SII-SWORD/CoKE huggingface dataset:
Cytochrome c oxidase-like, subunit I superfamily (Cyt_c_oxase-like_su1_sf)
Type: Homologous_superfamily

Cytochrome c oxidase (

) is a key enzyme in aerobic metabolism. Proton pumping haem-copper oxidases represent the terminal, energy-transfer enzymes of respiratory chains in prokaryotes and eukaryotes. The CuB-haem a3 (or haem o) binuclear centre, associated with the largest subunit I of cytochrome c and ubiquinol oxidases (

), is directly involved in the coupling between dioxygen reduction and proton pumping .
Some terminal oxidases generate a transmembrane proton gradient across the plasma membrane (prokaryotes) or the mitochondrial inner membrane (eukaryotes).

The enzyme complex consists of 3-4 subunits (prokaryotes) up to 13 polypeptides (mammals) of which only the catalytic subunit (equivalent to mammalian subunit I (CO I) is found in all haem-copper respiratory oxidases. The presence of a bimetallic centre (formed by a high-spin haem and copper B) as well as a low-spin haem, both ligated to six conserved histidine residues near the outer side of four transmembrane spans within CO I is common to all family members . In contrast to eukaryotes the respiratory chain of prokaryotes is branched to multiple terminal oxidases. The enzyme complexes vary in haem and copper composition, substrate type and substrate affinity. The different respiratory oxidases allow the cells to customize their respiratory systems according to a variety of environmental growth conditions .

This entry represents a structural domain superfamily found in subunit I of cytochrome c oxidase as well as related proteins, including quinol oxidase. Structurally, it is composed of twelve transmembrane helices in an approximate threefold rotational symmetric arrangement.
Amidase signature (AS) superfamily (AS_sf)
Type: Homologous_superfamily

Amidase signature (AS) enzymes are a large group of hydrolytic enzymes that contain a conserved stretch of approximately 130 amino acids known as the AS sequence. They are widespread, being found in both prokaryotes and eukaryotes. AS enzymes catalyse the hydrolysis of amide bonds (CO-NH2), although the family has diverged widely with regard to substrate specificity and function. Nonetheless, these enzymes maintain a core α/β/α structure, where the topologies of the N-and C-terminal halves are similar. AS enzymes characteristically have a highly conserved C-terminal region rich in serine and glycine residues, but devoid of aspartic acid and histidine residues, therefore they differ from classical serine hydrolases. These enzymes posses a unique, highly conserved Ser-Ser-Lys catalytic triad used for amide hydrolysis, although the catalytic mechanism for acyl-enzyme intermediate formation can differ between enzymes .

Examples of AS enzymes include:

Peptide amidase (Pam) , which catalyses the hydrolysis of the C-terminal amide bond of peptides.

Fatty acid amide hydrolases , which hydrolyse fatty acid amid substrates (e.g. cannabinoid anandamide and sleep-inducing oleamide), thereby controlling the level and duration of signalling induced by this diverse class of lipid transmitters.

Malonamidase E2 , which catalyses the hydrolysis of malonamate into malonate and ammonia, and which is involved in the transport of fixed nitrogen from bacteroids to plant cells in symbiotic nitrogen metabolism.

Subunit A of Glu-tRNA(Gln) amidotransferase ,a heterotrimeric enzyme that catalyses the formation of Gln-tRNA(Gln) by the transamidation of misacylated Glu-tRNA(Gln) via amidolysis of glutamine.

