SII-SWORD/CoKE huggingface dataset:
Knottin, scorpion toxin-like superfamily (Scorpion_toxin-like_sf)
Type: Homologous_superfamily

Knottins are small proteins characterised by a cystine-knot . They constitute a large family of structurally related peptides with diverse biological functions, including inhibitors, anti-microbial peptides and toxins . Their structure is composed of a disulfide-bound fold and contains β-hairpin with two adjacent disulfides.

The scorpion toxin-like domain is found in a subgroup of metazoan knottins mainly from the arthropoda, which include the antibacterial defensins and the scorpion alpha-neurotoxins . The plant sequences include members of the gamma-thionin family, which are plant defensins that have no antifungal activity. Other members are insect alpha-amylase inhibitors, cysteine-rich antifungal proteins and proteins annotated as proteinase inhibitors; those that are characterised belong to MEROPS inhibitor family I18, clan I.
Transcription elongation factor S-II, central domain superfamily (TFIIS_cen_dom_sf)
Type: Homologous_superfamily

Transcription factor S-II (TFIIS) induces mRNA cleavage by enhancing the intrinsic nuclease activity of RNA polymerase (Pol) II, past template-encoded pause sites. It is widely distributed being found in mammals, Drosophila, yeast and in the archaebacteria Sulfolobus acidocaldarius . S-II proteins have a relatively conserved C-terminal region but variable N-terminal region, and some members of this family are expressed in a tissue-specific manner .

TFIIS is a modular factor that comprises an N-terminal domain I, a central domain II, and a C-terminal domain III . The weakly conserved domain I forms a four-helix bundle and is not required for TFIIS activity. Domain II forms a three-helix bundle, and domain III adopts a zinc-ribbon fold with a thin protruding β-hairpin. Domain II and the linker between domains II and III are required for Pol II binding, whereas domain III is essential for stimulation of RNA cleavage. TFIIS extends from the polymerase surface via a pore to the internal active site, spanning a distance of 100 Angstroms. Two essential and invariant acidic residues in a TFIIS loop complement the Pol II active site and could position a metal ion and a water molecule for hydrolytic RNA cleavage. TFIIS also induces extensive structural changes in Pol II that would realign nucleic acids in the active centre.

The superfamily represents the central domain of transcription elongation factor S-II and similar domains.
WRKY domain superfamily (WRKY_dom_sf)
Type: Homologous_superfamily

This entry represents the WRKY domain superfamily.

The WRKY domain is a 60 amino acid region that is defined by the conserved amino acid sequence WRKYGQK at its N-terminal end, together with a novel zinc-finger-like motif. The WRKY domain is found in one or two copies in a superfamily of plant transcription factors involved in the regulation of various physiological programs that are unique to plants, including pathogen defence, senescence, trichome development and the biosynthesis of secondary metabolites. The WRKY domain binds specifically to the DNA sequence motif (T)(T)TGAC(C/T), which is known as the W box. The invariant TGAC core of the W box is essential for function and WRKY binding . Some proteins known to contain a WRKY domain include Arabidopsis thaliana ZAP1 (Zinc-dependent Activator Protein-1) and AtWRKY44/TTG2, a protein involved in trichome development and anthocyanin pigmentation; and wild oat ABF1-2, two proteins involved in the gibberelic acid-induced expression of the alpha-Amy2 gene.

