SII-SWORD/CoKE huggingface dataset:
Proteasome activator PA28, C-terminal domain superfamily (PA28_C_sf)
Type: Homologous_superfamily

The specificity of the 20S proteasome, which degrades many intracellular proteins, is regulated by protein complexes that bind to one or both ends of the cylindrical proteasome structure. Proteasome activator 28 (PA28), also known as 11S regulator or REG, is one of these complexes. PA28 binds to the 20S proteasome and stimulates peptidase activity in and ATP-independent manner.

Three PA28 subunits that have been identified, PA28alpha, PA28beta and PA28gamma (also known as the Ki antigen), which share extensive sequence similarity, apart from a highly variable internal segment . PA28alpha and PA28beta form a ring shaped hexameric structure of alternating alpha and beta subunits. The catalytic properties of PA28alpha and PA28beta-activated proteosome are similar .

This entry represents the C-terminal domain superfamily found in the proteasome activator 28 subunits.
Porin, LamB-type superfamily (Porin_LamB_sf)
Type: Homologous_superfamily

Maltoporin (LamB protein) forms a trimeric structure which facilitates the diffusion of maltodextrins across the outer membrane of Gram-negative bacteria. The membrane channel is formed by an antiparallel β-barrel . Loop 3 folds into the core to constrict pore size. Long irregular loops are found on the extracelllular side, while short turns are in the periplasm. Tightly-bound water molecules are found in the eyelet of the passage, and only substrates that can displace and replace the broken hydrogen bonds are likely to enter the pore. Loops 4, 6, and 9 have the greatest mobility and are highly variable; these are postulated to attract maltodextrins .

The porin LamB family also includes porin BglH, which may be a sugar porin with a broad carbohydrate specificity, and sucrose porin .
Diol/glycerol dehydratase, large subunit superfamily (Diol/glycerol_deHase_lsu_sf)
Type: Homologous_superfamily

This entry represents the large subunit superfamily of adenosylcobalamin-dependent diol dehydratases (

) and glycerol dehydratases (

). These enzymes are produced by some enterobacteria in response to growth substances. The enzyme have an TIM β/α barrel fold . Inactivated holoenzymes are reactivated by their own reactivating factors that mediate the ATP-dependent exchange of an enzyme-bound, damaged cofactor for free adenosylcobalamin through intermediary formation of apoenzyme. The reactivation takes place in two steps: (a) ADP-dependent cobalamin release and (b) ATP-dependent dissociation of the resulting apoenzyme-reactivating factor complexes .
Ski-like, DNA-binding domain superfamily (Ski_DNA-bd_sf)
Type: Homologous_superfamily

The c-ski proto-oncogene has been shown to influence proliferation, morphological transformation and myogenic differentiation . It may play a role in terminal differentiation of skeletal muscle cells but not in the determination of cells to the myogenic lineage. Sno, a Ski proto-oncogene homologue, is expressed in two isoforms and plays a role in the response to proliferation stimuli.

Ski is a multidomain protein that includes a domain bearing high sequence similarity with the retinal determination protein Dachshund . This conserved domain contains a DNA binding motif .
Ammonia/particulate methane monooxygenase, subunit A superfamily (NH3/CH4_mOase_suA_sf)
Type: Homologous_superfamily

Ammonia monooxygenase and the particulate methane monooxygenase are both integral membrane proteins, occurring in ammonia oxidisers and methanotrophs respectively, which are thought to be evolutionarily related . These enzymes have a relatively wide substrate specificity and can catalyse the oxidation of a range of substrates including ammonia, methane, halogenated hydrocarbons and aromatic molecules . These enzymes are composed of 3 subunits - A (

), B (

,

) and C (

) - and contain various metal centres, including copper. Particulate methane monooxygenase from Methylococcus capsulatus str. Bath is an ABC homotrimer, which contains mononuclear and dinuclear copper metal centres, and a third metal centre containing a metal ion whose identity in vivo is not certain.

The A subunit from Methylococcus capsulatus str. Bath resides primarily within the membrane and consists of 7 transmembrane helices and a β-hairpin which interacts with the soluble region of the B subunit. A conserved glutamate residue is thought to contribute to a metal centre .
Microviridae F protein superfamily (Microviridae_protein_F_sf)
Type: Homologous_superfamily

This entry represents the Microviridae F protein superfamily, including capsid protein F and capsid protein VP1. Capsid protein F is the major capsid component in single-stranded DNA bacteriophages. 60 copies of this protein are present in the virion .
Translocated intimin receptor, central domain superfamily (Tir_central_sf)
Type: Homologous_superfamily

Secretion of virulence factors in Gram-negative bacteria involves transportation of the protein across two membranes to reach the cell exterior. There have been four secretion systems described in animal enteropathogens, such as Salmonella and Yersinia, with further sequence similarities in plant pathogens like Ralstonia and Erwinia .