The amidase signature enzymes consist structurally of a core domain that is covered by α-helices .
Thiol:disulfide interchange protein DsbD, N-terminal domain superfamily (DsbDN_sf)
Type: Homologous_superfamily

Folding of secreted proteins within the periplasm of Escherichia coli requires the formation of disulfide bonds, a process that is dependent on the Dsb (disulfide bond) proteins. The reduction of Dsb proteins DsbC, DsbE, and DsbG occurs by transport of electrons from cytoplasmic thioredoxin to the C-terminal thioredoxin-like domain of DsbD (DsbDC). The N-terminal domain of DsbD (DsbDN) is capable of forming disulfides with oxidized DsbC, DsbE, or DsbG as well as with reduced DsbD . This entry represents the DsbDN superfamily. Structurally, this domain has an immunoglobulin-like β-sandwich fold which consists of seven strands arranged in two sheets with a greek-key topology.
WGR domain superfamily (WGR_dom_sf)
Type: Homologous_superfamily

This domain superfamily is named after the most conserved central motif of the domain. It is found in a variety of polyA polymerases as well as the Escherichia coli molybdate metabolism regulator

and other proteins of unknown function.The domain is found in isolation in proteins such as

and is between 70 and 80 residues in length. Structurally,
it has a β(4)-α-X-β motif arranged into two layers (α/β) with antiparallel β-sheet, there is also β-hairpin insertion in strand 1 which results in the formation of a beta-triangle structure.
Polyomavirus capsid protein VP1 superfamily (Polyomavir_VP1_sf)
Type: Homologous_superfamily

This entry represents the major capsid protein VP1 (viral protein 1) from Polyomaviruses, such as Murine polyomavirus (strain P16 small-plaque) (MPyV) . Polyomaviruses are dsDNA viruses with no RNA stage in their life cycle. The virus capsid is composed of 72 icosahedral units, each of which is composed of five copies of VP1. The virus attaches to the cell surface by recognition of oligosaccharides terminating in alpha(2,3)-linked sialic acid. The capsid protein VP1 forms a pentamer. The complete capsid is composed of 72 VP1 pentamers, with a minor capsid protein, VP2 or VP3, inserted into the centre of each pentamer like a hairpin. This structure restricts the exposure of internal proteins during viral entry. Polyomavirus coat assembly is rigorously controlled by chaperone-mediated assembly. During viral infection, the heat shock chaperone hsc70 binds VP1 and co-localises it in the nucleus, thereby regulating capsid assembly .
Large ribosomal subunit protein bL9, N-terminal domain superfamily (Ribosomal_bL9_N_sf)
Type: Homologous_superfamily

This entry represents the large ribosomal subunit protein bL9. In Escherichia coli, bL9 is known to bind directly to the 23S rRNA. It belongs to a family of ribosomal proteins grouped on the basis of sequence similarities .

The crystal structure of Bacillus stearothermophilus bL9 shows the 149-residue protein comprises two globular domains connected by a rigid linker . Each domain contains an rRNA binding site, and the protein functions as a structural protein in the large subunit of the ribosome. The C-terminal domain consists of two loops, an α-helix and a three-stranded mixed parallel, anti-parallel β-sheet packed against the central α-helix. The long central α-helix is exposed to solvent in the middle and participates in the hydrophobic cores of the two domains at both ends.
CRIB domain superfamily (CRIB_dom_sf)
Type: Homologous_superfamily

This entry represents the CRIB domain superfamily.

Many putative downstream effectors of the small GTPases Cdc42 and Rac contain a GTPase binding domain (GBD), also called p21 binding domain (PBD), which has been shown to specifically bind the GTP bound form of Cdc42 or Rac, with a preference for Cdc42 . The most conserved region of GBD/PBD domains is the N-terminal Cdc42/Rac interactive binding motif (CRIB), which consists of about 16 amino acids with the consensus sequence I-S-x-P-x(2,4)-F-x-H-x(2)-H-V-G .

Although the CRIB motif is necessary for the binding to Cdc42 and Rac, it is not sufficient to give high-affinity binding . A less well conserved inhibitory switch (IS) domain responsible for maintaining the proteins in a basal (autoinhibited) state is located at the C-terminal of the CRIB-motif .