Structural studies indicate that this domain is a four-stranded β-sheet with a zinc binding pocket, forming a novel zinc and DNA binding structure . The WRKYGQK residues correspond to the most N-terminal β-strand, which enables extensive hydrophobic interactions, contributing to the structural stability of the β-sheet.
Photosystem I PsaF, reaction centre subunit III superfamily (PSI_PsaF_sf)
Type: Homologous_superfamily

Photosystem I (PSI) is an integral membrane protein complex that uses light energy to mediate electron transfer from plastocyanin to ferredoxin. Subunit III (or PsaF) is one of at least 14 different subunits that compose the photosystem I reaction centre (PSI-RC) .
SMAD MH1 domain superfamily (SMAD_MH1_sf)
Type: Homologous_superfamily

Smad proteins are signal transducers and transcriptional comodulators of the TGF-beta superfamily of ligands, which play a central role in regulating a broad range of cellular responses, including cell growth, differentiation, and specification of developmental fate, in diverse organisms from Caenorhabditis elegans to humans. Ligand binding to specific transmembrane receptor kinases induces receptor oligomerisation and phosphorylation of the receptor specific Smad protein (R-Smad) in the cytoplasm. The R-Smad proteins regulate distinct signalling pathways. Smad1, 5 and 8 mediate the signals of bone morphogenetic proteins (BMPs), while Smad2 and 3 mediate the signals of activins and TGF-betas. Upon ligand stimulation, R-Smad proteins are phosphorylated at the conserved C-terminal tail sequence, SS*xS* (where S* denotes a site of phosphorylation). The phosphorylated states of R-Smad proteins form heteromeric complexes with Smad4 and are translocated into the nucleus. In the nucleus, the heteromeric complexes function as gene-specific transcription activators by binding to promoters and interacting with transcriptional coactivators. Smad6 and Smad7 are inhibitory Smad proteins that inhibit TGF-beta signalling by interfering with either receptor-mediated phosphorylation or hetero-oligomerisation between Smad4 and R-Smad proteins. Smad proteins comprise two conserved MAD homology domains, one in the N terminus (MH1) and one in the C terminus (MH2), separated by a more variable, proline-rich linker region. The MH1 domain has a role in DNA binding and negatively regulates the functions of MH2 domain, whereas the MH2 domain is responsible for transactivation and mediates phosphorylation-triggered heteromeric assembly between Smad4 and R-Smad .
Photosystem I, reaction centre subunit PsaD superfamily (PsaD_sf)
Type: Homologous_superfamily

PsaD is a small, extrinsic polypeptide located on the stromal side (cytoplasmic side in cyanobacteria) of the photosystem I reaction centre complex. It is required for native assembly of PSI reaction clusters and is implicated in the electrostatic binding of ferredoxin within the reaction centre . PsaD forms a dimer in solution which is bound by PsaE however PsaD is monomeric in its native complexed PSI environment .

Structurally, PsaD has a β-β(2)-β-α-β(2) fold with antiparallel sheet packed against helix, has β-hairpin on the same side and has an irregular C-terminal tail.
Phosphatase 2C, C-terminal domain superfamily (PP2C_C_sf)
Type: Homologous_superfamily

Protein phosphatase 2C (PP2C, also known as Protein phosphatase 1) is involved in regulating cellular responses to stress in various eukaryotes. It consists of two domains: an N-terminal catalytic domain and a C-terminal domain characteristic of mammalian PP2Cs. This domain consists of three antiparallel α helices, one of which packs against two corresponding α-helices of the N-terminal domain. The C-terminal domain does not seem to play a role in catalysis, but it may provide protein substrate specificity due to the cleft that is created between it and the catalytic domain .
Cyanate lyase, C-terminal domain superfamily (Cyanate_lyase_C_sf)
Type: Homologous_superfamily

Some bacteria can overcome the toxicity of environmental cyanate by hydrolysis of cyanate. This reaction is catalyzed by cyanate lyase (also known as cyanase) . Cyanate lyase is found in bacteria and plants and catalyzes the reaction of cyanate with bicarbonate to produce ammonia and carbon dioxide.

