SII-SWORD/CoKE huggingface dataset:
Tumour necrosis factor-like domain superfamily (Tumour_necrosis_fac-like_dom)
Type: Homologous_superfamily

The tumour necrosis factor (TNF)-like domains are found in both TNF and C1q protein families. Structurally these domains self-associate to make a compact bell-shaped homotrimer, each monomer being composed of an anti-parallel β-sheet sandwich with a jellyroll topology. Both TNF and C1q family members can be expressed as soluble plasma proteins or as type II membrane-bound proteins.

TNF family members bind extracellularly to cysteine-rich receptors, thereby inducing a clustering of the receptors, which subsequently triggers the intracellular apoptotic cascade. The TNF proteins are important mediators in inflammation, immune responses and cytotoxicity through their interaction with the TNF-R55 and the TNF-R75 cell-surface receptors . Other TNF family members include the CD40 ligand (C-terminal TNF-like domain) which is involved in the immune response via the CD40 receptor ; TRAIL, which selectively induces apoptosis in tumour cells via DR4 and DR5 receptors ; the RANK ligand (TNFSF11), which triggers osteoclastogenesis via the RANK receptor ; and TALL-1 (soluble domain), which is involved in the immune response via the TACI, BCMA, and BAFF-R receptors .

C1q proteins also contain TNF-like domains. C1q family members include the Adiponectin/ACRP30 (C-terminal TNF-like domain), which regulates metabolism and energy homeostasis , and NC1 (non-collagenous domain 1), the C-terminal TNF-like domain of collagen X, which is crucial for collagen X assembly in bone tissue .
SMAD/FHA domain superfamily (SMAD_FHA_dom_sf)
Type: Homologous_superfamily

FHA and SMAD (MH2) domains share a common structure consisting of a sandwich of eleven β-strands in two sheets with Greek key topology. Forkhead-associated (FHA) domains were originally identified as a sequence profile of about 75 amino acids, whereas the full-length domain is closer to about 150 amino acids. FHA domains are found in transcription factors, kinesin motors, and in a variety of other signalling molecules in organisms ranging from eubacteria to humans. FHA domains are protein-protein interaction domains that are specific for phosphoproteins. FHA-containing proteins function in maintaining cell-cycle checkpoints, DNA repair and transcriptional regulation. FHA domain proteins include the Chk2/Rad53/Cds1 family of proteins that contain one or more FHA domains, as well as a Ser/Thr kinase domain .

SMAD (Mothers against decapentaplegic (MAD) homologue) domain proteins are found in a range of species from nematodes to humans. These highly conserved proteins contain an N-terminal MH1 domain that contacts DNA, and is separated by a short linker region from the C-terminal MH2 domain, the later showing a striking similarity to FHA domains. SMAD proteins mediate signalling by the TGF-beta/activin/BMP-2/4 cytokines from receptor Ser/Thr protein kinases at the cell surface to the nucleus. SMAD proteins fall into three functional classes: the receptor-regulated SMADs (R-SMADs), including SMAD1, -2, -3, -5, and -8, each of which is involved in a ligand-specific signalling pathway ; the comediator SMADs (co-SMADs), including SMAD4, which interact with R-SMADs to participate in signalling ; and the inhibitory SMADs (I-SMADs), including SMAD6 and -7, which block the activation of R-SMADs and Co-SMADs, thereby negatively regulating signalling pathways .

Domains with this fold are also found as the transactivation domain of interferon regulatory factor 3 (IRF3), which has a weak homology to SMAD domains , and the N-terminal domain of EssC protein in Staphylococcus aureus.
EV matrix protein (EV_matrix)
Type: Family

Ebola virus sp. are non-segmented, negative-strand RNA viruses that causes severe haemorrhagic fever in humans with high rates of mortality. The virus matrix protein VP40 is a major structural protein that plays a central role in virus assembly and budding at the plasma membrane of infected cells. VP40 proteins associate with cellular membranes, interact with the cytoplasmic tails of glycoproteins, and bind to the ribonucleoprotein complex. The VP40 monomer consists of two domains, the N-terminal oligomerization domain and the C-terminal membrane-binding domain, connected by a flexible linker. Both the N-and C-terminal domains fold into β sandwich structures of similar topology . Within the N-terminal domain are two overlapping L-domains with the sequences PTAP and PPEY at residues 7 to13, which are required for efficient budding . L-domains are thought to mediate their function in budding through their interaction with specific host cellular proteins, such as tsg101 and vps-4 .
Baseplate structural protein Gp9/Gp10, N-terminal domain (Baseplate_struct_prot_Gp9/10_N)
Type: Domain

