SII-SWORD/CoKE huggingface dataset:
Serine proteases, trypsin domain (Trypsin_dom)
Type: Domain

This entry represents the active-site-containing domain found in the trypsin family members. The catalytic activity of the serine proteases from the trypsin family is provided by a charge relay system involving an aspartic acid residue hydrogen-bonded to a histidine, which itself is hydrogen-bonded to a serine. The sequences in the vicinity of the active site serine and histidine residues are well conserved in this family of proteases . A partial list of proteases known to belong to the trypsin family is shown below.

Acrosin.

Blood coagulation factors VII, IX, X, XI and XII, thrombin, plasminogen, and protein C.

Cathepsin G.

Chymotrypsins.

Complement components C1r, C1s, C2, and complement factors B, D and I.

Complement-activating component of RA-reactive factor.

Cytotoxic cell proteases (granzymes A to H).

Duodenase I.

Elastases 1, 2, 3A, 3B (protease E), leukocyte (medullasin).

Enterokinase (EC 3.4.21.9) (enteropeptidase).

Hepatocyte growth factor activator.

Hepsin.

Glandular (tissue) kallikreins (including EGF-binding protein types A, B, and C, NGF-gamma chain, gamma-renin, prostate specific antigen (PSA) and tonin).

Plasma kallikrein.

Mast cell proteases (MCP) 1 (chymase) to 8.

Myeloblastin (proteinase 3) (Wegener's autoantigen).

Plasminogen activators (urokinase-type, and tissue-type).

Trypsins I, II, III, and IV.

Tryptases.

All the above proteins belong to family S1 in the classification of peptidases and originate from eukaryotic species. It should be noted that bacterial proteases that belong to family S2A are similar enough in the regions of the active site residues that they can be picked up by the same patterns. These proteases are listed below.

Achromobacter lyticus protease I.

Lysobacter alpha-lytic protease.

Streptogrisin A and B (Streptomyces proteases A and B).

Streptomyces griseus glutamyl endopeptidase II.

Streptomyces fradiae proteases 1 and 2.
Parvovirus non-structural protein 1, helicase domain (Parvovirus_NS1_helicase)
Type: Domain

Parvoviruses are some of the smallest viruses containing linear, non-segmented single-stranded DNA genomes, with an average genome size of 5000 nucleotides. Parvoviruses have been described that infect a wide range of invertebrates and vertebrates and are well known for causing enteric disease in mammals. Genomes contain two large ORFs: NS1 and VP1; other ORFs are found in some sub-types and different gene products can arise from splice variants and the use of different start codons .

This entry represents the helicase domain of the Parvovirus NS1 protein; which is required for viral DNA replication . This domain contains the ATP/GTP-binding site motif A (P-loop). Parvoviral NS1 also regulates host gene expression through histone acetylation .
NHL repeat (NHL_repeat)
Type: Repeat

The NHL repeat, named after NCL-1, HT2A and Lin-41, is a conserved structural motif present in a large number of eukaryotic and prokaryotic proteins. For example, the repeat is found in a variety of enzymes of the copper type II, ascorbate-dependent monooxygenase family, which catalyse the C-terminal alpha-amidation of biological peptides and in a large family of growth regulators. Many NHL-containing proteins have additional domains such as a RING finger, a B-box zinc finger or a coiled-coil motif. In many, it occurs in tandem arrays, for example in the ring finger β-box, coiled-coil (RBCC) eukaryotic growth regulators or the 'Brain Tumor' protein (Brat) .

The NHL repeats are also found in serine/threonine protein kinase (STPK) in a diverse range of pathogenic bacteria. These STPK are transmembrane receptors with an intracellular N-terminal kinase domain and extracellular C-terminal sensor domain. In the STPK PknD from Mycobacterium tuberculosis, the sensor domain forms a rigid, six-bladed b-propeller composed of NHL repeats with a flexible tether to the transmembrane domain .

The NHL domain is a six-bladed β-propeller, with the blades arrayed in a radial fashion around a central axis, and each blade composed of a highly twisted four-stranded antiparallel β-sheet . The innermost strand of each blade is labelled 'a' and the outermost strand, 'd'. Like in other β-propellers, the sequence repeats are offset with respect to the blades of the propeller, such that any given 40-residue NHL repeat spans strands 'b-d' of one propeller blade and strand 'a' of the subsequent blade. This offset ensures circularisation of the propeller because the last strand of the final sequence repeat acts as an innermost strand of the blade that harbours strands 'b-d' from the first sequence repeat. According to structural model analysis, the NHL domain could be involved in protein-protein interaction .
Proteinase inhibitor I27, calpastatin (Prot_inh_calpain)
Type: Repeat

This entry represents repeats on calpain inhibitor proteins.