GBD domains can adopt related but distinct folds depending on context. Although GBD domains are largely unstructured in the free state, the IS domain forms an N-terminal beta; hairpin that immediately follows the conserved CRIB motif and a central bundle of three alpha; helices in the autoinhibited state. The interaction between GBD domains and their respective G proteins leads to the formation of a high-affinity complex in which unstructured regions of both the effector and the G protein become rigid. CRIB motifs from various GBD domains interact with Cdc42 in a similar manner, forming an intermolecular beta;-sheet with strand beta;-2 of Cdc42. Outside the CRIB motif, the C-termini of the various GBD domains are very divergent and show variation in their mode of binding to Cdc42, perhaps determining the specificity of the interaction. Binding of Cdc42 or Rac to the GBD domain causes a dramatic conformational change, refolding part of the IS domain and unfolding the rest .

Some proteins known to contain a CRIB domain are listed below:

Mammalian activated Cdc42-associated kinases (ACKs), nonreceptor tyrosine kinases implicated in integrin-coupled pathways.

Mammalian p21-activated kinases (PAK1 to PAK4), serine/threonine kinases that modulate cytoskeletal assembly and activate MAP-kinase pathways.

Mammalian Actin nucleation-promoting factor WAS proteins (WASPs), non-kinase proteins involved in the organisation of the actin cytoskeleton.

Yeast STE20 and CLA4, the homologues of mammalian PAKs. STE20 is involved in the mating/pheromone MAP kinase cascade.
Fimbrial-type adhesion domain superfamily (Adhesion_dom_fimbrial_sf)
Type: Homologous_superfamily

This domain superfamily is found in bacterial proteins that are involved in regulation of length and mediation of adhesion of fimbriae. Fimbriae (also called pili), are polar filaments radiating from the surface of the bacterium to a length of 0.5-1.5 micrometers, that enable bacteria to colonize the epithelium of specific host organs. Fimbriae are also responsible to promote virulence .
Phosphatidic acid phosphatase type 2/haloperoxidase superfamily (PAP2/HPO_sf)
Type: Homologous_superfamily

This entry represents type 2 phosphatidic acid phosphatase (PAP2;

) enzymes, such as phosphatidylglycerophosphatase B

from Escherichia coli. PAP2 enzymes have a core structure consisting of a 5-helical bundle, where the beginning of the third helix binds the cofactor . PAP2 enzymes catalyse the dephosphorylation of phosphatidate, yielding diacylglycerol and inorganic phosphate . In eukaryotic cells, PAP activity has a central role in the synthesis of phospholipids and triacylglycerol through its product diacylglycerol, and it also generates and/or degrades lipid-signalling molecules that are related to phosphatidate.

Other related enzymes have a similar core structure, including haloperoxidases (HPO) such as bromoperoxidase (contains one core bundle, but forms a dimer), chloroperoxidases (contains two core bundles arranged as in other family dimers), bacitracin transport permease from Bacillus licheniformis, glucose-6-phosphatase from rat. The vanadium-dependent haloperoxidases exclusively catalyse the oxidation of halides, and act as histidine phosphatases, using histidine for the nucleophilic attack in the first step of the reaction . Amino acid residues involved in binding phosphate/vanadate are conserved between the two families, supporting a proposal that vanadium passes through a tetrahedral intermediate during the reaction mechanism.
Copper type II, ascorbate-dependent monooxygenase, N-terminal domain superfamily (Cu2_ascorb_mOase_N_sf)
Type: Homologous_superfamily

Copper type II, ascorbate-dependent monooxygenases are a class of enzymes that requires copper as a cofactor and which uses ascorbate as an electron donor. This family contains two related enzymes, dopamine-beta-monooxygenase (

) and peptidyl-glycine alpha-amidating monooxygenase (

). There are a few regions of sequence similarities between these two enzymes, two of these regions contain clusters of conserved histidine residues which are most probably involved in binding copper.