The cyanate lyase monomer is composed of two domains. The N-terminal domain shows structural similarity to the DNA-binding α-helix bundle motif. The C-terminal domain has an 'open fold' with no structural homology to other proteins. The dimer structure reveals the C-terminal domains to be intertwined, and the decamer is formed by a pentamer of these dimers. The active site of the enzyme is located between dimers and is comprised of residues from four adjacent subunits of the homodecamer .
Copper amine oxidase-like, N-terminal domain superfamily (Mao_N_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 a domain superfamily found at the N-terminal of certain copper amine oxidases, as well as in related proteins such as cell wall hydrolase and N-acetylmuramoyl-L-alanine amidase. This domain consists of a five-stranded antiparallel β-sheet twisted around an α helix .
23S rRNA-intervening sequence superfamily (23S_rRNA_IVS_sf)
Type: Homologous_superfamily

This superfamily consists of bacterial proteins encoded within an intervening sequence present within some 23S rRNA genes . It folds into an anti-parallel four-helix bundle and forms homopentamers .
Flagellar protein FliS superfamily (FliS_sf)
Type: Homologous_superfamily

The fliD operon of several bacteria consists of three flagellar genes, fliD, fliS, and fliT, and is transcribed in this order . In Bacillus subtilis the operon encoding the flagellar proteins FliD, FliS, and FliT is sigma D-dependent .

FliS is a flagellin-specific T3S chaperone that binds in 1:1 stoichiometry to the C-terminal region of flagellin and facilitates its export, preventing polymerization in the cytoplasm . The fliS gene is necessary for flagellation. In Aeromonas, deletion of this gene (called flaJ) resulted in the complete loss of motility, flagellin expression, and adherence .

Structurally, FliS can form closed, open and helix-swapped bundles.
Attractin superfamily (Attractin_sf)
Type: Homologous_superfamily

This superfamily consists of attractin water-borne pheromones. Mate attraction in Aplysia involves a long-distance water-borne signal in the form of the attractin peptide that is released during egg laying. These peptides contain 6 conserved cysteines and are folded into 2 antiparallel helices. The second helix contains the IEECKTS sequence conserved in Aplysia attractins .
Neurotoxin B-IV-like superfamily (Neurotoxin_B-IV-like_sf)
Type: Homologous_superfamily

The members of this superfamily resemble neurotoxin B-IV (

), which is a crustacean-selective neurotoxin produced by the marine worm Cerebratulus lacteus. This highly cationic peptide is approximately 55 residues and is arranged to form two antiparallel helices connected by a well-defined loop in a hairpin structure. The branches of the hairpin are linked by four disulphide bonds. Three residues identified as being important for activity, namely Arg-17, -25 and -34, are found on the same face of the molecule, while another residue important for activity, Trp30, is on the opposite side. The protein's mode of action is not entirely understood, but it may act on voltage-gated sodium channels, possibly by binding to an as yet uncharacterised site on these proteins. Its site of interaction may also be less specific, for example it may interact with negatively charged membrane lipids .
Nuclease A inhibitor-like superfamily (NucleaseA_inhib-like_sf)
Type: Homologous_superfamily

This superfamily consists of protein sequences that are similar to the nuclease A inhibitor expressed by bacteria of the genus Anabaena (NuiA,

). This sequence is organised to form an α-β-α sandwich fold, which is similar to the PR-1-like fold. NuiA interacts with nuclease A by means of residues located at one end of the molecule, including residues making up the loop between helices III and IV and the loop between strands C and D. The mechanism of inhibition of nuclease A by NuiA is as yet incompletely understood .
Precorrin-8X methylmutase CobH/CbiC superfamily (CobH/CbiC_sf)
Type: Homologous_superfamily

This entry represents CbiC and CobH precorrin-8X methylmutase (

), both as stand-alone enzymes and when CobJ forms part of a bifunctional enzyme. CobH and CbiC from the aerobic and anaerobic pathways, respectively, catalyse a methyl rearrangement in precorrin-8 that moves the methyl group from C-11 to C-12 to produce hydrogenobyrinic acid . Hydrogenobyrinic acid now contains all the major framework alterations associated with corrin synthesis .

CobH and CbiC can sometimes be fused to other enzymes in the cobalamin pathway to make bifunctional enzymes: e.g., with CobJ/CibH and with CbiX.

