SII-SWORD/CoKE huggingface dataset:
Copper amine oxidase, catalytic domain superfamily (Cu_amine_oxidase_C_sf)
Type: Homologous_superfamily

Amine oxidases (AO) are enzymes that catalyse the oxidation of a wide range of biogenic amines including many neurotransmitters, histamine and xenobiotic amines. There are two classes of amine oxidases: flavin-containing (

) and copper-containing (

). Copper-containing AO act as a disulphide-linked homodimer. They catalyse the oxidation of primary amines to aldehydes, with the subsequent release of ammonia and hydrogen peroxide, which requires one copper ion per subunit and topaquinone as cofactor :

RCH
2
NH
2
+ H
2
O + O
2
= RCHO + NH
3
+ H
2
O
2

Copper-containing amine oxidases are found in bacteria, fungi, plants and animals. In prokaryotes, the enzyme enables various amine substrates to be used as sources of carbon and nitrogen . In eukaryotes they have a broader range of functions, including cell differentiation and growth, wound healing, detoxification and cell signalling .

The copper amine oxidases occur as mushroom-shaped homodimers of 70-95kDa, each monomer containing a copper ion and a covalently bound redox cofactor, topaquinone (TPQ). TPQ is formed by post-translational modification of a conserved tyrosine residue. The copper ion is coordinated with three histidine residues and two water molecules in a distorted square pyramidal geometry, and has a dual function in catalysis and TPQ biogenesis. The catalytic domain is the largest of the 3-4 domains found in copper amine oxidases, and consists of a β sandwich of 18 strands in two sheets. The active site is buried and requires a conformational change to allow the substrate access. The two N-terminal domains share a common structural fold, its core consisting of a five-stranded antiparallel β-sheet twisted around an α-helix. The D1 domains from the two subunits comprise the stalk, of the mushroom-shaped dimer, and interact with each other but do not pack tightly against each other .

This entry represents the C-terminal catalytic domain superfamily of copper amine oxidases, and has a super-sandwich fold consisting of 18 β-strands in 2 sheets . A domain with a similar structural fold can be found as the third domain in lysyl oxidase PplO .
Urease, beta subunit superfamily (Urease_betasu_sf)
Type: Homologous_superfamily

Urease is a nickel-dependent metalloenzyme that catalyses the hydrolysis of urea to form ammonia and carbon dioxide. Nickel-dependent ureases are found in bacteria, archaea, fungi and plants. Their primary role is to allow the use of external and internally-generated urea as a nitrogen source. The enzyme consists of three subunits, alpha, beta and gamma, which can exist as separate proteins or can be fused on a single protein chain. The α-β-γ heterotrimer forms multimers, mainly trimers. The large alpha subunit is the catalytic domain containing an active site with a bi-nickel centre complexed by a carbamylated lysine. The beta and gamma subunits play a role in subunit association to form the higher order trimers .

This entry represents the urease beta subunit superfamily. In Helicobacter pylori, the gamma and beta subunits are fused and known (confusingly) as the alpha subunit.

The urease beta subunit structure is composed of double-stranded ribbon sharply bent in two places where the ribbon ends form incomplete barrel and has a jelly-roll.
Fumarylacetoacetase, N-terminal domain superfamily (Fumarylacetoacetase_N_sf)
Type: Homologous_superfamily

Fumarylacetoacetase (

; also known as fumarylacetoacetate hydrolase or FAH) catalyses the hydrolytic cleavage of a carbon-carbon bond in fumarylacetoacetate to yield fumarate and acetoacetate as the final step in phenylalanine and tyrosine degradation . This is an essential metabolic function in humans, the lack of FAH causing type I tyrosinaemia, which is associated with liver and kidney abnormalities and neurological disorders . The enzyme mechanism involves a catalytic metal ion, a Glu/His catalytic dyad, and a charged oxyanion hole . FAH folds into two domains: an N-terminal domain SH3-like β-barrel, and a C-terminal with an unusual fold consisting of three layers of β-sheet structures .

This entry represents the N-terminal domain superfamily of fumarylacetoacetase. This domain adopts a structure consisting of an SH3-like barrel .
Urease, gamma subunit superfamily (Urease_gamma_sf)
Type: Homologous_superfamily

Urease (urea amidohydrolase,

) is a nickel-dependent metalloenzyme that catalyses the hydrolysis of urea to form ammonia and carbon dioxide. Nickel-dependent ureases are found in bacteria, archaea, fungi and plants. Their primary role is to allow the use of external and internally-generated urea as a nitrogen source. The enzyme consists of three subunits, alpha, beta and gamma, which can exist as separate proteins or can be fused on a single protein chain. The α-β-γ heterotrimer forms multimers, mainly trimers. The subunit composition of urease from different sources varies , but each holoenzyme consists of four domains : three structural domains and a nickel-binding catalytic domain common to amidohydrolases .

