SII-SWORD/CoKE huggingface dataset:
Bombyxin B (Bombyxin_B)
Type: Family

Bombyxin family can be classified into 7 families, A to G, according to their sequence similarity . This entry represents Bombyxin B.

Bombyxin is a brain peptide responsible for activation of prothoracic glands to produce ecdysone in insects . When cleaved, bombyxins produce both subunits of the biologically active heterodimer. Several molecular species of bombyxin have now been identified in Bombyx, Agrius and Samia moth species. Both bombyxin and insulin contain six cysteine residues with identical distributions and are predicted to have similar tertiary structures, especially in their core regions . They are not functionally equivalent. However, the similarity to insulin has prompted speculation that it may play a role in the regulation of growth, and it has been shown to act as a growth factor for wing imaginal discs and midgut stem cells in some lepidopteran species .
Prostacyclin synthase (PTGIS)
Type: Family

Prostacyclin synthase (also known as prostaglandin I2 (prostacyclin) synthase (PTGIS) or CYP8A1) (

) catalyses the isomerization of prostaglandin H2 to prostacyclin. It plays an important role for prostanoid biosynthesis in humans. Although it shows homology with cytochrome P450, it does not require molecular oxygen. Instead it uses its heme cofactor to catalyse the isomerization of prostaglandin H2 to prostacyclin .
Glycoprotein E, immunoglobulin-like domain, flavivirus (Flavi_E_Ig-like)
Type: Domain

Flaviruses are small, enveloped RNA viruses that use arthropods such as mosquitoes for transmission to their vertebrate hosts, and include Yellow fever virus, West Nile virus, Tick-borne encephalitis virus, Japanese encephalitis virus, and Dengue virus 2 . Flaviviruses consist of three structural proteins: the core nucleocapsid protein C (

), and the envelope glycoproteins M (

) and E. Glycoprotein E is a class II viral fusion protein that mediates both receptor binding and fusion. Class II viral fusion proteins are found in flaviviruses and alphaviruses, and are structurally distinct from class I fusion proteins from influenza-type viruses and retroviruses. Glycoprotein E is comprised of three domains: domain I (dimerisation domain) is an 8-stranded β barrel, domain II (central domain) is an elongated domain composed of twelve β strands and two α helices, and domain III (immunoglobulin-like domain) is an IgC-like module with ten β strands. This entry represents the Ig-like domain III, which contains a putative receptor-binding loop .
Platelet-derived growth factor receptor beta (PGFRB)
Type: Family

Platelet-derived growth factor (PDGF) is a growth factor that plays a significant role in cell proliferation and embryonic develpment. It is regulated through the platelet-derived growth factor receptor (PDGFR), a tyrosine kinase (RTK) . There are two types of PDGFR: alpha and beta. This entry represents the beta type PDGFR (PGFRB).
Oestrogen-related receptor (Oest-rel_rcp)
Type: Family

Oestrogen-related receptors (ERR-alpha, ERR-beta, and ERR-gamma) are orphan nuclear receptors whose physiological ligands have not yet been identified. ERRs are closely related to oestrogen receptors (ERs), and bind and regulate transcription via oestrogen response elements (EREs) and extended ERE half-sites termed ERR response elements (ERREs) . However, they do not respond to oestrogens . ERR-alpha has been shown to play a role in energy homeostasis and defects in ERR-beta are the cause of deafness autosomal recessive type 35 (DFNB35), which is a form of sensorineural hearing loss. .
Platelet-derived growth factor receptor alpha (PDGFRA)
Type: Family

Platelet-derived growth factor (PDGF) is a growth factor that plays a significant role in cell proliferation and embryonic develpment. It is regulated through the platelet-derived growth factor receptor (PDGFR), a tyrosine kinase (RTK) . There are two types of PDGFR: alpha and beta. This entry represents the alpha type PDGFR (PDGFRA).
Glycoside hydrolase 38, N-terminal domain superfamily (Glyco_hydro_38_N_sf)
Type: Homologous_superfamily

This superfamily represents a structural domain found in glycoside hydrolase families 38 (

, e.g. alpha-mannosidase) .

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.

Glycoside hydrolase family 38

comprises enzymes with only one known activity; alpha-mannosidase (

) (

).