This entry represents the N-terminal domain of Gp10 and Gp9 which includes an N-terminal helix and a seven-stranded β-sandwich with unique topology.

The members of this family 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 .
Transcriptional repressor, C-terminal (Transcriptional_repressor_C)
Type: Homologous_superfamily

The C-terminal domain of several bacterial transcriptional repressors show structural homology to one another. These domains are characterised by an SH3-like structure consisting of a partly opened β-barrel, where the last strand is interrupted by a 3-10 helical turn. The C-terminal domain displays a metal-binding function in DTXR and IDER and may act to stabilising the dimeric form of the Escherichia coli KorB repressor, thereby enhancing specific operator binding by the repressor. The N-terminal region of these proteins is responsible for binding DNA.
Myosin S1 fragment, N-terminal (Myosin_S1_N)
Type: Homologous_superfamily

Myosin is a molecular motor that undergoes ATP-driven conformational changes during force production and motility. The S1 fragment myosin head consists of both the globular motor domain, containing the ATP-and actin-binding sites, and the lever arm, which amplifies small conformational changes in the motor domain into larger motions by which myosin moves actin. The motor domain contains four major subdomains linked by three single-stranded joints: the N-terminal subdomain, the upper 50kDa subdomain, the lower 50kDa subdomain, and the C-terminal converter subdomain . The N-terminal subdomain has an SH3-like partly opened β barrel topology, with the last strand being interrupted by a 3-10 helical turn. The N-terminal and upper 50kDa subdomains together form the nucleotide-binding pocket. The binding of specific nucleotides alters the structural state of the myosin head during the contractile cycle.
Electron transport accessory-like domain superfamily (Elect_transpt_acc-like_dom_sf)
Type: Homologous_superfamily

The electron transport accessory proteins adopt the β topology of an SH3 domain, with a partly opened β barrel and a 3-10 helical turn interrupting the last strand. Other proteins displaying this topology include R67 dihydrofolate reductase, which catalyses the hydration of nitriles to amides , photosystem I accessory proteins (PsaE), which participate in cyclic electron transport and modulate the interaction of photosystem I with ferrodoxin , the alpha chain of ferrodoxin thioredoxin reductase (FTR), which is involved in the regulation of the activity of chloroplast enzymes , and the beta chain of nitrile hydratase, which confers trimethoprim-resistance to R67-expressing bacteria .
Translation protein SH3-like domain superfamily (Translation_prot_SH3-like_sf)
Type: Homologous_superfamily

This entry represents domains with SH3-like topology that are found in various proteins associated with translation machinery.

The fundamental activity of the ribosome is two-fold: to decode the message of the mRNA in the small subunit, and to form a peptide bond between peptidyl-tRNA and aminoacyl-tRNA by a peptidyl transferase activity in the large subunit. Several prokaryotic and eukaryotic proteins that are involved in the translation process contain an SH3-like domain. The structure of the translation protein SH3-like domain is a partly opened β barrel, where the last strand is interrupted by a 3-10 helical turn. The structure of the RNA-binding C-terminal domain of the Bacillus stearothermophilus (Geobacillus stearothermophilus) ribosomal protein L2 has been shown to adopt the SH3-like barrel topology . The L2 protein is located near the peptidyl transferase centre in the large ribosomal subunit where it may contribute to peptidyl transferase activity, and is involved in the assembly of the 23SrRNA. Likewise, the N-terminal domain of the ubiquitous eukaryotic translation elongation factor 5a (IF5A) protein adopts the SH3-like barrel topology . IF5A, previously thought to be an initiation factor, is now considered to be involved in translation elongation and in cell-cycle regulation. IF5A acts as a cofactor of the Rev protein in HIV-1-infected cells and of the Rex protein in T-cell leukaemia virus 1-infected cells.
Enterotoxin (Enterotoxin)
Type: Homologous_superfamily

