites at the neuromuscular junction and may be involved in clustering acetylcholine receptors. In muscle and non-muscle tissues, syntrophin is associated with dystrophin, utrophin, and two homologues of the dystrophin carboxy-terminal region .

The five known syntrophin isoforms share a common domain organisation which includes two tandem pleckstrin homology (PH) domains at the N terminus, a PDZ domain and a C-terminal domain of ~70 amino acids that is unique to syntrophins (syntrophin unique, SU) .
CD3 protein, epsilon/gamma/delta subunit (CD3_esu/gsu/dsu)
Type: Family

The closely related CD3 epsilon, gamma and delta subunits constitute part of the invariant portion of the T cell receptor (TCR) complex. Both are transmembrane proteins with immunoglobulin-like domains in their extracellular regions. Each protein contains a single immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain that becomes phosphorylated upon ligation of the invariant TCR chains and provides binding sites for various downstream effectors .
Interleukin-2 receptor alpha (IL-2_rcpt_alpha)
Type: Family

The interleukin-2 receptor is a heterotrimer composed of one alpha chain, one beta chain, and one gamma chain, all of which are in contact with the ligand when the receptor is occupied . IL-2 itself has been shown to regulate IL-2R alpha expression in vitro .
Myb transcription factor, plants (Myb_TF_plants)
Type: Family

This entry represents a group of Myb transcription factors from plants which are involved in a variety of plant developmental processes and stress responses . Members of the family play crucial roles in anther development, microsporogenesis, and tapetal function, which are essential for pollen development. They are also key regulators of metabolic pathways, such as the biosynthesis of aliphatic glucosinolates, which contribute to plant defense against herbivores Additionally, some MYB proteins are implicated in the plant's response to abiotic stresses, including salt and osmotic stress, by regulating stress-responsive genes and metabolic adjustments . The family includes proteins that act as probable transcription factors, with some members specifically involved in the regulation of cell wall modification and suberin deposition under stress conditions .
Ubiquilin (Ubiquilin)
Type: Family

Ubiquitin is a protein of seventy six amino acid residues, found in all eukaryotic cells and whose sequence is extremely well conserved from protozoan to vertebrates. It is widely known as a post-translational tag used to signal a protein's hydrolytic destruction. Other functions for ubiquitin, depend on its differential internal isopeptide linkages. In addition, several ubiquitin-like proteins have been discovered from genome-sequencing efforts, other structural studies, and genetic screens. These new data show that proteins with the ubiquitin domain are adaptable, transposable genetic elements, which have been appended to other genes and utilised for many different cellular functions, depending on the ubiquitin-like protein's identity, subcellular location, and method of covalent attachment. The post-translational ligation of proteins to members of the ubiquitin superfamily can signal many different fates for the target protein .

Ubiquitin is a globular protein, the last four C-terminal residues (Leu-Arg-Gly-Gly) extending from the compact structure to form a 'tail' important for its function. The latter is mediated by the covalent conjugation of ubiquitin to target proteins, by an isopeptide linkage between the C-terminal glycine and the epsilon amino group of lysine residues in the target proteins.

Ubiquilin is a Ubiquitin-like (UBL) protein and has an N-terminal UBL domain and a C-terminal Ub-associated (UBA) domain in its structure.
Cholecystokinin-like (CCK-like)
Type: Family

Gastrin and cholecystokinin (CCK) are structurally and functionally related peptide hormones that function as hormonal regulators of various digestive processes and feeding behaviours. They are known to induce gastric secretion, stimulate pancreatic secretion, increase blood circulation and water secretion in the stomach and intestine, and stimulate smooth muscle contraction. Originally found in the gut, these hormones have since been shown to be present in various parts of the nervous system. Like many other active peptides they are synthesized as larger protein precursors that are enzymatically converted to their mature forms. They are found in several molecular forms due to tissue-specific post-translational processing. The biological activity of gastrin and CCK is associated with the last five C-terminal residues. One or two positions downstream, there is a conserved sulphated tyrosine residue. The amphibian caerulein skin peptide, the cockroach leukosulphakinin I and II (LSK) peptides, Drosophila melanogaster putative CCK-homologues Drosulphakinins I and II, cionin, a chicken gastrin/cholecystokinin-like peptide and cionin, a neuropeptide from the protochordate Ciona intestinalis belong to the same family.

