SII-SWORD/CoKE huggingface dataset:
Large ribosomal subunit protein bL12, oligomerization domain superfamily (Ribosomal_bL12_oligo_N_sf)
Type: Homologous_superfamily

Large ribosomal subunit protein bL12 consists of two domains that are connected by a flexible region. The N-terminal domain is required for dimer formation and for anchoring the protein to the ribosome by binding to ribosomal protein L10, while the C-terminal domain is required for translation factors binding .

This entry represents the oligomerization domain superfamily of the large ribosomal subunit protein bL12. It has a multihelical structure with an intertwined tetramer topology.

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 .
Zinc finger C2H2 superfamily (Znf_C2H2_sf)
Type: Homologous_superfamily

C2H2-type (classical) zinc fingers (Znf) were the first class to be characterised. They contain a short β-hairpin and an α-helix (β/β/α structure), where a single zinc atom is held in place by Cys(2)His(2) (C2H2) residues in a tetrahedral array. C2H2 Znf's can be divided into three groups based on the number and pattern of fingers: triple-C2H2 (binds single ligand), multiple-adjacent-C2H2 (binds multiple ligands), and separated paired-C2H2 . C2H2 Znf's are the most common DNA-binding motifs found in eukaryotic transcription factors, and have also been identified in prokaryotes . Transcription factors usually contain several Znf's (each with a conserved β/β/α structure) capable of making multiple contacts along the DNA, where the C2H2 Znf motifs recognise DNA sequences by binding to the major groove of DNA via a short α-helix in the Znf, the Znf spanning 3-4 bases of the DNA . C2H2 zinc fingers can also bind to RNA and protein targets .

Zinc finger (Znf) domains are relatively small protein motifs which contain multiple finger-like protrusions that make tandem contacts with their target molecule. Some of these domains bind zinc, but many do not; instead binding other metals such as iron, or no metal at all. For example, some family members form salt bridges to stabilise the finger-like folds. They were first identified as a DNA-binding motif in transcription factor TFIIIA from Xenopus laevis (African clawed frog), however they are now recognised to bind DNA, RNA, protein and/or lipid substrates . Their binding properties depend on the amino acid sequence of the finger domains and of the linker between fingers, as well as on the higher-order structures and the number of fingers. Znf domains are often found in clusters, where fingers can have different binding specificities. There are many superfamilies of Znf motifs, varying in both sequence and structure. They display considerable versatility in binding modes, even between members of the same class (e.g. some bind DNA, others protein), suggesting that Znf motifs are stable scaffolds that have evolved specialised functions. For example, Znf-containing proteins function in gene transcription, translation, mRNA trafficking, cytoskeleton organisation, epithelial development, cell adhesion, protein folding, chromatin remodelling and zinc sensing, to name but a few . Zinc-binding motifs are stable structures, and they rarely undergo conformational changes upon binding their target.
Xylose isomerase-like superfamily (Xyl_isomerase-like_sf)
Type: Homologous_superfamily

Proteins in this superfamily contain a structural motif with a β/α TIM barrel, such as xylose isomerase . These proteins share similar, but not identical, metal-binding sites. In addition, xylose isomerase and L-rhamnose isomerase each have additional α-helical domains involved in tetramer formation.
Transglutaminase, C-terminal domain superfamily (Transglutaminase_C_sf)
Type: Homologous_superfamily

Transglutaminases catalyse the post-translational modification of proteins at glutamine residues, with formation of isopeptide bonds. Members of the transglutaminase family usually have three domains: N-terminal (

), middle (

) and C-terminal. The middle domain is usually well conserved, but family members can display major differences in their N- and C-terminal domains, although their overall structure is conserved . This entry represents the C-terminal domain found in transglutaminases, which consists of an immunoglobulin-like β-sandwich consisting of seven strands in two sheets with a Greek key topology.

The best known transglutaminase is blood coagulation factor XIII, a plasma tetrameric protein composed of two catalytic A subunits and two non-catalytic B subunits. Factor XIII is responsible for cross-linking fibrin chains, thus stabilising the fibrin clot. Protein-glutamine gamma-glutamyltransferases (

) are calcium-dependent enzymes that catalyse the cross-linking of proteins by promoting the formation of isopeptide bonds between the γ-carboxyl group of a glutamine in one polypeptide chain and the ε-amino group of a lysine in a second polypeptide chain. TGases also catalyse the conjugation of polyamines to proteins .