Lysosomal alpha-mannosidase is necessary for the catabolism of N-linked carbohydrates released during glycoprotein turnover. The enzyme catalyses the hydrolysis of terminal, non-reducing alpha-D-mannose residues in alpha-D-mannosides, and can cleave all known types of alpha-mannosidic linkages. Defects in the gene cause lysosomal alpha-mannosidosis (AM), a lysosomal storage disease characterised by the accumulation of unbranched oligo-saccharide chains.
DNA nucleotidylexotransferase (TdT) (TdT)
Type: Family

DNA carries the biological information that instructs cells how to exist in an ordered fashion: accurate replication is thus one of the most important events in the cell life cycle. This function is mediated by DNA-directed DNA-polymerases, which add nucleotide triphosphate (dNTP) residues to the 5'-end of the growing DNA chain, using a complementary DNA as template. Small RNA molecules are generally used as primers for chain elongation, although terminal proteins may also be used. Three motifs, A, B and C , are seen to be conserved across all DNA-polymerases, with motifs A and C also seen in RNA- polymerases. They are centred on invariant residues, and their structural significance was implied from the Klenlow (Escherichia coli) structure: motif A contains a strictly-conserved aspartate at the junction of a β-strand and an α-helix; motif B contains an α-helix with positive charges; and motif C has a doublet of negative charges, located in a β-turn-beta secondary structure .

DNA polymerases (

) can be classified, on the basis of sequence similarity , into at least four different groups: A, B, C and X. Members of family X are small (about 40 Kd) compared with other polymerases and encompass two distinct polymerase enzymes that have similar functionality: vertebrate polymerase beta (same as Saccharomyces cerevisiae pol 4), and terminal deoxynucleotidyl-transferase (TdT) (

). The former functions in DNA repair, while the latter terminally adds single nucleotides to polydeoxynucleotide chains. Both enzymes catalyse addition of nucleotides in a distributive manner, i.e. they dissociate from the template-primer after addition of each nucleotide. DNA-polymerases show a degree of structural similarity with RNA-polymerases.

This entry represents terminal deoxynucleotidyl-transferase (TdT).
Neuropeptide S receptor (NPS_rcpt)
Type: Family

Neuropeptide S (NPS) is a neuropeptide found in human and mammalian brain and is mainly produced by neurons in the amygdala, expression has also been found in other areas of the brain such as the lateral parabrachial nucleus and hypothalamus . Overall, the expression of NPS is restricted in the brain, but it has been found in peripheral sites that include mostly endocrine tissues such as thyroid, mammary gland, salivary gland and testis. Neuropeptide S has been was found to suppress anxiety and appetite , induce wakefulness and hyperactivity, including hyper-sexuality , and plays a significant role in the extinction of conditioned fear. Central administration of NPS was also found to modulate hypothalamic-pituitary-adrenal axis activity .

This entry represents the neuropeptide S receptor (NPSR), which is a member of the rhodopsin G protein-coupled receptor family and it binds NPS . Like the tissue distribution of NPS, the neuropeptide S receptor is widely distributed in the brain, with high expression levels in cortex, hypothalamus, amygdala and multiple midline thalamic nuclei. Many of these areas have been functionally associated processing of emotional behaviour, promoting arousal and anxiolytic-like effects . In addition to this, activation of NPSR in the airway epithelium has a number of effects including up-regulation of matrix metalloproteinases which are involved in the pathogenesis of asthma . It is also thought to be involved in irritable bowel syndrome .
DNA fragmentation factor 45kDa, C-terminal (DFF-C)
Type: Homologous_superfamily

One of the hallmarks of the terminal stages of apoptosis is internucleosomal DNA breakdown. DNA fragmentation factor (DFF) and endonuclease G (Endo G) are responsible for this process. DFF exists in the nucleus as a heterodimer composed of a 45kDa chaperone and inhibitor subunit (DFF45, also called ICAD-L) and a 40kDa latent nuclease subunit (DFF40/CAD). Apoptotic activation of caspase-3 or -7 results in the cleavage of DFF45 and release of active DFF40 nuclease, which forms homo-oligomers. DFF40's nuclease activity is further activated by proteins such as histone H1, HMGB1/2, and topoisomerase II .

The C-terminal region of DNA fragmentation factor 45kDa (DFF-C) consists of four α-helices, which are folded in a helix-packing arrangement, with alpha-2 and alpha-3 packing against a long C-terminal helix (alpha-4) . The main function of this region is the inhibition of DFF40 by binding to its C-terminal catalytic domain through ionic interactions, thereby inhibiting the fragmentation of DNA in the apoptotic process. In addition to blocking the DNase activity of DFF40, the C-terminal region of DFF45 is also important for the DFF40-specific folding chaperone activity, as demonstrated by the ability of DFF45 to refold DFF40 .
Agouti domain (Agouti_dom)
Type: Domain

The agouti signaling protein (ASIP or the agouti protein) and its neuropeptide homologue the agouti-related protein (AgRP) are paracrine signaling molecules that act as inverse agonists at distinct subsets of melanocortin receptors. ASIP antagonizes the binding of alpha-melanocyte stimulating hormone (alpha-MSH) to melanocortin 1 receptor (MC1R), switching melanin synthesis from eumelanin (black/brown) to phaeomelanin (red/yellow). The effect of ASIP on pigment type-switching is responsible for a variety of coat color patterns accross a broad range of mammalian species. AgRP is involved in energy balance and acts normally at the MC3R and MC4R to control body weight regulation and metabolism .