The type III secretion system is of great interest, as it is used to transport virulence factors from the pathogen directly into the host cell and is only triggered when the bacterium comes into close contact with the host. The protein subunits of the system are very similar to those of bacterial flagellar biosynthesis. However, while the latter forms a ring structure to allow secretion of flagellin and is an integral part of the flagellum itself , type III subunits in the outer membrane translocate secreted proteins through a channel-like structure.

Exotoxins secreted by the type III system do not possess a secretion signal, and are considered unique for this reason . Enteropathogenic and entero-haemorrhagic Escherichia coli secrete the bacterial adhesion mediation molecule intimin , which targets the translocated intimin receptor (Tir). Tir is secreted by the bacteria and is embedded in the target cell's plasma membrane . This facilitates bacterial cell attachment to the host.

This entry represents the Tir intimin-binding domain superfamily which is needed to bind intimin and support the predicted topology for Tir, with both N- and C-terminal regions in the mammalian cell cytosol .
Exonuclease VII, small subunit superfamily (Exonuc_VII_ssu_sf)
Type: Homologous_superfamily

Exonuclease VII is composed of two non-identical subunits; one large subunit and 4 small ones . This enzyme catalyses exonucleolytic cleavage in either 5'-3' or 3'-5' direction to yield nucleoside 5'-phosphates.
S-ribosylhomocysteinase (LuxS) superfamily (LuxS_sf)
Type: Homologous_superfamily

In bacteria, the regulation of gene expression in response to changes in cell density is called quorum sensing. Quorum-sensing bacteria produce, release, and respond to hormone-like molecules (autoinducers) that accumulate in the external environment as the cell population grows. For example, enteric bacteria use quorum sensing to regulate several traits that allow them to establish and maintain infection in their host, including motility, biofilm formation, and virulence-specific genes . The LuxS/AI-2 system is one of several quorum sensing mechanisms. AI-2 (autoinducer-2) is a signalling molecule that functions in interspecies communication by regulating niche-specific genes with diverse functions in various bacteria, often in response to population density. LuxS (S-ribosylhomocysteinase;

) is an autoinducer-production protein that has a metabolic function as a component of the activated methyl cycle. LuxS converts S-ribosylhomocysteine to homocysteine and 4,5-dihydroxy-2,3-pentanedione (DPD); DPD can then spontaneously cyclise to active AI-2 . LuxS is a homodimeric iron-dependent metalloenzyme containing two identical tetrahedral metal-binding sites similar to those found in peptidases and amidases .
Histidine kinase CheA-like, homodimeric domain superfamily (CheA-like_homodim_sf)
Type: Homologous_superfamily

Signal transducing histidine kinases are the key elements in two-component signal transduction systems, which control complex processes such as the initiation of development in microorganisms . Examples of histidine kinases are EnvZ, which plays a central role in osmoregulation , and CheA, which plays a central role in the chemotaxis system . Histidine kinases usually have an N-terminal ligand-binding domain and a C-terminal kinase domain, but other domains may also be present. The kinase domain is responsible for the autophosphorylation of the histidine with ATP, the phosphotransfer from the kinase to an aspartate of the response regulator, and (with bifunctional enzymes) the phosphotransfer from aspartyl phosphate back to ADP or to water . The kinase core has a unique fold, distinct from that of the Ser/Thr/Tyr kinase superfamily.

This helical bundle domain is the homodimer interface of signal transducing histidine kinases like CheA .
Epstein Barr virus nuclear antigen-1, DNA-binding domain superfamily (EBNA1_DNA-bd_sf)
Type: Homologous_superfamily

The Epstein-Barr virus (strain GD1) nuclear antigen 1 (EBNA1) binds to and activates DNA replication from the latent origin of replication. The crystal structure of the DNA-binding and dimerization domains were solved , and it was found that EBNA1 appears to bind DNA via two independent regions, the core and the flanking DNA-binding domains. This DNA-binding domain has a ferredoxin-like fold.
Cytochrome bc1 complex subunit Rieske, transmembrane domain superfamily (bc1_Rieske_TM_sf)
Type: Homologous_superfamily

The ubiquinol cytochrome c reductase (cytochrome bc1) complex is a respiratory chain that generates an electrochemical potential coupled to ATP synthesis. The bc1 complex contains 11 subunits, 3 respiratory subunits (cytochrome B, cytochrome C1, Rieske protein), 2 core proteins and 6 low-molecular weight proteins . Each subunit of the cytochrome bc1 complex provides a single helix to make up the transmembrane region of the complex.