Proteins containing this domain also include Protein 4.2 (also known as Epb42), which is one of the most abundant protein components of the erythrocyte membrane. The protein shares significant sequence homology with transglutaminases, but lacks the catalytic triad residues required for transglutaminase activity . The complete or nearly complete absence of protein 4.2 is associated with an atypical form of hereditary spherocytosis (HS) .
Prenyltransferase-like superfamily (PrenylTrfase-like_sf)
Type: Homologous_superfamily

This superfamily is characterised by a barrel fold consisting of a cylindrical β-sheet comprising anti-parallel β-strands arranged around a central solvent-filled core . This fold can be found in:

Aromatic prenyltransferases NovQ from Streptomyces niveus and CloQ from Streptomyces roseochromogenes. They catalyse the transfer of a dimethylallyl group to 4-hydroxyphenylpyruvate to produce the ring A structure in the novobiocin and clorobiocin biosynthesis pathways, respectively .

Flaviolin linalyltransferase from Streptomyces cinnamonensis. It is involved in the biosynthesis of furanonaphthoquinone I (FNQ I). It catalyses C- and O-prenylations of different phenolic substrates .

5,10-dihydrophenazine-1-carboxylate 9-dimethylallyltransferase from Streptomyces anulatus. It is involved in the biosynthesis of prenylated phenazines. It catalyses the transfer of a dimethylallyl moiety to C-9 of 5,10-dihydrophenazine 1-carboxylate (dihydro-PCA). It is specific for both dimethylallyl diphosphate and dihydro-PCA .
Gp9-like superfamily (Gp9-like_sf)
Type: Homologous_superfamily

Members of this entry are similar to gene products 9 (gp9) and 10 (gp10) of bacteriophage T4. Both proteins are components of the viral baseplate . Gp9 connects the long tail fibres of the virus to the baseplate and triggers tail contraction after viral attachment to a host cell. The protein is active as a trimer, with each monomer being composed of three domains. The N-terminal domain consists of an extended polypeptide chain and two α helices. The alpha1 helix from each of the three monomers in the trimer interacts with its counterparts to form a coiled-coil structure. The middle domain is a seven-stranded β-sandwich that is thought to be a novel protein fold. The C-terminal domain is thought to be essential for gp9 trimerisation and is organised into an eight- stranded antiparallel β-barrel, which was found to resemble the 'jelly roll' fold found in many viral capsid proteins. The long flexible region between the N-terminal and middle domains may be required for the function of gp9 to transmit signals from the long tail fibres . Together with gp11, gp10 initiates the assembly of wedges that then go on to associate with a hub to form the viral baseplate .
NSFL1 cofactor p47, SEP domain superfamily (NSFL1C_SEP_dom_sf)
Type: Homologous_superfamily

The SEP (after shp1, eyc and p47) domain is an eukaryotic domain, which occurs frequently and mainly in single units. Almost all proteins containing a SEP domain are succeeded closely by a UBX domain (see

). The function of the SEP domain is as yet unknown but it has been proposed to act as a reversible competitive inhibitor of the lysosomal cysteine protease cathepsin L .

The sructure of the SEP domain comprises a β-sheet composed of four strands, and two α-helices. One side of the β-sheet faces alpha1 and alpha2. The longer helix alpha1 packs against the four-stranded β-sheet, where as the shorter helix alpha2 is located at one edge of the globular structure formed by alpha1 and the four stranded β sheet. A number of highly conserved hydrophobic residues are present in the SEP domain, which are predominantly buried and form the hydrophobic core .

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

Eukaryotic NSFL1 cofactor p37 (or p97 cofactor p37), an adapter protein required for Golgi and endoplasmic reticulum biogenesis. It is involved in Golgi and endoplasmic reticulum maintenance during interphase and in their reassembly at the end of mitosis.