In Klebsiella aerogenes, urease exists as an alpha, beta and gamma subunit, with the alpha subunit possessing the catalytic domain. In Helicobacter pylori, the gamma and beta subunits are fused and called the alpha subunit, while the catalytic subunit is called the beta subunit. In Canavalia ensiformis, urease has a fused gamma-beta-alpha organisation.

This entry represents the urease gamma subunit superfamily. It also identifies gamma subunits fused with other urease subunits, as found in Helicobacter and other species.

The urease gamma subunit has an α(3)-β(2) fold with an antiparallel hairpin topology.
Rubisco LSMT, substrate-binding domain superfamily (Rubisco_LSMT_subst-bd_sf)
Type: Homologous_superfamily

The domain in this superfamily adopts a multihelical structure, with an irregular array of long and short α-helices. It allows binding of the protein to substrate, such as the N-terminal tails of histones H3 and H4 and the large subunit of the Rubisco holoenzyme complex .
von Willebrand factor A-like domain superfamily (vWFA_dom_sf)
Type: Homologous_superfamily

The von Willebrand factor is a large multimeric glycoprotein found in blood plasma. Mutant forms are involved in the aetiology of bleeding disorders
. In von Willebrand factor, the type A domain (vWF) is the prototype for a protein superfamily. The vWF domain is found in various plasma proteins: complement factors B, C2, CR3 and CR4; the integrins (I-domains); collagen types VI, VII, XII and XIV; and other extracellular proteins . Although the majority of VWA-containing proteins are extracellular, the most ancient ones present in all eukaryotes are all intracellular proteins involved in functions such as transcription, DNA repair, ribosomal and membrane transport and the proteasome. A common feature appears to be involvement in multiprotein complexes. Proteins that incorporate vWF domains participate in numerous biological events (e.g. cell adhesion, migration, homing, pattern formation, and signal transduction), involving interaction with a large array of ligands . A number of human diseases arise from mutations in VWA domains.
Pollen allergen ole e 6 superfamily (Pollen_allergen_ole-e-6_sf)
Type: Homologous_superfamily

This superfamily represents pollen allergens, such as ole-e-6, a small acidic protein from Olea europaea (Common olive) which mediates olive allergy. Members of this family have an α-helical hairpin structure cross-linked by three disulphides, followed by a long, unstructured C-terminal tail .
Lumazine/riboflavin synthase superfamily (LS/RS_sf)
Type: Homologous_superfamily

6,7-dimethyl-8-ribityllumazine synthase (lumazine synthase, LS), catalyzes the formation of 6,7-dimethyl-8-ribityllumazine by condensation of 5-amino-6-(D-ribitylamino)uracil with 3,4-dihydroxy-2-butanone 4-phosphate, the penultimate step in the biosynthesis of riboflavin.

The biosynthesis of one riboflavin molecule requires one molecule of GTP and two molecules of ribulose 5-phosphate as substrates. The final step in the biosynthesis of the vitamin involves the dismutation of 6,7-dimethyl-8-ribityllumazine catalyzed by riboflavin synthase (RS). The second product, 5-amino-6-ribitylamino-2,4(1H,3H)-pyrimidinedione, is recycled in the biosynthetic pathway by 6,7-dimethyl-8-ribityllumazine synthase . N-[2,4-dioxo-6-d-ribitylamino-1,2,3,4-tetrahydropyrimidin-5-yl]oxalamic acid derivatives inhibit riboflavin synthase .

This superfamily includes both lumazine synthase and riboflavin synthase. Both share sequence similarity, they appear to have diverged early in the evolution of archaea from a common ancestor.

The lumazine synthase structure is a pentamer consisting of five subunits related by 5-fold local symmetry . Each subunits consists of a three layers (α/β/α) with a parallel β-sheet of four strands.
AHSP superfamily (AHSP_sf)
Type: Homologous_superfamily

Alpha-haemoglobin stabilising protein (AHSP) acts a molecular chaperone for free alpha-haemoglobin, preventing the harmful aggregation of alpha-haemoglobin during normal erythroid cell development: it specifically protects free alpha-haemoglobin from precipitation. AHSP adopts a helical secondary structure consisting of an elongated antiparallel three α-helix bundle .
Gametocyte protein Pfg27 superfamily (Pfg27_sf)
Type: Homologous_superfamily

Members of this superfamily are essential for gametocytogenesis in Plasmodium falciparum. They contain a fold composed of two pseudo dyad-related repeats of the helix-turn-helix motif, serving as a platform for RNA and Src homology-3 (SH3) binding .
Elicitin superfamily (Elicitin_sf)
Type: Homologous_superfamily

Elicitins are small, highly-conserved proteins secreted by phytopathogenic fungi belonging to Phytophthora species . They are toxic proteins that induce a necrotic and systemic hypersensitive response in plants from the Solanaceae and Cruciferae families. Leaf necrosis provides immediate control of fungal invasion and induces systemic acquired resistance; both responses mediate basic protection against subsequent pathogen inoculation.