This entry represents the transmembrane domain of the iron-sulfur subunit Rieske.
mRNA triphosphatase Cet1-like superfamily (mRNA_triPase_Cet1_sf)
Type: Homologous_superfamily

The mRNA capping enzyme in yeast is composed of two subunits, alpha and beta. The alpha subunit has guanylyltransferase activity, whilst the beta subunit is an RNA 5'-triphosphatase (RTPase) . This entry represents a domain found in the mRNA capping enzyme beta subunit Cet1. RTPase catalyzes the first step in the mRNA cap formation process, the removal of the gamma-phosphate of triphosphate terminated pre-mRNA. This activity is metal-dependent. The 5'-end of the resulting mRNA diphosphate is subsequently capped with GMP by RNA guanylytransferase, and then further modified by one or more methyltransferases. The mRNA cap-forming activity is an essential step in mRNA processing. The RTPases are not conserved among eukarya and this subgroup includes fungal and protozoal RTPases. The RTPase domain of the mimivirus RTPase-GTase fusion mRNA capping enzyme also belongs to this subgroup. The domain is related to the CYTH domain. Cet1 has a novel active site fold whereby an eight-strand β-barrel forms a topologically closed tunnel known as the "triphosphate tunnel" . Enzymes with similar structures are able to bind triphosphorylated substrates and requiring divalent metal ions as activators. They were thus called triphosphate tunnel metalloenzymes (TTMs) .

Cetl paralogue, Ctl1 (capping enzyme RNAtriphosphatase-like 1), is a RNA 5'-triphosphatase probably involved in an RNA processing event other than mRNA capping .
Vitamin B12-dependent methionine synthase, activation domain superfamily (VitB12-dep_Met_synth_activ_sf)
Type: Homologous_superfamily

Vitamin B12 dependent methionine synthase

(5-methyltetrahydrofolate--homocysteine S-methyltransferase) catalyses the conversion of 5-methyltetrahydrofolate and L-homocysteine to tetrahydrofolate and L-methionine as the final step in
de novo
methionine biosynthesis. The enzyme requires methylcobalamin as a cofactor. In humans, defects in this enzyme are the cause of autosomal recessive inherited methylcobalamin deficiency (CBLG), which causes mental retardation, macrocytic anemia and homocystinuria. Mild deficiencies in activity may result in mild hyperhomocysteinemia, and mutations in the enzyme may be involved in tumorigenesis. Vitamin B12 dependent methionine synthase is found in prokaryotes and eukaryotes, but in prokaryotes the cofactor is cobalamin.

In Escherichia coli, methionine synthase is a large enzyme composed of four structurally and functionally distinct modules: the first two modules bind homocysteine and tetrahydrofolate, the third module binds the B12 cofactor (

,

), and the C-terminal module (activation domain) binds S-adenosylmethionine. The activation domain is essential for the reductive activation of the enzyme. During the catalytic cycle, the highly reactive cob(I)alamin intermediate can be oxidised to produce an inactive cob(II)alamin enzyme; the enzyme is then reactivated via reductive methylation by the activation domain . The activation domain adopts an unusual α/β fold.
Phycoerythrin-like alpha chain superfamily (Phycoerythr-like_a_sf)
Type: Homologous_superfamily

Cryptophytes are unicellular photosynthetic algae that use a lumenally located light-harvesting system, which is distinct from the phycobilisome structure found in cyanobacteria and red algae. One of the key components of this system is water-soluble phycoerythrin (PE) 545 whose expression is enhanced by low light levels . Phycoerythrin (PE) 545 is a heterodimeric of α(1)α(2)betabeta subunits. Each alpha subunit carries a covalently linked 15,16-dihydrobiliverdin chromophore that probably acts as the final energy acceptor. The architecture of the heterodimer suggests that PE 545 may dock to an acceptor protein via a deep cleft and that energy may be transferred via this intermediary protein to the reaction centre .