Cholera toxin produced by Vibrio cholerae and heat-labile enterotoxin, produced by enterotoxigenic Escherichia coli, are AB5 heterohexamers, consisting of one A polypeptide and five identical B polypeptides, with an ADP-ribosylating A subunit and a GM1 receptor binding B pentamer. These toxins are among the most potent mucosal adjuvants known. The B pentamer is required for binding to the cell surface receptor ganglioside GM1. The A subunit can be proteolytically cleaved within the single disulphide-linked loop between two cysteine residues to produce the enzymatically active A1 polypeptide and the smaller A2 polypeptide that links fragment A1 to the B pentamer. Upon entry into enterocytes by endocytosis and following reduction and translocation, CT-A1 ADP-ribosylates a regulatory G-protein (Gsalpha), which leads to constitutive activation of adenylate cyclase, increased intracellular concentration of cyclic AMP, and secretion of fluid and electrolytes into the lumen of the small intestine .
Tissue inhibitor of metalloproteinases-like, OB-fold (TIMP-like_OB-fold)
Type: Homologous_superfamily

Tissue inhibitors of metalloproteinases (TIMP) are a family of proteins that can form complexes with extracellular matrix metalloproteinases (such as collagenases) and irreversibly inactivate them . TIMP and related proteins contains a five-stranded antiparallel β-sheet that is rolled over on itself to form a closed β-barrel, and two short helices, which pack close to one another on the same barrel face. A comparison of the delta TIMP-2 structure with other known protein folds reveals that the β-barrel topology is homologous to that seen in proteins of the oligosaccharide/oligonucleotide binding (OB) fold family, a five-stranded β-sheet coiled to form a closed β-barrel capped by an α-helix located between the third and fourth strands .

Other proteins contain domains with a similar OB-like fold:

Netrin-like domain (NTR/C345C module), found in procollagen c-proteinase enhancer protein PCOLCE, and in the complement C5 domain.

Laminin-binding domain, found in agrin.
Molybdate/tungstate binding, C-terminal (Mo/tungstate-bd_C_term_dom)
Type: Homologous_superfamily

Transport of molybdenum into bacteria involves a high-affinity ABC transporter system whose expression is controlled by a repressor protein called ModE. While molybdate transport is tightly coupled to utilization in some bacteria, other organisms have molybdenum storage proteins. One class of putative molybdate storage proteins is characterised by a sequence consisting of about 70 amino acids (Mop). A tandem repeat of Mop sequences also constitutes the molybdate binding domain of ModE.

The 7kDa Mop protein from the methanol-utilizing anaerobe Sporomusa ovata occurs as highly symmetric hexamers binding eight oxyanions. Each peptide assumes an OB fold, which has previously also been observed in ModE. Each hexameric Mop molecule contains eight metal binding sites of two different types; all of them are only formed upon oligomer assembly, i.e., each binding site is located on the interface between two or three dimers .
Cytokine IL1/FGF (IL1/FGF)
Type: Homologous_superfamily

This entry includes IL-1 and FGF.

The interleukin-1 (IL-1) and fibroblast growth factor (FGF, also known as heparin-binding growth factor) families share low sequence similarity (about 25% ) but have very similar structures. They belong to a superfamily that also contains the Kunitz-type soybean trypsin inhibitors (STIs), all of which have very similar structures. However, IL-1 and FGF share no sequence similarity with the STI family.

The crystal structures of interleukin-1 beta and HGF1 have been solved, showing both families to have the same 12-stranded β-sheet structure ; the β-sheets are arranged in 3 similar lobes around a central axis, 6 strands forming an anti-parallel β-barrel . The β-sheets are generally well preserved and the crystal structures superimpose in these areas. The intervening loops are less well conserved - the loop between β-strands 6 and 7 is slightly longer in interleukin-1 beta.
Agglutinin domain (Agglutinin)
Type: Domain

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 .
Actin-crosslinking (Actin-crosslinking)
Type: Homologous_superfamily

This superfamily represents an actin-crosslinking domain with a β-trefoil structure, consisting of a triplet of β-hairpins packed against a six-stranded antiparallel β-barrel. Proteins containing this domain include fascin, which carries a tandem repeat of four copies of this domain, and the histidine-rich actin-binding protein hisactophilin. Actin-crosslinking proteins organise actin filaments into dynamic and complex subcellular scaffolds that orchestrate important mechanical functions, including cell motility and adhesion .