Cobalamin (vitamin B12) is a structurally complex cofactor, consisting of a modified tetrapyrrole with a centrally chelated cobalt. Cobalamin is usually found in one of two biologically active forms: methylcobalamin and adocobalamin. Most prokaryotes, as well as animals, have cobalamin-dependent enzymes, whereas plants and fungi do not appear to use it. In bacteria and archaea, these include methionine synthase, ribonucleotide reductase, glutamate and methylmalonyl-CoA mutases, ethanolamine ammonia lyase, and diol dehydratase . In mammals, cobalamin is obtained through the diet, and is required for methionine synthase and methylmalonyl-CoA mutase .
Homocysteine-binding domain superfamily (HCY_dom_sf)
Type: Homologous_superfamily

The homocysteine (Hcy) binding domain is an ~300-residue module which is found in a set of enzymes involved in alkyl transfer to thiols:

Prokaryotic and eukaryotic B12-dependent methionine synthase (MetH) (

), a large, modular protein that catalyses the transfer of a methyl group from methyltetrahydrofolate (CH3-H4folate) to Hcy to form methionine, using cobalamin as an intermediate methyl carrier.

Mammalian betaine-homocysteine S-methyltransferase (BHMT) (

). It catalyses the transfer of a methyl group from glycine betaine to Hcy, forming methionine and dimethylglycine.

Plant selenocysteine methyltransferase ([ec:2.1.1.-]).

Plant and fungal AdoMet homocysteine S-methyltransferases (

).

The Hcy-binding domain utilises a Zn(Cys)3 cluster to bind and activate Hcy. It has been shown to form a (β/α)8 barrel. The Hcy binding domain barrel is distorted to form the metal- and substrate-binding sites. To accommodate the substrate, strands 1 and 2 of the barrel are loosely joined by nonclassic hydrogen bonds; to accommodate the metal, strands 6 and 8 are drawn together and strand 7 is extruded from the end of the barrel. The cysteines ligating the catalytic zinc atom are located at the C-terminal ends of strands 6 and 8 .
SOS response associated peptidase-like (SRAP-like)
Type: Homologous_superfamily

This entry represents the SOS response associated peptidase (SRAP) superfamily.

The SRAP (SOS-response associated peptidase) family is characterised by the SRAP domain with a novel thiol autopeptidase activity, whose active site in human HMCES is comprised of the catalytic triad residues C2, E127, and H210 . SRAP proteins are evolutionarily conserved in all domains of life. For instance, human HMCES and E. coli YedK are similar in both sequence and structure . HMCES was originally identified as a possible reader of 5hmC in embryonic stem cell extracts using a double-stranded DNA molecule containing 5hmC as bait . The bacterial members have operonic associations with the SOS DNA damage response, mutagenic translesion DNA polymerases, non-homologous DNA-ending-joining networks that employ Ku and an ATP-dependent ligase, and other repair systems .
YggU-like superfamily (YggU-like_sf)
Type: Homologous_superfamily

This entry describes a group of proteins of unknown function found in all cellular organisms. Structures for two of these proteins, YggU from Escherichia coli and MTH637 from the archaea Methanobacterium thermoautotrophicum, have been determined; they have a core 2-layer α/β structure consisting of β(2)-loop-α-β(2)-α structural elements .
Photosystem I PsaL, reaction centre subunit XI superfamily (PSI_PsaL_sf)
Type: Homologous_superfamily

The trimeric photosystem I of the cyanobacterium Synechococcus elongatus recomprises 11 protein subunits. Subunit XI, PsaL, from plants and bacteria is one of the smaller subunits with only two transmembrane α helices. PsaL interacts closely with PsaI .
CPE0013-like superfamily (CPE0013-like_sf)
Type: Homologous_superfamily

Hypothetical archaeal and bacterial proteins make up this superfamily. A few proteins are annotated as being potential metal-binding proteins, and in fact the members of this family have four highly conserved cysteine residues, but no further literature evidence was found in this regard. The structure of Clostridium perfringens protein CPE0013 has been solved (