The structure of this domain found in the alpha chain is a long β-hairpin and a single α-helix.
NanQ anomerase/TabA/YiaL superfamily (NanQ/TabA/YiaL_sf)
Type: Homologous_superfamily

This superfamily is composed of bacterial proteins. N-acetylneuraminate anomerase NanQ (NanQ, previously known as YhcH) plays a role sialic acid catabolism by opening both the alpha- and beta-forms of N-acetylneuraminate (sialic acid; Neu5Ac) to provide aceneuramate, the preferred substrate for the sialic acid aldolase (NanA) . TabA (YjgK), also included in this entry, influences biofilm formation by toxin-antitoxin systems .
Glutathione synthase, substrate-binding domain superfamily (GSH-S_sub-bd_sf)
Type: Homologous_superfamily

This superfamily represents the substrate-binding domain of glutathione synthetase (

) (GSS), a homodimeric enzyme that catalyses the conversion of gamma-L-glutamyl-L-cysteine and glycine to phosphate and glutathione in the presence of ATP. This is the second step in glutathione biosynthesis, the first step being catalysed by gamma-glutamylcysteine synthetase . In humans, defects in GSS are inherited in an autosomal recessive way and are the cause of severe metabolic acidosis, 5-oxoprolinuria, and increased rate of haemolysis and defective function of the central nervous system. The substrate-binding domain has a 3-layer α/β/α structure .
Dedicator of cytokinesis protein 4, DHR2 domain (DHR2_DOCK4)
Type: Domain

DOCK family members are evolutionarily conserved guanine nucleotide exchange factors (GEFs) for Rho-family GTPases . DOCK proteins are required during several cellular processes, such as cell motility and phagocytosis. The N-terminal SH3 domain of the DOCK proteins functions as an inhibitor of GEF, which can be relieved upon its binding to the ELMO1-3 adaptor proteins, after their binding to active RhoG at the plasma membrane . DOCK family proteins are categorised into four subfamilies based on their sequence homology: DOCK-A subfamily (DOCK1/180, 2, 5), DOCK-B subfamily (DOCK3, 4), DOCK-C subfamily (DOCK6, 7, 8), DOCK-D subfamily (DOCK9, 10, 11) . All DOCKs contain two homology domains: the DHR-1 (Dock homology region-1), also called CZH1 (CED-5, Dock180, and MBC-zizimin homology 1), and DHR-2 (also called CZH2 or Docker).

DOCK4 is an atypical guanine nucleotide exchange factor (GEF) that lacks the conventional Dbl homology (DH) domain. It activates small GTPases by exchanging bound GDP for free GTP. It plays a role in regulating dendritic growth and branching in hippocampal neurons, where it is highly expressed. It may also regulate spine morphology and synapse formation and has been linked to autism, dyslexia, and schizophrenia . DOCK4 activates the Ras family GTPase Rap1, probably indirectly through interaction with Rap regulatory proteins. DOCK4 plays a critical role in mediating TGF-beta's prometastatic effects in lung cancer .

This entry represents the DHR-2 domain of DOCK4, which contains the catalytic GEF activity for Rac and/or Cdc42.
Aerolysin/Pertussis toxin (APT), N-terminal domain superfamily (APT_N_sf)
Type: Homologous_superfamily

This entry represents the N-terminal domain superfamily of aerolysin and pertussis toxin which contains a type-C lectin like fold.

Aerolysin causes the pathogenicity of Aeromonas hydrophila, a bacterium associated with diarrhoeal diseases and deep wound infections. Like many other microbial toxins, the protein changes in a multistep process from a completely water-soluble form to produce a transmembrane channel that breaks the permeability barrier of cells .

Pertussis toxin is a major virulence factor of Bordetella pertussis, which causes whooping cough. The protein is a hexamer containing a catalytic subunit (S1) that is tightly associated with a pentameric cell-binding component (B-oligomer). ATP, detergents and phospholipids assist in activating the holotoxin by destabilising the interaction between S1 and the B-oligomer . Pertussis toxin is an exotoxin and is an essential component of acellular vaccines . The catalytic A-subunit (S1) shares structural homology with other ADP-ribosylating bacterial toxins, although differences in the carboxy-terminal portion explain its unique activation mechanism . The diverse biological activities of the toxin depend on its ability to recognise carbohydrate-containing receptors on a wide variety of eukaryotic cells.
Anthrax toxin, edema factor, central domain superfamily (Anthrax_toxin_edema_cen_sf)
Type: Homologous_superfamily