The fascins are a structurally unique and evolutionarily conserved group of actin cross-linking proteins. Fascins function in the organisation of two major forms of actin-based structures: dynamic, cortical cell protrusions and cytoplasmic microfilament bundles .

A related protein, hisactophilin, is an essential protein for the osmoprotection of dictyostelium cells .
Translation protein, beta-barrel domain superfamily (Transl_B-barrel_sf)
Type: Homologous_superfamily

A β-barrel of circularly permuted topology is found in many transcription proteins, including initiation and elongation factors, and also some ribosomal proteins, although in these cases the fold is elaborated with additional structures. The β-barrel domain is represented by domain 2 of the elongation factors EF-Tu and eEF1A , both of which function to recognise and transport aminoacyl-tRNA to the acceptor (A) site of the ribosome during the elongation process, and of EF-G , which functions in translocating the peptidyl tRNA from the A site to the peptidyl (P) site. This domain is also present in initiation factors, in domain 2 of eIF2 gamma subunit , and domains 2 and 4 of IF2/eIF5B , both of which function to transport the initiator methionyl-tRNA to the ribosome. This β-barrel domain may be involved in interactions with the switch 2 region to stabilise the relative orientations of the domains, which undergo functionally important conformational changes between GTP-and GDP-bound states.
Translation elongation factor EF1A/initiation factor IF2gamma, C-terminal (Transl_elong_EF1A/Init_IF2_C)
Type: Homologous_superfamily

A β barrel of circularly permuted topology is found in the C terminus of many translation elongation and initiation factors. This domain is found in the elongation factors EF1A (or EF-Tu) of both eukaryotes and prokaryotes, which functions to recognise and transport aminoacyl-tRNA to the acceptor (A) site of the ribosome during the elongation process . This domain is also found in the initiation factor IF2 gamma subunit of eukaryotes , which functions to transport the initiator methionyl-tRNA to the ribosome. The C-terminal extension of mitochondrial EF1A (or EF-Tu) has structural similarities with DNA recognising zinc fingers, suggesting that the extension may be involved in recognition of RNA.
Transposase, Mu, C-terminal (Transposase_Mu_C)
Type: Homologous_superfamily

Transposons are abundant in nature and they play critical roles in pathogenesis, the spread of antibiotic resistance, and genome evolution. Transposition involves cleavage at the 3' ends of the transposon followed by the rejoining of the 3' OH termini to a target DNA. These steps are catalyzed by transposon-encoded transposases, and they occur in the context of higher order protein-DNA complexes called transpososomes. Mu transpososomes are named according to the chemical steps the Mu ends have undergone. The stable synaptic complex (SSC, or type 0 complex) is the first transpososome detected. Single-strand cleavage at the 3' ends of the Mu sequence then generates the cleaved donor complex (CDC, or type 1 complex). The strand transfer complex (STC, or type II complex) is formed by covalent joining of the Mu 3' ends to the strands of target DNA.

The C-terminal end of the MuA protein interacts with the MuB protein that is involved in target DNA site selection and transpososome activation .
Alanine racemase/group IV decarboxylase, C-terminal (Ala_racemase/Decarboxylase_C)
Type: Homologous_superfamily

This superfamily represents a β-barrel domain found at the C-terminal of alanine racemase (

) and in group IV pyridoxal-5'-phosphate (PLP)-dependent decarboxylases, such as eukaryotic ornithine decarboxylase (

), arginine decarboxylase (

) and diaminopimelate decarboxylase (

). These enzymes belong to the same structural family .

