SII-SWORD/CoKE huggingface dataset:
Amyloidogenic glycoprotein, copper-binding domain superfamily (Amyloid_Cu-bd_sf)
Type: Homologous_superfamily

This superfamily represents a copper-binding domain found within the extracellular domain, which is at the N-terminal of amyloidogenic glycoproteins such as amyloid-beta precursor protein (APP, or A4). The copper-binding domain has a dodecin-like fold consisting of a 2-layer α/β topology .

Amyloid-beta precursor protein (APP, or A4) is associated with Alzheimer's disease (AD), because one of its breakdown products, amyloid-beta (A-beta), aggregates to form amyloid or senile plaques . Mutations in APP or in proteins that process APP have been linked with early-onset, familial AD. Individuals with Down's syndrome carry an extra copy of chromosome 21, which contains the APP gene, and almost invariably develop amyloid plaques and Alzheimer's symptoms.

APP is important for the neurogenesis and neuronal regeneration, either through the intact protein, or through its many breakdown products . APP consists of a large N-terminal extracellular region containing heparin-binding and copper-binding sites, Kunitz domain, E2 domain, a short hydrophobic transmembrane domain, and a short C-terminal intracellular domain. The N-terminal region is similar in structure to cysteine-rich growth factors and appears to function as a cell surface receptor, contributing to neurite growth, neuronal adhesion, axonogenesis and cell mobility . APP acts as a kinesin I membrane receptor to mediate the axonal transport of beta-secretase and presenilin 1. The N-terminal domain can regulate neurite outgrowth through its binding to heparin and collagen I and IV, which are components of the extracellular matrix. APP is also coupled to apoptosis-inducing pathways, and is involved in copper homeostasis/oxidative stress through copper ion reduction, where copper-metallated APP induces neuronal death . The C-terminal intracellular domain appears to be involved in transcription regulation through protein-protein interactions. APP can promote transcription activation through binding to APBB1/Tip60, and may bind to the adaptor protein FE65 to transactivate a wide variety of different promoters.

APP can be processed by different sets of enzymes:

In the non-amyloidogenic (non-plaque-forming) pathway, APP is cleaved by alpha-secretase to yield a soluble N-terminal sAPP-alpha (neuroprotective) and a membrane-bound CTF-alpha. CTF-alpha is broken-down by presenilin-containing gamma-secretase to yield soluble p3 and membrane-bound AICD (nuclear signalling).

In the amyloidogenic pathway (plaque-forming), APP is broken down by beta-secretase to yield soluble sAPP-beta and membrane-bound CTF-beta. CTF-beta is broken down by gamma-secretase to yield soluble amyloid-beta and membrane-bound AICD. Amyloid-beta is required for neuronal function, but can aggregate to form amyloid plaques that seem to disrupt brain cells by clogging points of cell-cell contact.
SecA, preprotein cross-linking domain superfamily (SecA_X-link_sf)
Type: Homologous_superfamily

The SecA ATPase is involved in the insertion and retraction of preproteins through the plasma membrane. This domain superfamily has been found to cross-link to preproteins, thought to indicate a role in preprotein binding. The pre-protein cross-linking domain is comprised of two sub domains that are inserted within the ATPase domain .
DPH-type metal-binding domain superfamily (DPH_MB_sf)
Type: Homologous_superfamily

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.

This entry represents the DPH-type metal binding domain consists of a three-stranded β-sandwich with one sheet comprising two parallel strands: (i) β1 and (ii) β6 and one antiparallel strand: β5. The second sheet in the β-sandwich is comprised of strands β2, β3, and β4 running anti-parallel to each other. The two β-sheets are separated by a short stretch α-helix. It can be found in proteins such as DPH3 and DPH4. This domain is also found associated with N-terminal domain of heat shock protein DnaJ

domain .
TCL1/MTCP1 superfamily (TCL1_MTCP1_sf)
Type: Homologous_superfamily

Two related oncogenes, TCL-1

and MTCP-1

, are overexpressed in T cell prolymphocytic leukemias as a result of chromosomal rearrangements that involve the translocation of one T cell receptor gene to either chromosome 14q32 or Xq28 .