Anthrax toxin is a plasmid-encoded toxin complex produced by the Gram-positive, spore-forming bacteria, Bacillus anthracis. The toxin consists of three non-toxic proteins: the protective antigen (PA), the lethal factor (LF) and the edema factor (EF) . These component proteins self-assemble at the surface of host cell receptors, yielding a series of toxic complexes that can produce shock-like symptoms and death. Anthrax toxin is one of a large group of Bacillus and Clostridium exotoxins referred to as binary toxins, forming independent enzymatic (A moiety) and binding (B moiety) components. The LF and EF proteins are the enzymes (A moiety) that act on cytosolic substrates, while PA is a multi-functional protein (B moiety) that binds to cell surface receptors, mediates the assembly and internalisation of the complexes, and delivers them to the host cell endosome . Once PA is attached to the host receptor , it must then be cleaved by a host cell surface (furin family) protease before it is able to bind EF and LF. The cleavage of the N terminus of PA enables the C-terminal fragment to self-associate into a ring-shaped heptameric complex (prepore) that can bind LF or EF competitively. The PA-LF/EF complex is then internalised by endocytosis, and delivered to the endosome, where PA forms a pore in the endosomal membrane in order to translocate LF and EF to the cytosol. LF is a Zn-dependent metalloprotease that cleaves and inactivates mitogen-activated protein (MAP) kinases, kills macrophages, and causes death of the host by inhibiting cell proliferation . EF is a calcium-and calmodulin-dependent adenylyl cyclase that can cause edema (fluid-filled swelling) when associated with PA. EF is not toxic by itself, and is required for the survival of germinated Bacillus spores within macrophages at the early stages of infection. EF dramatically elevates the level of host intracellular cAMP, a ubiquitous messenger that integrates many processes of the cell; increases in cAMP can interfere with host intracellular signalling .

This entry represents a central domain superfamily in the edema factor adenylyl cyclase protein of anthrax toxin, as well as in adenylyl cylcases from other bacterial toxins.
Glycoside hydrolase family 65, N-terminal domain (GH65_N)
Type: Homologous_superfamily

This entry represents the N-terminal domain superfamily of the glycoside hydrolase families 65 and 94. The family of glycosyl hydrolases (

) containing this domain includes vacuolar acid trehalase and maltose phosphorylase. Maltose phosphorylase (MP) is a dimeric enzyme that catalyses the conversion of maltose and inorganic phosphate into beta-D-glucose-1-phosphate and glucose. This domain is believed to be essential for catalytic activity although its precise function remains unknown. Members of this family include:

trehalose a-1,1-glucosidase

hydroxylysine exo-a-1,2-glucosidase

kojibiose a-1,2-glucosidase

branched-dextran exo-1,2-a-glucosidase

maltose phosphorylase

trehalose phosphorylase

trehalose 6-phosphate phosphorylase

kojibiose phosphorylase

nigeriose phosphorylase

a-1,3-glucosyl-L-rhamnose phosphorylase

a-glucosyl-glycerol phosphorylase

a-1,3-glucan phosphorylase

[ec:2.4.1.-] a-glucan phosphorylase

The family of glycosyl hydrolases 94 (

) is formerly known as the glycosyltransferase family GT36 . It contains microbial enzymes that phosphorolyze β-glycosidic linkages and produce α-d-glucose 1-phosphate (α-Glc1P) or α-N-acetyl-d-glucosamine 1-phosphate [

.

]. Members of this family include:

cellobiose phosphorylase

laminaribiose phosphorylase

cellodextrin phosphorylase

chitobiose phosphorylase

cellobionic acid phosphorylase

b-1,2-glucan phosphorylase

solabiose phosphorylase

b-1,3-glucosyl-glucuronic acid phosphorylase

[ec:2.4.1.-] b-1,4-glucosyl-galactose phosphorylase

[ec:2.4.1.-] acholetin phosphorylase

[ec:2.4.1.-] b-1,4-mixed linkage glucan phosphorylase

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 7, catalytic domain superfamily (Glyco_hydro_7_sf)
Type: Homologous_superfamily

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 7

comprises enzymes with several known activities; endoglucanase (

) and cellobiohydrolase (

). These enzymes were formerly known as cellulase family C.

Exoglucanases and cellobiohydrolases play a role in the conversion of cellulose to glucose by cutting the dissaccharide cellobiose from the nonreducing end of the cellulose polymer chain. Structurally, cellulases and xylanases generally consist of a catalytic domain joined to a cellulose-binding domain (CBD) via a linker region that is rich in proline and/or hydroxy-amino acids. In type I exoglucanases, the CBD domain is found at the C-terminal extremity of these enzyme (this short domain forms a hairpin loop structure stabilised by 2 disulphide bridges).

This entry represents the catalytic core domain of these enzymes .