Calpain inhibitor (calpastatin) is restricted to the metazoa and specifically inhibits calpain (calcium-dependent cysteine protease) . Calpastatin belongs to MEROPS inhibitor family I27, clan II. It plays a key role in post-mortem tenderisation of meat and may be involved in muscle protein degradation in living tissue.

The calpain system originally comprised three molecules: two Ca2+-dependent proteases, mu-calpain and m-calpain, and a third polypeptide, calpastatin, whose only known function is to inhibit the two calpains. Both mu-and m-calpain are heterodimers containing an identical 28kDa subunit and an 80kDa subunit that shares 55-65% sequence homology between the two proteases. The single calpastatin gene can produce eight or more calpastatin polypeptides ranging from 17kDa to 85kDa by use of different promoters and alternative splicing events. The physiological significance of these different calpastatins is unclear, although all bind to three different places on the calpain molecule; binding to at least two of the sites is Ca2+ dependent.
Coproporphyrinogen III oxidase, aerobic (Coprogen_oxidase_aer)
Type: Family

Coprogen oxidase (i.e. coproporphyrin III oxidase or coproporphyrinogenase) catalyses the oxidative decarboxylation of coproporphyrinogen III to proto-porhyrinogen IX in the haem and chlorophyll biosynthetic pathways . The protein is a homodimer containing two internally bound iron atoms per molecule of native protein . The enzyme is active in the presence of molecular oxygen that acts as an electron acceptor. The enzyme is widely distributed having been found in a variety of eukaryotic and prokaryotic sources.
ArgE/DapE/ACY1/CPG2/YscS, conserved site (ArgE/DapE_CS)
Type: Conserved_site

This group contains metallopeptidases belonging to MEROPS peptidase family M20 (clan MH), subfamilies M20A and M20B; many are classified as unassigned peptidases or non-peptidase homologues.

In addition to the metallopeptidases this group of sequences contain a variety of other protein families from the archaea, bacteria and eukaryota that hydrolyse substrates that share a common structure and are dependent on cobalt or zinc for their activity . They include:

glutamate acetyltransferase (

)

acetylornithine deacetylase (argE) (

)

leucoanthocyanidin dioxygenase

succinyldiaminopimelate desuccinylase (dapE) (

)

aminoacylase-1 (ACY1), carboxypeptidase G2 (CPG2) (

)

vacuolar carboxypeptidase S (yscS) (

)

peptidase T (

)

Xaa-His dipeptidase (

).
Hyperglycemic hormone type 2 (Hyperglycemic2)
Type: Family

Hyperglycemic hormone, which controls blood sugar levels, is an abundant peptide in the sinus glands of isopods and decapods . The peptide is a potent secretagogue, releasing digestive enzymes from the hepatopancreas. It may act as a stress hormone. The peptide contains around 70 amino acid residues, and includes six cysteine residues involved in disulphide bond formation . The sequences show a high degree of similarity to the American lobster molt-inhibiting hormone , which also shows hyperglycemic hormone activity.

Sequence analysis reveals at least 2 discrete sequence families, characterised by distinctive N- and C-terminal signatures: broadly, the families represent separate groups of the crustacean hyperglycemic-like hormones and the molt-inhibiting-like hormones. The positions of five of the six cysteine residues are conserved between these families, the first Cys being displaced by one residue position.

This entry represents the type 2 that includes the molt-inhibiting-like hormones.
Phosphoinositide 3-kinase, accessory (PIK) domain (PI3K_accessory_dom)
Type: Domain

Phosphatidylinositol 3-kinase (PI3K) (

) is an enzyme that phosphorylates phosphoinositides on the 3-hydroxyl group of the inositol ring. The role of the accessory domain of phosphoinositide 3-kinase (PI3-kinase) is unclear. It may be involved in substrate presentation .
Glycosyl transferase, family 51 (Glyco_trans_51)
Type: Domain

The biosynthesis of disaccharides, oligosaccharides and polysaccharides involves the action of hundreds of different glycosyltransferases. These enzymes catalyse the transfer of sugar moieties from activated donor molecules to specific acceptor molecules, forming glycosidic bonds. A classification of glycosyltransferases using nucleotide diphospho-sugar, nucleotide monophospho-sugar and sugar phosphates ([ec:2.4.1.-]) and related proteins into distinct sequence based families has been described . This classification is available on the CAZy (CArbohydrate-Active EnZymes) web site. The same three-dimensional fold is expected to occur within each of the families. Because 3-D structures are better conserved than sequences, several of the families defined on the basis of sequence similarities may have similar 3-D structures and therefore form 'clans'.