Members of this superfamily share a high level of sequence similarity, but they differ in net charge, dividing them into two classes: alpha and beta . Alpha-elicitins are highly acidic, with a valine residue at position 13, whereas beta-elicitins are basic, with a lysine at the same position. Residue 13 is known to be involved in the control of necrosis and, being exposed, is thought to be involved in ligand/receptor binding . Phenotypically, the two classes can be distinguished by their necrotic properties: beta-elicitins are 100-fold more toxic and provide better subsequent protection .

The elicitin structure is composed of five helices arranged in an irregular disulfide-linked array and a small β-hairpin.
Colicin D superfamily (Colicin_D_sf)
Type: Homologous_superfamily

Colicin D is a bacteriocin that kills target cells by cleaving tRNA(Arg). Colicin D immunity protein (ImmD) inhibits the bactericidal activity of colicin D by binding to its tRNase catalytic domain .

This entry represents the domain containing four-helical up-and-down bundle found in ImmD and related klebicin and microcin immunity proteins.
Cholecystokinin A receptor, N-terminal domain superfamily (CholecystokininA_recpt_N_sf)
Type: Homologous_superfamily

This entry represents the extracellular N-terminal domain of the cholecystokinin A receptor. This domain adopts a tertiary structure consisting of a few helical turns and a disulphide-cross linked loop. It is required for interaction of the cholecystokinin A receptor with its corresponding hormonal ligand .
Molybdopterin cofactor biosynthesis MoaD-related, C-terminal domain superfamily (Mopterin_CF_MoaD-rel_C_sf)
Type: Homologous_superfamily

In Escherichia coli, the MoaD protein plays a central role in the conversion of precursor Z to molybdopterin (MPT) during molybdenum cofactor biosynthesis. Proteins are found in Thermus thermophilus, including threonine synthase (

), which catalyses the conversion of O-phospho-L-homoserine to L-threonine and phosphate.

MoaD-related proteins have an N-terminal MoaD domain, with a fold similar to that of ubiquitin, and contain a highly conserved C-terminal Gly-Gly motif, which in its active form contains a transferrable sulphur in the form of a thiocarboxylate group . This entry represents the domain found at the C terminus, which consists of a TBP-like fold of β/α/β(4)/α.
Transcription regulator MotA, C-terminal domain superfamily (MotA_Tscrpt_reg_C_sf)
Type: Homologous_superfamily

Transcription factor MotA is required for the activation of middle promoters in Bacteriophage T4, in addition to phage T4 co-activator AsiA, and sigma-70-containing Escherichia coli RNA polymerase. Phage T4 middle promoters have the sigma70 -10 DNA element, but not the -35 element; instead, they have a MotA box at -30 to which the transcription factor MotA binds . MotA and AsiA interact with the C-terminal of sigma70 (region 4), which normally binds the -35 element and the β-flap, thereby diverting sigma70 away from host promoters that require -35 element-binding to phage T4 middle promoters.
Mitogen Ypm superfamily (Mitogen_Ypm_sf)
Type: Homologous_superfamily

Members of this family of Yersinia pseudotuberculosis mitogens adopt a sandwich structure consisting of nine strands in two β sheets, in a jelly-roll topology. As with other superantigens, they are able to excessively activate T cells by binding to the T cell receptor .
Talin, central domain superfamily (Talin_cent_sf)
Type: Homologous_superfamily

This domain adopts a structure consisting of five α-helices that fold into a bundle. It contains a vinculin binding site (VBS) composed of a hydrophobic surface spanning five turns of helix four. Activation of the VBS causes subsequent recruitment of vinculin, which enables maturation of small integrin/talin complexes into more stable adhesions. Formation of the complex between VBS and vinculin requires prior unfolding of this middle domain: once released from the talin hydrophobic core, the VBS helix is then available to induce the 'bundle conversion' conformational change within the vinculin head domain thereby displacing the intramolecular interaction with the vinculin tail, allowing vinculin to bind actin .
Formyl transferase, N-terminal domain superfamily (Formyl_transf_N_sf)
Type: Homologous_superfamily

A number of formyl transferases belong to this group. Methionyl-tRNA formyltransferase transfers a formyl group onto the amino terminus of the acyl moiety of the methionyl minoacyl-tRNA. The formyl group appears to play a dual role in the initiator identity of N-ormylmethionyl-tRNA by promoting its recognition by IF2 and by impairing its binding to EFTU-GTP. Formyltetrahydrofolate dehydrogenase produces formate from formyl-tetrahydrofolate. This is the N-terminal domain of these enzymes and is found upstream of the C-terminal domain (

).