Sequence similarity between ASIP and AgRP is confined to their Cys-rich C-terminal domains, which are also responsible for melanocortin receptor binding activity in vitro. Approximately 40 residues in length, there are ten cysteine residues in the C-terminal domain that form a network of five disulfide bonds. The agouti C-terminal domain contains a three-stranded antiparallel β sheet, where the last two strands form a β hairpin. The hairpin's turn region presents a triplet of residues (Arg-Phe-Phe) known to be essential for melanocortin receptor binding. The agouti C-terminal domain adopts the inhibitor cystine knot (ICK) or knottin fold identified in numerous invertebrate toxins .

This entry represents the agouti domain which covers the 10 cysteines involved in disulfide bonds.
Trigger factor/SurA domain superfamily (Trigger_fact/SurA_dom_sf)
Type: Homologous_superfamily

The C-terminal domain of trigger factor and the peptide-binding domain of porin chaperone SurA share a multi-helical structure consisting of an irregular array of long and short helices.

In the Escherichia coli cytosol, a fraction of the newly synthesised proteins requires the activity of molecular chaperones for folding to the native state. The major chaperones implicated in this folding process are the ribosome-associated Trigger Factor (TF), and the DnaK and GroEL chaperones with their respective co-chaperones. Trigger Factor is an ATP-independent chaperone and displays chaperone and peptidyl-prolyl-cis-trans-isomerase (PPIase) activities
in vitro
. It is composed of three domains, an N-terminal domain which mediates association with the large ribosomal subunit, a central PPIase domain with homology to FKBP proteins, and a C-terminal substrate-binding domain . The association between its N-terminal domain with the ribosomal protein L23 located next to the peptide tunnel exit is essential for the interaction with nascent polypeptides and its in vivo function .

The porin chaperon SurA facilitates correct folding of outer membrane proteins in Gram-negative bacteria .
WASH complex subunit 7 (WASH7)
Type: Family

The WASH (WASP and Scar homologue) complex is present at the surface of endosomes and recruits and activates the Arp2/3 complex to induce mediated actin nucleation. The WASH complex plays a key role in the fission of tubules that serve as transport intermediates during endosome sorting .

The WASH complex consists of several subunits: F-actin-capping protein subunit alpha (CAPZA1, CAPZA2 or CAPZA3), F-actin-capping protein subunit beta (CAPZB), WASH (WASH1, WASH2P, WASH3P, WASH4P, WASH5P or WASH6P), FAM21 (FAM21A, FAM21B or FAM21C), KIAA1033, KIAA0196 (strumpellin) and CCDC53.

This entry represents the WASH complex subunit SWIP (strumpellin and WASH-interacting protein; also known as subunit 4 or subunit 7 or KIAA1033). SWIP is a candidate gene for non-syndromic autosomal recessive intellectual disability .
P2X purinoreceptor extracellular domain superfamily (P2X_extracellular_dom_sf)
Type: Homologous_superfamily

P2X purinoceptors are cell membrane ion channels, gated by adenosine 5'-triphosphate (ATP) and other nucleotides. P2X purinoceptor adopts a chalice-shaped, homotrimetric architecture consisting of a large hydrophilic and glycosylated extracellular domain, a transmembrane domain composed of 6 α-helices and short intracellular amino and carboxy termini . This superfamily represents the extracellular domain which is characterised by a transthyretin-like β-sandwich motif . This domain contains binding sites for ATP, competitive antagonists and modulatory metal ions .
Profilin conserved site (Profilin_CS)
Type: Conserved_site

Profilin is a small eukaryotic protein that binds to monomeric actin (G-actin) in a 1:1 ratio thus preventing the polymerisation of actin into filaments (F-actin). It can also, in certain circumstance promotes actin polymerisation. Profilin also binds to polyphosphoinositides such as PIP2.