TCL-1 is an all-beta protein consisting of an eight-stranded antiparallel β barrel with a novel topology. The barrel consists of two four-stranded β-meander motifs, related by a two fold axis and connected by a long loop. The structure of MTCP-1 is very similar, diverging only in regions that are either flexible and/or involved in crystal packing .
Cyanovirin-N superfamily (Cyanovirin-N_sf)
Type: Homologous_superfamily

Cyanovirin-N (CV-N) is an 11kDa protein from the cyanobacterium Nostoc ellipsosporum that displays virucidal activity against several viruses, including human immunodeficiency virus (AIDS). The virucidal activity of CV-N is mediated through specific high-affinity interactions with the viral surface envelope glycoproteins gp120 and gp41, as well as to high-mannose oligosaccharides found on the HIV envelope . In addition, CV-N is active against rhinoviruses, human parainfluenza virus, respiratory syncytial virus, and enteric viruses. The virucidal activity of CV-N against influenza virus is directed towards viral haemagglutinin .

The CV-N domain is evolutionarily conserved and occurs as a protein module in eukaryotes . CV-N has a complex fold composed of a duplication of a tandem repeat of two homologous motifs comprising three-stranded β-sheet and β-hairpins .
p53-like tetramerisation domain superfamily (p53_tetramer_sf)
Type: Homologous_superfamily

This entry represents the tetramerisation domain of p53. The tetramerisation domain of human p53 extends from residues 325 to 356, and has a 4-helical bundle fold. The tetramerisation domain is essential for DNA binding, protein-protein interactions, post-translational modifications, and p53 degradation .

This superfamily also includes the structural-related C-terminal SARAH (Salvador-RassF-Hippo) domain found in tumor suppressors such as Serine/threonine-protein kinase 4 (human Hippo homologue, Mst), Serine/threonine-protein kinase 3, Serine/threonine-protein kinase cst-1 and Serine/threonine-protein kinase hippo, which is involved in dimerisation .
PurM-like, C-terminal domain superfamily (PurM-like_C_sf)
Type: Homologous_superfamily

This domain superfamily is found in carbamoyl dehydratase HypE, which is involved in the maturation of NifE hydrogenase; AIR synthase (PurM) and FGAM synthase (PurL), which are involved in de novo purine biosynthesis; and selenide, water dikinase, an enzyme which synthesizes selenophosphate from selenide and ATP.

In PurM this domain, which has an α-β-type fold, is found at the C terminus of the protein .
EutN/Ccml superfamily (EutN_CcmL_sf)
Type: Homologous_superfamily

The ethanolamine utilization protein EutN is involved in the cobalamin-dependent degradation of ethanolamine . The crystal structure of EutN contains a central five-stranded β-barrel, with an α-helix at the open end of this barrel (

). The structure also contains three additional β-strands, which help the formation of a tight hexamer, with a hole in the centre. This suggests that EutN forms a pore, with an opening of 26 Amstrong in diameter on one face and 14 Amstrong on the other face .

Beside the Escherichia coli ethanolamine utilization protein EutN and the Synechocystis sp. carboxysome (beta-type) structural protein CcmL, this family also includes alpha-type carboxysome structural proteins CsoS4A and CsoS4B (previously known as OrfA and OrfB), propanediol utilization protein PduN, and some hypothetical homologous of various bacterial microcompartments. The carboxysome, a polyhedral organelle, participates in carbon fixation by sequestering enzymes. It is the prototypical bacterial microcompartment. Its enzymatic components, ribulose bisphosphate carboxylase/oxygenase(RuBisCO) and carbonic anhydrase (CA), are surrounded by a polyhedral protein shell. Similarly, the ethanolamine utilization (eut) microcompartment, and the 1,2-propanediol utilization (pdu) microcompartment encapsulate the enzymes necessary for the process of cobalamin-dependent ethanolamine degradation, and coenzyme B12-dependent degradation of 1,2-propanediol, respectively, within its polyhedral protein shells. It is interesting that both carboxysome structural proteins CcmL and CsoS4A assemble as pentamers in the crystal structures, which might constitute the twelve pentameric vertices of a regular icosahedral carboxysome. However, the reported EutN structure is hexameric rather than pentameric. The absence of pentamers in Eut microcompartments might lead to less-regular icosahedral shell shapes. Due to the lack of structure evidence, the functional roles of the CsoS4A adjacent paralog, CsoS4B, and propanediol utilization protein PduN are not yet clear .