Eukaryotic NSFL1 cofactor p47 (or p97 cofactor p47), a major adaptor molecule of the cytosolic AAA-type ATPase (ATPases associated with various cellular activities) p97. p47 is required for the p97-regulated membrane reassembly of the endoplasmic reticulum (ER), the nuclear envelope and the Golgi apparatus.

Vertebrate UBX domain-containing protein 4 (UBXD4).

Plant UBA and UBX domain-containing protein.

Saccharomyces cerevisiae (Baker's yeast) UBX domain-containing protein 1 or Suppressor of high-copy PP1 protein (shp1), the homologue of p47.

Drosophila melanogaster (Fruit fly) eyes closed (eyc).
Agglutinin domain superfamily (Agglutinin_dom_sf)
Type: Homologous_superfamily

Agglutinins are sugar-specific lectins that can agglutinate erythrocytes and other cell types. Lectins occur widely in plants, as well as some microorganisms and animal . Agglutinin from Amaranthus caudatus (amaranthin) is a lectin from the ancient South American crop, amaranth grain. Although its biological function is unknown, it can agglutinate A, B and O red blood cells, and has a carbohydrate-binding site that is specific for the methyl-glycoside of the T-antigen found linked to serine or threonine residues of cell surface glycoproteins . The protein is comprised of a homodimer, with each homodimer consisting of two β-trefoil domains . Lectin B chains from ricin and related toxins also contain β-trefoil domain, however they are not related to agglutinin, showing little sequence similarity .
Photosystem I PsaX superfamily (PSI_PsaX_sf)
Type: Homologous_superfamily

This superfamily consists of photosystem I (PSI) protein subunit PsaX. PSI is a large multi-subunit pigment protein complex embedded in the thylakoid membranes of green plants and cyanobacteria. PsaX is one of the 12 protein subunits found in PSI and these subunits are arranged as monomers or trimers within the membrane as shown by the structure of the trimeric complex from Synechococcus elongatus .
TipA-like multidrug resistance regulator, antibiotic-recognition domain (TipA-like_antibiotic-bd)
Type: Homologous_superfamily

TipAL is a bacterial transcriptional regulator of the MerR family. The tipA gene can be expressed as a long form, TipAL, and a short form, TipAS, which constitutes the C-terminal part of TipAL. TipAS forms the antibiotic-recognition domain . This domain, which has an α-helical globin-like fold, is also found at the C terminus of other MerR family transcription factors, including Mta, a central regulator of multidrug resistance in Bacillus subtilis , and SkgA from Caulobacter crescentus .
Protozoan pheromone superfamily (Pheromone_protoz_sf)
Type: Homologous_superfamily

Protozoan pheromones are cell-type specific protein signals. This entry represents a superfamily of mating ciliate pheromones (or gamones) from the protozoan Euplotes raikovi, including Er-1, Er-2, Er-10, Er11 and Er22. These pheromones are diffusible extracellular communication signals that distinguish different intra-specific classes of cells commonly referred to as 'mating types'. Pheromones prepare these cells for conjugation by changing their cell surface properties. The mitogenic activity induced by Er pheromone autocrine signalling can be inhibited by cAMP . The NMR structure of several pheromones have been determined, revealing a closed up-and-down bundle of three helices with a left-handed twist . In some cases, different pheromones can compete with each other in binding to their cell-surface receptors.
Cytochrome c oxidase polypeptide 2A, ba3 type (Cyt_c_oxidase_su2a_ba3)
Type: Homologous_superfamily

The ba3-type cytochrome c oxidase from Thermus thermophilus is known as a two subunit enzyme. From its crystal structure, it was discovered that an additional transmembrane helix, subunit IIa, spans the membrane. This subunit consists of 34 residues forming one helix across the membrane. The presence of this subunit seems to be important for the function of cytochrome c oxidases .
Neurotoxin 3 superfamily (Neurotoxin_3_sf)
Type: Homologous_superfamily

This entry occurs within the Anemonia sulcata toxin III (ATX III) neurotoxin family. ATX III is a neurotoxin that is produced by sea anemone; it adopts a compact structure containing four reverse turns and two other chain reversals, but no regular α-helix or β-sheet. A hydrophobic patch found on the surface of the peptide may constitute part of the sodium channel binding surface .
Clostridium neurotoxin, translocation domain (Clostridium_toxin_transloc)
Type: Homologous_superfamily