Glycosyltransferase family 51

comprises enzymes with only one known activity; murein polymerases (

). These enzymes utilise MurNAc-GlcNAc-P-P-lipid II as the sugar donor.
Formin homology family, Cappuccino subfamily (Formin_Cappuccino_subfam)
Type: Family

Formins (formin homology proteins) proteins play a crucial role in the reorganisation of the actin cytoskeleton and associate with the fast-growing end (barbed end) of actin filaments . This entry represents the formin homologues from animals (and some fungi), including protein cappuccino from Drosophila melanogaster and formins from human and mouse. Protein cappuccino acts as an actin nucleation factor and promotes assembly of actin filaments together with spir. It may play a role in intracellular vesicle transport along actin fibres, providing a novel link between actin cytoskeleton dynamics and intracellular transport .
Small ribosomal subunit protein eS19 (Ribosomal_eS19)
Type: Family

This family includes a number of eukaryotic and archaebacterial ribosomal proteins known as small ribosomal subunit protein eS19, which were previously known as S19.

Ribosomes are the particles that catalyse mRNA-directed protein synthesis in all organisms. The codons of the mRNA are exposed on the ribosome to allow tRNA binding. This leads to the incorporation of amino acids into the growing polypeptide chain in accordance with the genetic information. Incoming amino acid monomers enter the ribosomal A site in the form of aminoacyl-tRNAs complexed with elongation factor Tu (EF-Tu) and GTP. The growing polypeptide chain, situated in the P site as peptidyl-tRNA, is then transferred to aminoacyl-tRNA and the new peptidyl-tRNA, extended by one residue, is translocated to the P site with the aid the elongation factor G (EF-G) and GTP as the deacylated tRNA is released from the ribosome through one or more exit sites . About 2/3 of the mass of the ribosome consists of RNA and 1/3 of protein. The proteins are named in accordance with the subunit of the ribosome which they belong to the small (S1 to S31) and the large (L1 to L44). Usually they decorate the rRNA cores of the subunits.

Many ribosomal proteins, particularly those of the large subunit, are composed of a globular, surfaced-exposed domain with long finger-like projections that extend into the rRNA core to stabilise its structure. Most of the proteins interact with multiple RNA elements, often from different domains. In the large subunit, about 1/3 of the 23S rRNA nucleotides are at least in van der Waal's contact with protein, and L22 interacts with all six domains of the 23S rRNA. Proteins S4 and S7, which initiate assembly of the 16S rRNA, are located at junctions of five and four RNA helices, respectively. In this way proteins serve to organise and stabilise the rRNA tertiary structure. While the crucial activities of decoding and peptide transfer are RNA based, proteins play an active role in functions that may have evolved to streamline the process of protein synthesis. In addition to their function in the ribosome, many ribosomal proteins have some function 'outside' the ribosome .
Thymidine kinase (Thymidine_kinase)
Type: Family

Thymidine kinase (TK) (

) is an ubiquitous enzyme that catalyzes the ATP-dependent phosphorylation of thymidine.
NADH:ubiquinone oxidoreductase, 30kDa subunit (NADH_UbQ_OxRdtase_30kDa_su)
Type: Domain

Respiratory-chain NADH dehydrogenase (

) (also known as complex I or NADH-ubiquinone oxidoreductase) is an oligomeric enzymatic complex located in the inner mitochondrial membrane which also seems to exist in the chloroplast and in cyanobacteria (as a NADH-plastoquinone oxidoreductase). Among the 25 to 30 polypeptide subunits of this bioenergetic enzyme complex there is one with a molecular weight of 30 Kd (in mammals) which has been found to be :

Nuclear encoded, as a precursor form with a transit peptide in mammals, and in Neurospora crassa.

Mitochondrial encoded in Paramecium (protein P1), and in the slime mold Dictyostelium discoideum (ORF 209).

Chloroplast encoded in various higher plants (ORF 159).

It is also present in bacteria:

In the cyanobacteria Synechocystis strain PCC 6803 (gene ndhJ).

Subunit C of Escherichia coli NADH-ubiquinone oxidoreductase (gene nuoC).