This entry refers to cholecystokinin and cholecystokinin-like proteins including cholecystoxin and preprocaerulein.
Peptidase S8, subtilisin-related (Peptidase_S8_subtilisin-rel)
Type: Family

This entry contains serine endopeptidases belonging to the MEROPS peptidase family S8 (subtilisin family , clan SB).

Limited proteolysis of most large protein precursors is carried out in vivo by the subtilisin-like pro-protein convertases. Many important biological processes such as peptide hormone synthesis, viral protein processing and receptor maturation involve proteolytic processing by these enzymes . The subtilisin-serine protease (SRSP) family hormone and pro-protein convertases (furin, PC1/3, PC2, PC4, PACE4, PC5/6, and PC7/7/LPC) act within the secretory pathway to cleave polypeptide precursors at specific basic sites, generating their biologically active forms. Serum proteins, pro-hormones, receptors, zymogens, viral surface glycoproteins, bacterial toxins, amongst others, are activated by this route . The SRSPs share the same domain structure, including a signal peptide, the pro-peptide, the catalytic domain, the P/middle or homo B domain, and the C terminus.
Coronin (Coronin)
Type: Family

Coronins are evoluntionarily conserved WD-repeat-containing proteins mostly involved in actin cytoskeleton organisation. The WD40 motif is found in a multitude of eukaryotic proteins involved in a variety of cellular processes . Repeated WD40 motifs act as a site for protein-protein interaction, and proteins containing WD40 repeats are known to serve as platforms for the assembly of protein complexes or mediators of transient interplay among other proteins. The final 40 amino acids are predicted to form a coiled-coil in a coronin homodimer .

Coronin was first identified as an actin binding protein in Dictyostelium discoideum. It was named Coronin because of its association with crown-shaped cell surface projections of growth-phase D . Since then, several Coronin homologues and isoforms have been identified from yeast to human. Mammalian Coronin isoforms include Coronin 1A/B/C, Coronin 2A/B, Coronin 6 and Coronin 7. The yeast Coronin homologue is known as Crn1, while the Drosophila homologue is known as pod1.

In budding yeast, Crn1 regulates the actin filament nucleation/branching activity of the actin-related protein 2/3 (Arp2/3) complex through interaction with the Arc35p subunit .

Mammalian Coronin 1A is exclusively expressed in leukocytes and involved in the regulation of leukocyte specific signaling events . The crystal structure of Coronin 1A has been solved . Mammalian Coronin 1B can protect new (ATP-rich) filaments from F-actin severing Cofilin and dismantle old (ADP-rich) filaments by inducing Arp2/3 dissociation in lamellipodia .
Dishevelled-related protein (Dsh/Dvl-rel)
Type: Family

This entry includes the dishevelled (Dsh) proteins and dixin (also known as coiled-coil-DIX1, Ccd1).

The transduction mechanism requires dishevelled protein (Dsh), a cytoplasmic phosphoprotein that acts directly downstream of frizzled . In addition to its role in Wnt signalling, Dsh is also involved in generating planar polarity in Drosophila and has been implicated in the Notch signal transduction cascade. Furthermore, Dsh plays a vital molecular role in neural tube closure. Disruption of dishevelled signalling in Xenopus and inactivation of the genes encoding dishevelled 1 and dishevelled 2 (Dvl1 and Dvl2) in the mouse yield similar phenotypes, in which the neural tube fails to close . Three human and mouse homologues of Dsh have been cloned (DVL-1 to 3); it is believed that these proteins, like their Drosophila counterpart, are involved in signal transduction. Human and murine orthologues share more than 95% sequence identity and are each 40-50% identical to Drosophila Dsh.

Sequence similarity amongst Dsh proteins is concentrated around three conserved domains: at the N terminus lies a DIX domain (mutations mapping to this region reduce or completely disrupt Wg signalling); a PDZ (or DHR) domain, often found in proteins involved in protein-protein interactions, lies within the central portion of the protein (point mutations within this module have been shown to have little effect on Wg-mediated signal transduction); and a DEP domain is located towards the C terminus and is conserved among a set of proteins that regulate various GTPases. Whilst genetic and molecular assays have shown this module to be dispensable for Wg signalling, it is thought to be important in planar polarity signalling in flies .