The Clostridium neurotoxin family is composed of tetanus neurotoxin and seven serotypes of botulinum neurotoxin. The structure of the botulinum neurotoxin reveals a four domain protein: a N-terminal catalytic domain (

), a central translocation domain and two receptor binding domains . Subsequent to cell surface binding and receptor mediated endocytosis of the neurotoxin, an acid induced conformational change in the neurotoxin translocation domain is believed to allow the domain to penetrate the endosome and from a pore, thereby facilitating the passage of the catalytic domain across the membrane into the cytosol . The structure of the translocation reveals a pair of helices that are 105 Angstroms long and is structurally distinct from other pore forming toxins .
Thioredoxin-like superfamily (Thioredoxin-like_sf)
Type: Homologous_superfamily

This entry represents the Thioredoxin-like superfamily which brings together a diverse group of proteins that play crucial roles in various cellular processes, particularly in redox reactions . This superfamily is characterised by two key features:

A conserved Cys-X-X-Cys (CXXC) motif at the active site, located at the N-terminal of an α-helix.

A distinctive structural fold known as the "thioredoxin fold," consisting of a central four-stranded mixed β-sheet, surrounded by α-helices, with a strand order: 2134 in which strand 3 is antiparallel to the others.

In a redox reaction, the side chains of the two cysteines in this active site motif can switch from the free thiol (SH) form to a disulphide bond (S-S) and/or back and hence donate or accept electrons. The preference for electron donation or acceptance, along with the cellular redox context, determines the biological function of each protein.

Several biological processes regulate the activity of target proteins through changes in the redox state of thiol groups (S2 to SH2), where a hydrogen donor is linked to an intermediary disulphide protein. Such processes include the ferredoxin/thioredoxin system, the NADP/thioredoxin system, and the glutathione/glutaredoxin system . Several of these disulphide proteins share a common structure, consisting of a three-layer α/β/α core. Proteins that contain domains with a thioredoxin-like fold include:

Arsenate reductase (ArsC)

Calsequestrin (contains three tandem repeats of this fold)

Circadian oscillation regulator KaiB

Disulphide bond isomerase DsbC and DsbG (C-terminal domain)

Disulphide bond facilitator DsbA (contains an α-helical insertion)

Endoplasmic reticulum protein ERP29 (N-terminal domain)

Glutathione S-transferase (GST) (N-terminal domain)

Mitochondrial ribosomal protein L51/S25/CI-B8 domain (variable positions for Cys residues in active site)

Phosducin

Protein disulphide isomerase (PDI) (contains two tandem repeats of this fold)

Glutathione peroxidase-like enzymes

Selenoprotein W-related

SH3-binding glutamic acid-rich protein like (SH3BGR) (lacks both conserved Cys residues)

Spliceosomal protein U5-15Kd

Thioltransferases, including thioredoxin , glutaredoxin , hybrid peroxiredoxin hyPrx5

Thioredoxin-like 2Fe-2S ferredoxin
Acyl-CoA dehydrogenase-like, C-terminal (AcylCo_DH-like_C)
Type: Homologous_superfamily

Acyl-CoA dehydrogenases (

) are a family of flavoproteins that catalyse the alpha,beta-dehydrogenation of acyl-CoA thioesters to the corresponding trans 2,3-enoyl CoA-products with the concomitant reduction of enzyme-bound FAD. Different family members share a high sequence identity, catalytic mechanisms, and structural properties, but differ in the position of their catalytic bases and in their substrate binding specificity. Butyryl-CoA dehydrogenase prefers short chain substrates, medium chain-and long-chain acyl-CoA dehydrogenases prefer medium and long chain substrates, respectively, and Isovaleryl-CoA dehydrogenase prefers branched-chain substrates.