Overall sequence similarity among profilin from organisms which belong to different phyla (ranging from fungi to mammals) is low, but the N-terminal region is relatively well conserved. That region is thought to be involved in the binding to actin. This entry represents a conserved site at the N-terminal extremity of profilin. A protein structurally similar to profilin is present in the genome of variola and vaccinia viruses (gene A42R).
Sda1 (Sda1)
Type: Family

Sda1 is required for 60S pre-ribosomal subunits export to the cytoplasm and may also be required for 60S ribosomal subunit maturation and accumulation. It is involved in G1 events and passage through start, and possibly actin cytoskeleton organisation .
Microtubule associated protein MAP2/MAP4/Tau (MAP2/MAP4/Tau)
Type: Family

Proteins in this family contains a microtubule binding domain that is found in MAP2, MAP4, Tau, and their homologues. All isoforms contain a conserved C-terminal domain containing tubulin-binding repeats (

), and a N-terminal projection domain of varying size. This domain has a net negative charge and exerts a long-range repulsive force. This provides a mechanism that can regulate microtubule spacing which might facilitate efficient organelle transport .

MAP2 may stabilise the microtubules against depolymerisation .

MAP4 is a non-neuronal microtubule-associated protein that promotes microtubule assembly .
Microtubule-associated protein RP/EB (MAPRE)
Type: Family

This entry represents the microtubule-associated protein RP/EB (MAPRE) family, including MAPRE1 (EB1), MAPRE2 (RP1, also known as EB2), MAPRE3 (EBF3, also known as EB3) and their homologues from eukaryotes. Despite their high protein sequence conservation, the individual EBs exhibit different regulatory and functional properties . For instance, EB1 and EB3, but not EB2, promote persistent microtubule growth by suppressing catastrophes .

EB1 contains an N-terminal calponin homology (CH) domain that is responsible for the interaction with microtubules (MTs), and a C-terminal coiled coil domain that extends into a four-helix bundle, required for dimer formation . Through their C-terminal sequences, EBs interact with most other known +TIPs (plus end tracking proteins) and recruit many of them to the growing MT ends . EB1 is involved in MT anchoring at the centrosome and cell migration .

EB2 is highly expressed in pancreatic cancer cells, and seems to be involved in perineural invasion .
TPX2, C-terminal (TPX2_C)
Type: Domain

This entry represents a conserved region approximately 60 residues long within the eukaryotic targeting protein for Xklp2 (TPX2). Xklp2 is a kinesin-like protein localised on centrosomes throughout the cell cycle and on spindle pole microtubules during metaphase. In Xenopus, it has been shown that Xklp2 protein is required for centrosome separation and maintenance of spindle bi-polarity . TPX2 is a microtubule-associated protein that mediates the binding of the C-terminal domain of Xklp2 to microtubules. It is phosphorylated during mitosis in a microtubule-dependent way .
TPX2 central domain (TPX2_central_dom)
Type: Domain

This entry represents the central domain found in the eukaryotic targeting protein for Xklp2 (TPX2) protein. TPX2 is a microtubule-associated protein that targets a plus end-directed motor (Xklp2) to the minus ends of microtubules in the mitotic spindle. This domain is close to the C-terminal of TPX2. The protein importin alpha regulates the activity of TPX2 by binding to the nuclear localisation signal in this domain .
Mas-related G protein-coupled receptor G (MRGPCRG)
Type: Family

Members of the mas-related receptor family (also known as oncogene-like MAS and mas-related G-protein coupled receptor MRG) have been implicated in the development, regulation and function of nociceptive neurons, specifically in the modulation of pain. Most members are orphaned, with no endogeneous ligand identified. Of the human mas-related GPCRs, four (MRGPRD, MRGPRE, MRGPRF and MRGPRG) are also found in rodents, whereas MRGPRX1, MRGPRX2, MRGPRX3 and MRGPRX4 are found exclusively in primates. Certain rodent MRGs have been reported to respond to adenine and to RF-amide peptides, including neuropeptide FF , but the relevance of these findings to man is unclear. MRGs are expressed predominantly in small diameter sensory neurons of the dorsal root ganglia, where there is emerging evidence that they may be mediators of histamine-independent itch .

This entry represents mas-related G protein-coupled receptor G. It is thought to be involved with nociceptor function and development, and directly involved in the modulation of pain. The receptor is currently orphaned, no specific endogenous ligand having been identified.
Glycosyltransferase family 23 (GT23) domain (GT23_dom)
Type: Domain

The fucosylation of glycoconjugates in mammalian organisms is related to a wide variety of biological processes, including cell adhesion, blood antigens, and some severe diseases including cancer metastasis, congenital disorders of glycosylation, and various microbial and virus infections. Fucosylation via alpha1,2-, alpha1,3- alpha1,4, and alpha1,6-linkages, and protein O-fucosylation are accomplished by the cation of specific individual fucosyltransferases .