This superfamily represents the central domain of the enzyme.
Phosphatidylinositol 3-/4-kinase, catalytic domain superfamily (PI3/4_kinase_cat_sf)
Type: Homologous_superfamily

This entry represents the catalytic domain superfamily in PI3 and PI4-kinases and related Serine/threonine-protein 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 .
Receptor L-domain superfamily (Rcpt_L-dom_sf)
Type: Homologous_superfamily

The structure for the first three domains of the extracellular portion of IGF-1R (type-1 insulin-like growth-factor receptor) has been solved and consists of two L-domains and a cysteine rich region (L1-Cys-rich-L2). The L-domains each consist of a single-stranded right-handed β-helix. The Cys-rich region is composed of eight disulphide-bonded modules, seven of which form a rod-shaped domain with modules associated in an unusual manner. The three domains surround a central space of sufficient size to accommodate a ligand molecule .

This entry represents the L-domain superfamily. This domain can also be found in insulin receptor(IR) and epidermal growth-factor receptor (EGFR) family members, and in yeast cell surface GPI protein ECM33 .
TonB-dependent receptor-like, beta-barrel domain superfamily (Beta-barrel_TonB_sf)
Type: Homologous_superfamily

This entry represents the β-barrel domain which contains the plug domain (

). This β-barrel domain is also found in vitamin B12 transporter BtuB and ferric citrate outer membrane transporter FecA , among others.
Fibronectin type II domain superfamily (FN_type2_sf)
Type: Homologous_superfamily

Fibronectin is a multi-domain glycoprotein, found in a soluble form in plasma, and in an insoluble form in loose connective tissue and basement membranes, that binds cell surfaces and various compounds including collagen, fibrin, heparin, DNA, and actin. Fibronectins are involved in a number of important functions e.g., wound healing; cell adhesion; blood coagulation; cell differentiation and migration; maintenance of the cellular cytoskeleton; and tumour metastasis .

The major part of the sequence of fibronectin consists of the repetition of three types of domains, which are called type I, II, and III (also called FN1, FN2 and FN3 respectively). In fibronectin the type II domain is duplicated. Type II domain is approximately forty residues long, contains four conserved cysteines involved in disulphide bonds and is part of the collagen-binding region of fibronectin. Type II domains have also been found in a range of proteins including blood coagulation factor XII; bovine seminal plasma proteins PDC-109 (BSP-A1/A2) and BSP-A3 ; cation-independent mannose-6-phosphate receptor ; mannose receptor of macrophages ; 180 Kd secretory phospholipase A2 receptor . DEC-205 receptor ; 72 Kd and 92 Kd type IV collagenase (

) ; and hepatocyte growth factor activator .
Peptidyl-prolyl cis-trans isomerase, FKBP-type, N-terminal domain superfamily (PPIase_FKBP_N_sf)
Type: Homologous_superfamily

Peptidyl-prolyl cis-trans isomerase (PPIase) catalyses the cis-trans isomerisation of proline imidic peptide bonds in oligopeptides . This α helical domain is found at the N terminus of proteins belonging to the FKBP-type peptidyl-prolyl cis-trans isomerase family.

Peptidyl-prolyl cis-trans isomerase has been shown to accelerate the refolding of several proteins in vitro ; the FKPB-type enzymes probably act in the folding of extracytoplasmic proteins.
Diacylglycerol kinase (DAGK) superfamily (DAGK_sf)
Type: Homologous_superfamily

Prokaryotic diacylglycerol kinase (DAGK) and undecaprenol kinase (UDPK) constitute a family of multispan membrane enzymes that are very small, lack relationships to any other family of proteins and exhibit an unusual structure. Escherichia coli DAGK plays an important role in recycling diacylglycerol produced as a by-product of biosynthesis of molecules located in the periplasmic space. UDPK seems to play an analogous role in Gram-positive bacteria, where it is essential for biofilm formation by the oral pathogen Streptococcus mutans . In Bacillus subtilis, UDPK is an essential kinase in the diacylglycerol cycle involved in lipoteichoic acid production and seems to be indispensable for the maintenance of spore stability and viability .