This entry represents a superfamily of related bacterial proteins with roles in ethanolamine and carbon dioxide metabolism. The structure of these domains has a close or partly open barrel fold and a greek-key topology.
MutS, connector domain superfamily (MutS_con_dom_sf)
Type: Homologous_superfamily

Mismatch repair contributes to the overall fidelity of DNA replication and is essential for combating the adverse effects of damage to the genome. It involves the correction of mismatched base pairs that have been missed by the proofreading element of the DNA polymerase complex. The post-replicative Mismatch Repair System (MMRS) of Escherichia coli involves MutS (Mutator S), MutL and MutH proteins, and acts to correct point mutations or small insertion/deletion loops produced during DNA replication . MutS and MutL are involved in preventing recombination between partially homologous DNA sequences. The assembly of MMRS is initiated by MutS, which recognises and binds to mispaired nucleotides and allows further action of MutL and MutH to eliminate a portion of newly synthesized DNA strand containing the mispaired base . MutS can also collaborate with methyltransferases in the repair of O(6)-methylguanine damage, which would otherwise pair with thymine during replication to create an O(6)mG:T mismatch . MutS exists as a dimer, where the two monomers have different conformations and form a heterodimer at the structural level . Only one monomer recognises the mismatch specifically and has ADP bound. Non-specific major groove DNA-binding domains from both monomers embrace the DNA in a clamp-like structure. Mismatch binding induces ATP uptake and a conformational change in the MutS protein, resulting in a clamp that translocates on DNA.

This superfamily represents the connector domain (domain 2) found in proteins of the MutS family. The structure of the MutS connector domain consists of a parallel β-sheet surrounded by four α helices, which is similar to the structure of the Holliday junction resolvase ruvC.
FlgN-like superfamily (FlgN-like_sf)
Type: Homologous_superfamily

Flagella synthesis protein FlgN is an export chaperone involved in flagellar synthesis . FlgN consists of a 4 long helices bundle, where the last helix is shorter than the three others. FlgN is required for the export of the hook-filament junction proteins, FlgK and FlgL. It is required for both swimming and swarming motility in B. subtilis .
Sporulation-like domain superfamily (SPOR-like_sf)
Type: Homologous_superfamily

This 70 residue domain, known as SPOR domain, is composed of two 35 residue repeats that are found in bacterial proteins involved in sporulation and cell division, such as FtsN, CwlM and RlpA. The SPOR domains in the FtsN cell division proteins from Escherichia coli and Caulobacter crescentus have been shown to bind peptidoglycan. SPOR domains can localise to the division site by binding preferentially to septal peptidoglycan .

FtsN is an essential cell division protein with a simple bitopic topology: a short N-terminal cytoplasmic segment fused to a large carboxy periplasmic domain through a single transmembrane domain. The repeats lie at the periplasmic C terminus, which has an RNP-like fold . FtsN localises to the septum ring complex. The CwlM protein is a cell wall hydrolase, where the C-terminal region, including the repeats, determines substrate specificity . RlpA is a rare lipoprotein A protein that may be important for cell division. Its N-terminal cysteine may be attached to thioglyceride and N-fatty acyl residues .
PgpA-like superfamily (PgpA-like_sf)
Type: Homologous_superfamily

This domain consists of a bundle of six α-helices where one central helix is surrounded by five others. It is found in uncharacterised proteins, including YutG from Bacillus subtilis (

), putative phosphatidylglycerophosphatases and bacterial phosphatidylglycerophosphatase PgpA .
Insect odorant-binding protein A10/Ejaculatory bulb-specific protein 3 superfamily (OS_D_A10/PebIII_sf)
Type: Homologous_superfamily

This entry represents the insect odorant-binding protein A10, also known as OS-D or pherokine-1, and ejaculatory bulb-specific protein 3 (PebIII), also known as pherokine-2 .
CO dehydrogenase flavoprotein, C-terminal domain superfamily (CO_DH_flav_C_dom_sf)
Type: Homologous_superfamily

Proteins containing this domain form structural complexes with other known families, such as

and

. The carbon monoxide (CO) dehydrogenase of Oligotropha carboxidovorans is a heterotrimeric complex composed of a apoflavoprotein, a molybdoprotein, and an iron-sulphur protein. It can be dissociated with sodium dodecylsulphate . CO dehydrogenase catalyses the oxidation of CO according to the following equation :
CO + H2O = CO2 + 2e + 2H+

Subunit S represents the iron-sulphur protein of CO dehydrogenase and is clearly divided into a C- and an N-terminal domain, each binding a [2Fe-2S] cluster .