Subunit Nqo5 of Paracoccus denitrificans NADH-ubiquinone oxidoreductase. Nqo5 composes the hydrogenase-like module together with the Nqo4, Nqo6, and Nqo9 subunits. Homologous proteins of the Nqo5 subunit are also contained in membrane-bound multisubunit hydrogenases, while soluble-type hydrogenases are not. This subunit is essential in complex I assembly .
tRNA-dihydrouridine synthase (DUS_fam)
Type: Family

Dihydrouridine synthases (Dus) is a large family of flavoenzymes comprising eight subfamilies. They catalyse the NADPH-dependent synthesis of dihydrouridine, a modified base found in the D-loop of most tRNAs. Mainly, they contain two functional conserved domains, an N-terminal catalytic domain (TBD) adopting a TIM barrel fold and a unique C-terminal helical domain (HD) devoted to tRNA recognition. However, DUS2 is distinguished from its paralogues and its fungi orthologues by the acquisition of an additional domain, a double stranded RNA binding domain (dsRBD), which serves as the main tRNA binding module .

Dus 1 (

) from Saccharomyces cerevisiae (Baker's yeast) acts on pre-tRNA-Phe, while Dus 2 (

) acts on pre-tRNA-Tyr and pre-tRNA-Leu. Dus 1 is active as a single subunit, requiring NADPH or NADH, and is stimulated by the presence of FAD . Some family members may be targeted to the mitochondria and even have a role in mitochondria . DUS3 (not included in this entry) contains an extra zinc finger N-terminal to the Dus domain.
ClpA/B family (ClpA/B)
Type: Family

This family belongs to the AAA+ (ATPase associated with diverse cellular activities) superfamily. Most of these proteins of this family (ClpA, ClpC, ClpD, ClpE, ClpX, HslU) are involved in proteolysis and associate with a separate proteolytic subunit (ClpP, HslV) to form the active protease. ClpB is not involved in proteolysis but rather acts in collaboration with the DnaK (Hsp70) chaperone system to disassemble and refold large protein aggregates.

A group of ATP-binding proteins that includes the regulatory subunit of the ATP-dependent protease clpA; heat shock proteins clpB, 104 and 78; and chloroplast proteins CD4a (ClpC) and CD4b belong to this family . The proteins are thought to protect cells from stress by controlling the aggregation and denaturation of vital cellular structures. They vary in size, but share a domain which contains an ATP-binding site.

These signatures which span the ATP binding region also identify the bacterial DNA polymerase III subunit tau (

), ATP-dependent protease La (

) and the mitochondrial lon protease homologue (

), both of which belong to MEROPS peptidase family S16.

This entry also includes Mitochondrial disaggregase from vertebrates, which despite its gene name (CLPB), this protein differs in domain structure from bacterial ClpB. Bacterial ClpB contains two AAA modules, one in the N-terminal part of the protein and one in the C-terminal part, separated by a coiled coil, while vertebrate CLPB contains a single C-terminal AAA region and an N-terminal ANK repeat region which is absent from bacterial ClpB.

Clp proteins are modular ATP-dependent chaperones and proteases that typically contain distinct domains essential for their function. Most Clp proteins have an N-terminal domain that often determines substrate specificity or interacts with adaptor proteins. In some Clp proteins, the N-domains are attached through flexible linkers to the corresponding AAA+ protein rings and mediate substrate specificity either directly or indirectly by serving as a binding platform for adaptor proteins that deliver their protein cargo upon binding to the AAA+ partner protein . The central region usually comprises one or two AAA+ domains, also known as D1 and D2 domains, which provide the energy for substrate unfolding and translocation . In some Clp proteins, such as ClpV, the C-terminal region is involved in interactions with components of the type VI secretion system (T6SS) .
Phosphoenolpyruvate carboxykinase, ATP-utilising (PEP_carboxykinase_ATP)
Type: Family

Phosphoenolpyruvate carboxykinase (PEPCK) catalyses the first committed (rate-limiting) step in hepatic gluconeogenesis, namely the reversible decarboxylation of oxaloacetate to phosphoenolpyruvate (PEP) and carbon dioxide, using either ATP or GTP as a source of phosphate. The ATP-utilising (

) and GTP-utilising (

) enzymes form two divergent subfamilies, which have little sequence similarity but which retain conserved active site residues. ATP-utilising PEPCKs are monomers or oligomers of identical subunits found in certain bacteria, yeast, trypanosomatids, and plants, while GTP-utilising PEPCKs are mainly monomers found in animals and some bacteria . Both require divalent cations for activity, such as magnesium or manganese. One cation interacts with the enzyme at metal binding site 1 to elicit activation, while the second cation interacts at metal binding site 2 to serve as a metal-nucleotide substrate. In bacteria, fungi and plants, PEPCK is involved in the glyoxylate bypass, an alternative to the tricarboxylic acid cycle.