Diacylglycerol kinase (

) (DAGK) is an enzyme that catalyses the formation of phosphatidic acid from diacylglycerol and ATP, an important step in phospholipid biosynthesis. In bacteria DAGK is a very small (13 to 15 kD) membrane protein which seems to contain three transmembrane domains .
Gamma-retroviral matrix domain superfamily (G_retro_matrix_sf)
Type: Homologous_superfamily

Retroviral matrix proteins (or major core proteins) are components of envelope-associated capsids, which line the inner surface of virus envelopes and are associated with viral membranes . Matrix proteins are produced as part of Gag precursor polyproteins. During viral maturation, the Gag polyprotein is cleaved into major structural proteins by the viral protease, yielding the matrix (MA), capsid (CA), nucleocapsid (NC), and some smaller peptides. Gag-derived proteins govern the entire assembly and release of the virus particles, with matrix proteins playing key roles in Gag stability, capsid assembly, transport and budding. Although matrix proteins from different retroviruses appear to perform similar functions and can have similar structural folds which predominantly consist of four closely packed α-helices that are interconnected through loops, their primary sequences can be very different .

This entry represents matrix proteins from gamma-retroviruses, such as Moloney murine leukemia virus (MoMLV), Feline leukemia virus (FLV), and Feline sarcoma virus (FESV) . This entry also identifies matrix proteins from several eukaryotic endogenous retroviruses, which arise when one or more copies of the retroviral genome becomes integrated into the host genome .
POLO box domain superfamily (POLO_box_dom_sf)
Type: Homologous_superfamily

A subgroup of serine/threonine protein kinases, Polo or Polo-like kinases play multiple roles during the cell cycle. Polo kinases are required at several key points through mitosis, starting from control of the G2/M transition through phosphorylation of Cdc25C and mitotic cyclins. They are also involved in meiosis I as regulators of kinetochore function . Polo kinases are characterised by an amino terminal catalytic domain, and a carboxy terminal non-catalytic domain consisting of three blocks of conserved sequences known as polo boxes which form one single functional domain . The domain is named after its founding member encoded by the polo gene of Drosophila melanogaster . This domain of around 70 amino acids has been found in species ranging from yeast to mammals. Polo boxes appear to mediate interaction with multiple proteins through protein:protein interactions; some but not all of these proteins are substrates for the kinase domain of the molecule .

The crystal structure of the polo domain of the murine protein, Sak, is dimeric, consisting of two α-helices and two six-stranded β-sheets . The topology of one polypeptide subunit of the dimer consists of, from its N-to C terminus, an extended strand segment, five β-strands, one α-helix (A) and C-terminal β-strand. β-strands from one subunit form a contiguous antiparallel β-sheet with β-strands from the second subunit. The two β-sheets pack with crossing angle of 110 degrees, orienting the hydrophobic surfaces inward and the hydrophilic surfaces outward. Helix A, which is colinear with β-strand 6 of the same polypeptide, buries a large portion of the non-overlapping hydrophobic β-sheet surfaces. Interactions involving helices A comprise a majority of the hydrophobic core structure and also the dimer interface.

Point mutations in the Polo box of the budding yeast Cdc5 protein abolish the ability of overexpressed Cdc5 to interact with the spindle poles and to organise cytokinetic structures .
Large ribosomal subunit protein eL21 superfamily (Ribosomal_eL21_sf)
Type: Homologous_superfamily

The eL21 superfamily contains proteins from a number of eukaryotic and archaebacterial organisms which include mammalian L2, Entamoeba histolytica eL21, Caenorhabditis elegans eL21 (C14B9.7), Saccharomyces cerevisiae (Baker's yeast) eL21 (URP1) and Haloarcula marismortui eL21 (HL31) .

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 .