).
Methionine synthase domain (Meth_synthase_dom)
Type: Homologous_superfamily

Cobalamin-dependent methionine synthase (

) is a large modular protein that catalyses methyl transfer from methyltetrahydrofolate (CH3-H4folate) to homocysteine. During the catalytic cycle, it supports three distinct methyl transfer reactions, each involving the cobalamin (vitamin B12) cofactor and a substrate bound to its own functional unit . The cobalamin cofactor plays an essential role in this reaction, accepting the methyl group from CH3-H4folate to form methylcob(III)alamin, and in turn donating the methyl group to homocysteine to generate methionine and cob(I)alamin.

Methionine synthase is a large enzyme composed of four structurally and functionally distinct modules: the first two modules bind homocysteine and CH3-H4folate, the third module binds the cobalamin cofactor and the C-terminal module binds S-adenosylmethionine. The cobalamin-binding module is composed of two structurally distinct domains: a 4-helical bundle cap domain (residues 651-740 in the Escherichia coli enzyme) and an α/β B12-binding domain (residues 741-896) (

). The 4-helical bundle forms a cap over the α/β domain, which acts to shield the methyl ligand of cobalamin from solvent . Furthermore, in the conversion to the active conformation of this enzyme, the 4-helical cap rotates to allow the cobalamin cofactor to bind the activation domain (

). The α/β domain is a common cobalamin-binding motif, whereas the 4-helical bundle domain with its methyl cap is a distinctive feature of methionine synthases.

This entry represents the 4-helical bundle cap domain. This domain is also present in other shorter proteins that bind to B12, and is always found N terminus to the α/β B12-binding domain.
Alpha-macroglobulin, receptor-binding domain superfamily (A-macroglobulin_rcpt-bd_sf)
Type: Homologous_superfamily

This superfamily represents the receptor-binding domain (RBD) of alpha-2-macroglobulin proteins. The RBD is located at the C terminus, its structure having an immunoglobulin-like fold consists of a sandwich of nine strands in two sheets with a Greek-key topology .

The alpha-macroglobulin (aM) family of proteins includes protease inhibitors , typified by the human tetrameric a2-macroglobulin (a2M); they belong to the MEROPS proteinase inhibitor family I39, clan IL. These protease inhibitors share several defining properties, which include (i) the ability to inhibit proteases from all catalytic classes, (ii) the presence of a 'bait region' and a thiol ester, (iii) a similar protease inhibitory mechanism and (iv) the inactivation of the inhibitory capacity by reaction of the thiol ester with small primary amines. aM protease inhibitors inhibit by steric hindrance . The mechanism involves protease cleavage of the bait region, a segment of the aM that is particularly susceptible to proteolytic cleavage, which initiates a conformational change such that the aM collapses about the protease. In the resulting aM-protease complex, the active site of the protease is sterically shielded, thus substantially decreasing access to protein substrates. Two additional events occur as a consequence of bait region cleavage, namely (i) the h-cysteinyl-g-glutamyl thiol ester becomes highly reactive and (ii) a major conformational change exposes a conserved COOH-terminal receptor binding domain (RBD). RBD exposure allows the aM protease complex to bind to clearance receptors and be removed from circulation . Tetrameric, dimeric, and, more recently, monomeric aM protease inhibitors have been identified .
Bacterial aa3 type cytochrome c oxidase subunit IV superfamily (Cyt-C_aa3_sf)
Type: Homologous_superfamily

Bacterial cytochrome c oxidase is found bound to the to the cell membrane, where it is involved in the generation of the transmembrane proton electrochemical gradient. It is composed of four subunits. Subunit IV consists of one transmembrane helix that does not interact directly with the other subunits, but maintains its position by indirect contacts via phospholipid molecules found in the structure. The function of subunit IV is as yet unknown .