FUT8, a eukaryotic alpha1,6-fucosyltransferase, catalyses the transfer of a fucosyl residue from guanine nucleotide diphosphate (GDP)-beta-L-fucose to the reducing terminal N-acetylglucosamine (GlcNAc) of asparagine-linked oligosaccharides (N-glycan). The catalytic domain of FUT8 is structurally similar to that of BodZ, a bacterial alpha1,6-fucosyltransferase. NodZ plays a role in the synthesis of the Nod factor, which is involved in the nodulation of legume roots for nitrogen fixing, and is known to catalyse the alpha1,6- fucosylation of lipo-chitooligosaccharides and variations thereof, including chitooligosaccharides. Both the eukaryotic and bacterial fucoslytransferase are classified into the GT23 family of Carbohydrate-Active enZYmes and share GDP-beta-L-fucose as the donor substrate. Although the acceptor substrates are different, a "common" chitobiose unit is contained in the reducing terminals of both substrates .

The GT23 domain is comprised of two structures, a N-terminal open sheet α/β structure and a C-terminal Rossmann fold which is frequently found in nucleotide binding proteins including glycosyltransferases . The entry represents the GT23 domain.
(+) RNA virus helicase core domain ((+)RNA_virus_helicase_core_dom)
Type: Domain

This entry represents the (+) RNA virus helicase core domain.

The (+) RNA virus helicase core contains two RecA-like α/β domains. The N-terminal ATP-binding domain contains a parallel six-stranded β-sheet surrounded by four helices on one side and two helices on the other. The C-terminal domain contains a parallel four-stranded β-sheet sandwiched between two helices on each of its sides. The (+)RNA virus helicase core is likely to bind NTP in cleft between the N terminus of the ATP-binding domain and the beginning of the C-terminal domain .

Helicases have been classified in 6 superfamilies (SF1-SF6) . All of the proteins bind ATP and, consequently, all of them carry the classical Walker A (phosphate-binding loop or P-loop) and Walker B (Mg2+-binding aspartic acid) motifs. The two largest superfamilies, commonly referred to as SF1 and SF2, share similar patterns of seven conserved sequence motifs, some of which are separated by long poorly conserved spacers. Helicase motifs appear to be organised in a core domain which provides the catalytic function, whereas optional inserts and amino- and carboxy-terminal sequences may comprise distinct domains with diverse accessory roles. The helicase core contains two structural domains, an N-terminal ATP-binding domain and a C-terminal domain. Putative SF1 helicases are extremely widespread among positive-stranded (+)RNA viruses. They have been identified in a variety of plant virus families, as well as alpha-rubi-, arteri-, hepatitis E, and coronaviruses. A number of these viral enzymes have been implicated in diverse aspects of transcription and replication but also in RNA stability and cell-to-cell movement .
Nonstructural protein 13, zinc-binding domain, coronavirus-like (NSP13_ZBD_CoV-like)
Type: Domain

Nidoviruses (Coronaviridae, Arteriviridae, and Roniviridae) feature the most complex genetic organization among plus-strand RNA viruses. Their
replicase genes encode an exceptionally large number of nonstructural protein domains which mediate the key functions required for genomic RNA synthesis (replication) and subgenomic RNA (sgRNA) synthesis (transcription). They encode a nonstructural protein, called NSP10 in arteriviruses (Av) and NSP13 in coronaviruses (CoV) , that is comprised of a C-terminal nucleoside triphosphate-binding/helicase (Hel) motif and a N-terminal cysteine-rich zinc-binding domain (ZBD). The ZBD is critically involved in nidovirus replication and transcription, modulating the ATPase/helicase activity in cis . In SARS-CoV, it has been shown that NSP12 directly interacts with NSP13 and enhances its helicase activity .

The ZBD is comprised of about 80 to 100 residues, including 12 to 13 conserved Cys/His residues. It consists of a RING-like module and treble-cleft zinc finger, together coordinating three Zn atoms. The N-terminal RING-like module has a notable binuclear structure with a cross-brace topology involving 6 Cys and 2 His residues that coordinate two zinc ions. The C-terminal zinc finger of ZBD adopts a treble-cleft fold distinct from that of
the RING module. It coordinates one Zn ion with a C[H/C]C[C/H] pattern .

This entry represents the ZBD domain of coronavirus helicase.