Alanine racemase plays a role in providing the D-alanine required for cell wall biosynthesis by isomerising L-alanine to D-alanine. Proteins containing this domain are found in both prokaryotic and eukaryotic proteins . The molecular structure of alanine racemase from Bacillus stearothermophilus (Geobacillus stearothermophilus) was determined by X-ray crystallography to a resolution of 1.9 A . The alanine racemase monomer is composed of two domains, an eight-stranded α/β barrel at the N terminus, and a C-terminal domain essentially composed of β-strand. The pyridoxal 5'-phosphate (PLP) cofactor lies in and above the mouth of the α/β barrel and is covalently linked via an aldimine linkage to a lysine residue, which is at the C terminus of the first β-strand of the α/β barrel.

Eukaryotic ornithine decarboxylase (ODC) acts as a homodimer to produce putrescine (1,4-diaminobutane) from ornithine, where putrescine is the precursor of other polyamines in animals, plants, and bacteria. Arginine decarboxylase is also involved in putrescine biosynthesis. This is the first committed step in polyamine biosynthesis. Alanine racemase is a structurally homologous enzyme. Both proteins share a common α/β barrel that binds the cofactor via a Schiff base on the C-terminal end of the barrel .

Diaminopimelate decarboxylase (DapDC) catalyses the final step of lysine biosynthesis in bacteria.
Valyl/Leucyl/Isoleucyl-tRNA synthetase, editing domain (Val/Leu/Ile-tRNA-synth_edit)
Type: Homologous_superfamily

Certain aminoacyl-tRNA synthetases prevent potential errors in protein synthesis through deacylation of mischarged tRNAs. The close homologues isoleucyl-tRNA synthetase (IleRS) and valyl-tRNA synthetase (ValRS) deacylate Val-tRNAIle and Thr-tRNAVal, respectively. These reactions strictly require the presence of the cognate tRNA. In the absence of tRNA, the enzymatically generated misactivated adenylates remain in the active site, sequestered from hydrolysis. Upon addition of cognate tRNA the misactivated amino acids are hydrolysed, regenerating the free tRNA and amino acid, while converting 1 equivalent of ATP to AMP. A prominent mechanism for editing misactivated amino acids is the rapid hydrolysis of transiently mischarged tRNA. This reaction is catalysed at a second active site on IleRS and ValRS. This site is located within a large insertion (termed CP1) into the canonical class I aminoacyl-tRNA synthetase active-site fold . The CP1 domain as an isolated polypeptide hydrolyses its cognate mischarged tRNA .
RlpA-like protein, double-psi beta-barrel domain (RlpA-like_DPBB)
Type: Domain

Rare lipoprotein A (RlpA) contains a conserved region that has the double-psi β-barrel (DPBB) fold . RlpA is a bacterial septal ring protein and a lytic transglycosylase that contributes to rod shape and daughter cell separation in Pseudomonas aeruginosa . It has been shown to act as a prc mutant suppressor in Escherichia coli . The DPBB fold is often an enzymatic domain. Proteins containing this domain are quite diverse and may have several different functions. Another example of this domain is found in the N terminus of pollen allergen . Some studies show that the full-length RlpA protein from Pseudomonas Aeruginosa is an outer membrane protein that is a lytic transglycolase with specificity for peptidoglycan lacking stem peptides. Residue D157 in Pseudomonas aeruginosa RlpA is critical for lytic activity .

β-barrels are commonly observed in protein structures. They are classified in terms of two integral parameters: the number of strands in the sheet, n, and the shear number, S, a measure of the stagger of the strands in the β-sheet. These two parameters have been shown to determine the major geometrical features of β-barrels. Six-stranded β-barrels with a pseudo-two-fold axis are found in several proteins. One involving parallel strands forming two psi structures is known as the double-psi barrel. The first psi structure consists of the loop connecting strands β1 and β2 (a 'ψ loop') and the strand β5, whereas the second psi structure consists of the loop connecting strands β4 and β5 and the strand β2. All the psi structures in double-psi barrels have a unique handedness, in that β1 (β4), β2 (β5) and the loop following β5 (β2) form a right-handed helix. The unique handedness may be related to the fact that the twisting angle between the parallel pair of strands is always larger than that between the antiparallel pair .