The trifunctional glycinamide ribonucleotide synthetase-aminoimidazole ribonucleotide synthetase-glycinamide ribonucleotide transformylase catalyses the second, third and fifth steps in de novo purine biosynthesis. The glycinamide ribonucleotide transformylase belongs to this group.

The formyl transferase N-terminal domain structure has a three layers (α/β/α) fold, with a mixed β-sheet of seven strands where strand 6 is antiparallel to the rest.
Exotoxin A, middle domain superfamily (Exotox-A_middle_dom_sf)
Type: Homologous_superfamily

This domain, found in Pseudomonas aeruginosa exotoxin A, is responsible for transmembrane targeting of the toxin, as well as transmembrane translocation of the catalytic domain into the cytoplasmic compartment. A furin cleavage site is present within the domain: cleavage generates a 37kDa carboxy-terminal fragment, which includes the enzymatic domain, which is then is translocated into the cytoplasm. It adopts a helical structure, with six α-helices forming a bundle .
Heat-stable enterotoxin B superfamily (STb_sf)
Type: Homologous_superfamily

Members of this superfamily assume a helical secondary structure, with two α helices forming a disulphide cross-linked α-helical hairpin. The disulphide bonds are crucial for the toxic activity of the protein, and are required for maintenance of the tertiary structure, and subsequent interaction with the particulate form of guanylate cyclase, increasing cyclic GMP levels within the host intestinal epithelial cells .
Carbamoyl-phosphate synthase small subunit, N-terminal domain superfamily (CarbP_synth_ssu_N_sf)
Type: Homologous_superfamily

This entry represents the N-terminal domain superfamily of the small subunit of carbamoyl phosphate synthase. Structurally, it forms a 3-layer β/β/α fold of a type that is thought to be mobile in most proteins that carry it .
Bcr-Abl oncoprotein oligomerisation domain superfamily (Bcr-Abl_oncoprot_oligo_sf)
Type: Homologous_superfamily

This entry represents the oligomerisation domain of the breakpoint cluster region oncoprotein Bcr, and the Bcr/Abl (Abelson-leukemia-virus) fusion protein created by a reciprocal (9;22) fusion . Brc displays serine/threonine protein kinase activity (

), acting as a GTPase-activating protein for RAC1 and CDC42. Brc promotes the exchange of RAC or CDC42-bound GDP by GTP, thereby activating them . The Bcr/Abl fusion protein loses some of the regulatory function of Bcr with regards to small Rho-like GTPases with negative consequences on cell motility, in particular on the capacity to adhere to endothelial cells .

The Bcr, Bcr/Abl oncoprotein oligomerisation domain consists of a short N-terminal helix (α1), a flexible loop and a long C-terminal helix (α2). Together these form an N-shaped structure, with the loop allowing the two helices to assume a parallel orientation. The monomeric domains associate into a dimer through the formation of an antiparallel coiled coil between the α2 helices and domain swapping of two α1 helices, where one α1 helix swings back and packs against the α2 helix from the second monomer. Two dimers then associate into a tetramer. The oligomerization domain is essential for the oncogenicity of the Bcr-Abl protein .
Hut operon regulatory protein HutP superfamily (Regulatory_HutP_sf)
Type: Homologous_superfamily

The HutP protein regulates the expression of Bacillus 'hut' structural genes by an anti-termination complex, which recognises three UAG triplet units, separated by four non-conserved nucleotides on the RNA terminator region. L-Histidine and Mg2+ ions are also required. These proteins exhibit the structural elements of alpha/beta proteins, arranged in the order: α-α-β-α-α-β-β-β in the primary structure, and the four antiparallel β-strands form a β-sheet in the order beta1-beta2-beta3-beta4, with two α-helices each on the front (alpha1 and alpha2) and at the back (alpha3 and alpha4) of the β-sheet .
PWI domain superfamily (PWI_dom_sf)
Type: Homologous_superfamily

This entry represents the PWI domain superfamily.