The monomeric enzyme is folded into three domains of approximately equal size, where the N-terminal domain is all-α, the middle domain is an open barrel, and the C-terminal domain is a four-helical bundle. This entry represents the C-terminal domain found in medium chain acyl-CoA dehydrogenases, as well as in the related peroxisomal acyl-CoA oxidase-II enzymes, where this domain occurs as a tandem duplication. Acyl-CoA oxidase (ACO;

) catalyses the first and rate-determining step of the peroxisomal beta-oxidation of fatty acids .
Arginine repressor, C-terminal domain superfamily (Arg_repress_C_sf)
Type: Homologous_superfamily

The arginine dihydrolase (AD) pathway is found in many prokaryotes and some primitive eukaryotes, an example of the latter being Giardia lamblia (Giardia intestinalis) . The three-enzyme anaerobic pathway breaks down L-arginine to form 1 mol of ATP, carbon dioxide and ammonia. In simpler bacteria, the first enzyme, arginine deiminase, can account for up to 10% of total cell protein .

Most prokaryotic arginine deiminase pathways are under the control of a repressor gene, termed ArgR . This is a negative regulator, and will only release the arginine deiminase operon for expression in the presence of arginine . The crystal structure of apo-ArgR from Bacillus stearothermophilus has been determined to 2.5A by means of X-ray crystallography . The protein exists as a hexamer of identical subunits, and is shown to have six DNA-binding domains, clustered around a central oligomeric core when bound to arginine. It predominantly interacts with A.T residues in ARG boxes. This hexameric protein binds DNA at its N terminus to repress arginine biosyntheis or activate arginine catabolism. Some species have several ArgR paralogs. In a neighbour-joining tree, some of these paralogous sequences show long branches and differ significantly from the well-conserved C-terminal region.

The C-terminal domain of the arginine repressor is responsible for arginine binding and multimerization . It can also bind ornithine, Pro and Tyr (Matilla et. al., FEMS Microbiology Reviews, fuab043, 45, 2021, 1. https://doi.org/10.1093/femsre/fuab043).
Proteasome activator superfamily (Proteasome_activ_sf)
Type: Homologous_superfamily

The 20S proteasome is a multicatalytic complex that is responsible for the non-lysosomal degradation of intracellular proteins. The proteasome is composed of a catalytic core that is regulated by protein complexes, which bind to the ends of the cylindrical core structure. One of these regulatory complexes is the PA28 activator complex (also known as the 11S regulator, or REG), a ring-shaped hexameric structure that enhances the peptidase activity of the core enzyme. Three REG subunits have been isolated, REGalpha, REGbeta and REGgamma. REGalpha and REGbeta preferentially form a heteromeric complex with alternating alpha and beta subunits. The structure of the human REGalpha subunit reveals a heptameric barrel-shaped assembly containing a central channel . The binding of REG is thought to create a pore through with substrates and products can pass.
Flavivirus glycoprotein, central and dimerisation domain superfamily (Glycoprot_cen/dimer_sf)
Type: Homologous_superfamily

Flaviviruses are small, enveloped RNA viruses that use arthropods such as mosquitoes for transmission to their vertebrate hosts, and include Yellow fever virus (YFV), West Nile virus (WNV), Tick-borne encephalitis virus, Japanese encephalitis virus (JE) and Dengue virus 2 viruses . Flaviviruses consist of three structural proteins: the core nucleocapsid protein C (IPR001122), and the envelope glycoproteins M (IPR000069) and E. Glycoprotein E is a class II viral fusion protein that mediates both receptor binding and fusion. Class II viral fusion proteins are found in flaviviruses and alphaviruses, and are structurally distinct from class I fusion proteins from influenza virus and HIV.

Glycoprotein E is comprised of three domains: domain I (dimerisation domain) is an 8-stranded β barrel, domain II (central domain) is an elongated domain composed of twelve β strands and two α helices, and domain III (immunoglobulin-like domain) is an IgC-like module with ten β strands. Domains I and II are intertwined . This superfamily represents the intertwined central and dimerisation domains.

The glycoprotein E dimers on the viral surface re-cluster irreversibly into fusion-competent trimers upon exposure to low pH, as found in the acidic environment of the endosome. The formation of trimers results in a conformational change in the hinge region of domain II, a key structural element that opens a ligand-binding hydrophobic pocket at the interface between domains I and II. The conformational change results in the exposure of a fusion peptide loop at the tip of domain II, which is required in the fusion step to drive the cellular and viral membranes together by inserting into the membrane .