Ccd1 is another DIX domain-possessing protein that forms complexes with the Dishevelled homologue Dvl and Axin. Ccd1 is a positive regulator of Wnt signalling . It regulates JNK activation by AXIN1 and DVL2 .
Ribosomal RNA large subunit methyltransferase E (rRNA-MeTfrase_E)
Type: Family

The ribosomal RNA large subunit methyltransferase E (

) methylates the 23S rRNA. It specifically methylates the uridine in position 2552 of 23s rRNA in the 50S particle using S-adenosyl-L-methionine as a substrate . It was previously known as cell division protein FtsJ.

This entry represents the ribosomal RNA large subunit methyltransferase E family, which also includes tRNA (uridine-2'-O-)-methyltransferases. This enzyme methylates the 2'-O-ribose of nucleotides at positions 32 and 34 of the tRNA anticodon loop .
Peptidoglycan recognition protein (PGRP)
Type: Family

This is a group of animal peptidoglycan recognition proteins homologous to Bacteriophage T3 lysozyme . The bacteriophage molecule, but not its moth homologue, has been shown to have N-acetylmuramoyl-L-alanine amidase activity. One member, Tag7, is a cytokine .
Semaphorin 3E, Sema domain (Semaphorin_3E_Sema)
Type: Domain

This entry represents the Sema domain of Semaphorin 3E, a protein interacting module located at the N-terminal end that contain four disulfide bonds formed by eight conserved cysteine residues. It serves as a receptor-recognition and -binding module .

Semaphorins were first cloned as recognised mediators of cellular guidance, and consist of a large family of phylogenetically conserved secreted and transmembrane signalling proteins. Among the best-characterised vertebrate Semaphorins are the five secreted Class 3 members that contain an approximately 500 amino acid N-terminal Semaphorin domain, a C2 type immunoglobulin domain, and a highly basic C-terminal tail . Two receptor families have been implicated in mediating the actions of class 3 semaphorins: the Neuropilins and Plexins. The nine known vertebrate Plexins are divided into four subfamilies (A through D) based on structure . Several Plexins have been shown to interact directly with some class 4, 7 and V Semaphorins, but class 3 Semaphorins, however, do not appear to bind Plexins directly. Rather, the functional receptors for these Semaphorins are complexes of Neuropilins and A-type Plexins, with the former serving as the ligand-binding moiety and the latter the signal-transducing component . There are two Neuropilins (NP-1 and NP-2), which bind the five class 3 Semaphorins preferentially. In particular, Sema3A binds NP-1, whereas Sema3F utilises NP-2, while NP-1 and NP-2 heterodimers are thought to serve as functional receptors for Sema3C .

Recent work suggests a possible role of Gallus gallus (Chicken) Sema3E/collapsin-5 in restricting growth of retinal ganglion cell axons to the optic fibre layer .
Deoxycytidylate deaminase-related (dCMP_deaminase-rel)
Type: Family

Deoxycytidylate deaminase (

) (dCMP deaminase) hydrolyzes deoxycytidylate mono phosphate (dCMP) into deoxyuridine mono phosphate (dUMP), thus providing the nucleotide substrate for thymidylate synthase. The enzyme requires zinc for catalytic activity which is regulated by the ratio of dCTP to dTTP, both the end products of the pyrimidine salvage pathway . It contains a cytidine and deoxycytidylate deaminase domain.

This entry also includes CDADC1 (cytidine and dCMP deaminase domain-containing protein 1), also known as testis development protein NYD-SP15, which may play an important role in testicular development and spermatogenesis . CDADC1 contains two cytidine and deoxycytidylate deaminase domains.
Imaginal disc growth factor (IDGF)
Type: Family

Imaginal disc growth factors (IDGFs), also known as chitinase-like proteins, are soluble factors involved in the regulation of proliferation in imaginal discs . They are a family of growth factors identified in insects that include at least five members, some of which are encoded by genes in a tight cluster . The IDGFs have an eight-stranded α/β barrel fold and are related to the glycosyl hydrolase family 18 (GH18) chitinases, but they have an amino acid substitution known to abolish chitinase catalytic activity . IDGFs may have evolved from chitinases to gain new functions as growth factors, interacting with cell surface glycoproteins involved in growth-promoting processes .