PEPCK helps to regulate blood glucose levels. The rate of gluconeogenesis can be controlled through transcriptional regulation of the PEPCK gene by cAMP (the mediator of glucagon and catecholamines), glucocorticoids and insulin. In general, PEPCK expression is induced by glucagon, catecholamines and glucocorticoids during periods of fasting and in response to stress, but is inhibited by (glucose-induced) insulin upon feeding . With type II diabetes, this regulation system can fail, resulting in increased gluconeogenesis that in turn raises glucose levels .

PEPCK consists of an N-terminal and a catalytic C-terminal domain, with the active site and metal ions located in a cleft between them. Both domains have an α/β topology that is partly similar to one another . Substrate binding causes PEPCK to undergo a conformational change, which accelerates catalysis by forcing bulk solvent molecules out of the active site . PCK uses an α/β/α motif for nucleotide binding, this motif differing from other kinase domains. GTP-utilising PEPCK has a PEP-binding domain and two kinase motifs to bind GTP and magnesium.

This entry represents ATP-utilising phosphoenolpyruvate carboxykinase enzymes.
Aromatic amino acid hydroxylase (ArAA_hydroxylase)
Type: Family

Phenylalanine, tyrosine and tryptophan hydroxylases constitute a family of tetrahydrobiopterin-dependent aromatic amino acid hydroxylases, all of which are rate-limiting catalysts for important metabolic pathways . The proteins are structurally and functionally related, each containing iron, and catalysing ring hydroxylation of aromatic amino acids, using tetra-hydrobiopterin (BH4) as a substrate. All are regulated by phosphorylation at serines in their N-termini. It has been suggested that the proteins each contain a conserved C-terminal catalytic (C) domain and an unrelated N-terminal regulatory (R) domain. It is possible that the R domains arose from genes that were recruited from different sources to combine with the common gene for the catalytic core. Thus, by combining with the same C domain, the proteins acquired the unique regulatory properties of the separate R domains.

A variety of enzymes belong to this family that includes, phenylalanine-4-hydroxylase from Chromobacterium violaceum where it is copper-dependent; it is iron-dependent in Pseudomonas aeruginosa, phenylalanine-4-hydroxylase catalyzes the conversion of phenylalanine to tyrosine. In humans, deficiencies are the cause of phenylketonuria, the most common inborn error of amino acid metabolism , tryptophan 5-hydroxylase catalyzes the rate-limiting step in serotonin biosynthesis: the conversion of tryptophan to 3-hydroxy-anthranilate and tyrosine 3-hydroxylase catalyzes the rate limiting step in catecholamine biosynthesis: the conversion of tyrosine to 3,4-dihydroxy-L-phenylalanine.
DM DNA-binding domain (DM_DNA-bd)
Type: Domain

DMRT genes encode a conserved family of transcription factors that share a unique DNA binding motif, the DM domain . This domain was first discovered in the doublesex proteins of Drosophila melanogaster . In D. melanogaster the doublesex gene controls somatic sexual differentiation by producing alternatively spliced mRNAs encoding related sex-specific polypeptides . These proteins are believed to function as transcription factors on downstream sex-determination genes, especially on neuroblast differentiation and yolk protein genes transcription . The DM domain binds DNA as a dimer, allowing the recognition of pseudopalindromic sequences . The NMR analysis of the DSX DM domain revealed a novel zinc module containing 'intertwined' CCHC and HCCC zinc-binding sites. The recognition of the DNA requires the carboxy-terminal basic tail which contacts the minor groove of the target sequence.
CXC chemokine receptor 4/atypical chemokine receptor 2 (CXCR4/ACKR2)
Type: Family

CXC chemokine receptor 4 (CXCR4), also known as fusin, which is a specific receptor for a CXCL12 (or SDF1). CXCR4 has a wide cellular distribution, with expression on most immature and mature hematopoietic cell types . In addition, CXCR4 can also be found on vascular endothelial cells and neuronal/nerve cells . Upon binding to CXCR4, CXCL12 causes mobilisation of intracellular calcium and chemotaxis . CXCL12 is known to be important in hematopoietic stem cell homing to the bone marrow and in hematopoietic stem cell quiescence. CXCR4 has a rather broad activity, and has been linked to cardiac, cerebellar gastric vasculature development and to hematopoiesis .