The PWI domain, named after a highly conserved PWI tri-peptide located within its N-terminal region, is a ~80 amino acid module, which is found either at the N terminus or at the C terminus of eukaryotic proteins involved in pre-mRNA processing . It is generally found in association with other domains such as RRM and RS. The PWI domain is a RNA/DNA-binding domain that has an equal preference for single- and double-stranded nucleic acids and is likely to have multiple important functions in pre-mRNA processing . Proteins containing this domain include the SR-related nuclear matrix protein of 160kDa (SRm160) splicing and 3'-end cleavage-stimulatory factor, and the mammalian splicing factor PRP3. This domain is also present in Rmn1 from S.pombe, a component of a MTREC submodule, which promotes degradation of meiotic mRNAs and regulatory ncRNAs, and is the major nuclear exosome targeting complex for cryptic unstable transcripts (CUTs) and unspliced pre-mRNAs . Rmn1 homologues from human RBM26/27 may be involved in turnover of nuclear polyadenylated RNA and are important for PAXT-mediated nuclear RNA decay .

The PWI domain is a soluble, globular and independently folded domain which consists of a four-helix bundle, with structured N- and C-terminal elements .
Protein-tyrosine phosphatase, YopH, N-terminal domain superfamily (ProtTyrPase_YopH_N_sf)
Type: Homologous_superfamily

This entry represents the N-terminal domain of YopH protein tyrosine phosphatase (PTP). This domain has a compact structure composed of four α-helices and two β-hairpins. Helices alpha-1 and alpha-3 are parallel to each other and antiparallel to helices alpha-2 and alpha-4. This domain targets YopH for secretion from the bacterium and translocation into eukaryotic cells, and has phosphotyrosyl peptide-binding activity, allowing for recognition of p130Cas and paxillin . YopH from Yersinia sp. is essential for pathogenesis, as it allows the bacteria to resist phagocytosis by host macrophages through its ability to dephosphorylate host proteins, thereby interfering with the host signalling process. Yersinia has one of the most active PTP enzymes known. YopH contains a loop of ten amino acids (the WPD loop) that covers the entrance of the active site of the enzyme during substrate binding .
Glutamate synthase, alpha subunit, C-terminal domain superfamily (Glu_synth_asu_C_sf)
Type: Homologous_superfamily

Glutamate synthase (GltS) is a complex iron-sulphur flavoprotein that catalyses the reductive synthesis of L-glutamate from 2-oxoglutarate and L-glutamine via intramolecular channelling of ammonia, a reaction in the bacterial, yeast and plant pathways for ammonia assimilation . GltS is a multifunctional enzyme that functions through three distinct active centres carrying out multiple reaction steps: L-glutamine hydrolysis, conversion of 2-oxoglutarate into L-glutamate, and electron uptake from an electron donor. The active centres are synchronised to avoid the wasteful consumption of L-glutamine . There are three classes of GltS, which share many functional properties: bacterial NADPH-dependent GltS, ferredoxin-dependent GltS from photosynthetic cells, and NAD(P)H-dependent GltS from yeast, fungi and lower animals.

The dimeric alpha subunits each consist of four domains: N-terminal amidotransferase domain, the central domain, the FMN binding domain and the C-terminal domain. The C-terminal domain forms a right-handed β-helix that comprises seven helical turns . Each helical turn has a sharp bend that is associated with a repeated sequence motif consisting of G-XX-G-XXX-G. This domain does not contain any residues directly involved in catalysis, but has a crucial structural role.

This domain superfamily is also found in proteins such as subunit C of formylmethanofuran dehydrogenase, which catalyses the first step in methane formation from carbon dioxide in methanogenic archaea. There are two isoenzymes of formylmethanofuran dehydrogenase: a tungsten-containing isoenzyme (FwdC) and a molybdenum-containing isoenzyme (FmdC). The tungsten isoenzyme is constitutively transcribed, whereas transcription of the molybdenum operon is induced by molybdate .
Anti-Sigma Factor A superfamily (AsiA_sf)
Type: Homologous_superfamily

Anti-sigma factor A is a transcriptional inhibitor that inhibits sigma 70-directed transcription by weakening its interaction with the core of the host's RNA polymerase. It is an all-helical protein, composed of six helical segments and intervening loops and turns, as well as a helix-turn-helix DNA binding motif, although neither free anti-sigma factor nor anti-sigma factor bound to sigma-70 has been shown to interact directly with DNA. In solution, the protein forms a symmetric dimer of small (10.59kDa) protomers, which are composed of helix and coil regions and are devoid of β-strand/sheet secondary structural elements .