The structure of the C-terminal domain has a β(3,4)-α(3) fold arranged in an α+β sandwich.
Calcium-mediated lectin superfamily (Ca_lectin_sf)
Type: Homologous_superfamily

This entry represents calcium-mediated lectins. Structures have been determined for both fucose-binding lectin II (PA-IIL) and mannose-specific lectin II (RS-IIL) . These proteins have homologous structures, their monomers consisting of a 9-stranded β sandwich with Greek-key topology. Each monomer contains two calcium ions that mediate an exceptionally high binding affinity to the monosaccharide ligand in a recognition mode unique among carbohydrate-protein interactions. In Pseudomonas aeruginosa, PA-IIL contributes to the pathogenic virulence of the bacterium, functioning as a tetramer when binding fucose . In the plant pathogen Ralstonia solanacearum (Pseudomonas solanacearum), RS-IIL recognises fucose, but displays much higher affinity to mannose and fructose, which is opposite to the preference of PA-IIL.
YehU-like superfamily (YehU-like_sf)
Type: Homologous_superfamily

There is currently no experimental data for members of this group or their homologues, nor do they exhibit features indicative of any function. Members of this entry are mainly found in proteobacteria.
Class II Hydrophobin superfamily (Class_II_Hydrophobin_sf)
Type: Homologous_superfamily

This is a superfamily of fungal Class II hydrophobins that seems to be restricted to ascomycetes. The superfamily includes cryparin, which is a cell-surface-associated hydrophobin secreted by filamentous fungi , and cerato-ulmin, a secreted toxin hydrophobin involved in Dutch Elm disease .

Hydrophobins are small, moderately hydrophobic extracellular proteins characterised by eight cysteine residues arranged in a strictly conserved motif. They are typically found on the outer surface of conidia and the hyphal wall, where they are thought to mediate contact and communication between the fungus and its environment . The hydrophobin family includes proteins such as cryparin, a cell surface-associated hydrophobin secreted by filamentous fungi ; cerato-ulmin, a secreted toxin implicated in Dutch elm disease ; and trihydrophobin from Claviceps fusiformis, which self-assembles at hydrophilic-hydrophobic interfaces on the hyphal surface . Hydrophobins are broadly categorised into two classes based on their solubility and assembly properties. Class I hydrophobins form rodlet bundles that coat aerial cell surfaces and contribute to cellular hydrophobicity, supporting fungal growth, development, and dispersal. In contrast, Class II hydrophobins form highly ordered films at water-air interfaces via intermolecular interactions but do not form rodlet structures. Hyd1 is a class II hydrophobin that not only fulfils structural roles but also functions as an elicitor of induced systemic resistance (ISR) in plants. During interaction with maize, Hyd1 binds the host target protein UBL and recruits additional UBL proteins in the roots, triggering defence responses such as cell death and activation of brassinosteroid, jasmonate (JA), and ethylene (ET) signalling pathways .
DinI-like superfamily (DinI-like_sf)
Type: Homologous_superfamily

This superfamily of short proteins includes DNA-damage-inducible protein I (DinI) and related proteins. The SOS response, a set of cellular phenomena exhibited by eubacteria, is initiated by various causes that include DNA damage-induced replication arrest, and is positively regulated by the co- protease activity of RecA. Escherichia coli DinI, a LexA-regulated SOS gene product, shuts off the initiation of the SOS response when overexpressed
in vivo
. Biochemical and genetic studies indicated that DinI physically interacts with RecA to inhibit its co-protease activity . The structure of DinI is known .
MoeA, C-terminal, domain IV superfamily (MoeA_C_domain_IV_sf)
Type: Homologous_superfamily

The majority of molybdenum-containing enzymes utilise a molybdenum cofactor (MoCF or Moco) consisting of a Mo atom coordinated via a cis-dithiolene moiety to molybdopterin (MPT). MoCF is ubiquitous in nature, and the pathway for MoCF biosynthesis is conserved in all three domains of life. MoCF-containing enzymes function as oxidoreductases in carbon, nitrogen, and sulphur metabolism .

This domain is found in proteins involved in biosynthesis of molybdopterin cofactor however the exact molecular function of this domain is uncertain. The structure of this domain is known and forms an incomplete β barrel.
ESAT-6-like superfamily (ESAT-6-like_sf)
Type: Homologous_superfamily

The ESAT-6/WXG100 superfamily includes proteins that are secreted in a full-length form and adopt a four-helix bundle structure . They represent the prototypical substrates of bacterial type VII secretion systems . The best-characterised member of the superfamily is ESAT-6, a small protein that appears to be of fundamental importance in virulence and protective immunity in Mycobacterium tuberculosis. Homologues have been detected in other Gram-positive bacterial species .
Ferrodoxin-fold anticodon-binding domain superfamily (Fdx_antiC-bd_sf)
Type: Homologous_superfamily

Aminoacyl-tRNA synthetases (aaRSs) play a crucial role in the translation of the genetic code by means of covalent attachment of amino acids to their cognate tRNAs. Phenylalanine-tRNA synthetase (PheRS, also known as Phenylalanine-tRNA ligase) is known to be among the most complex enzymes of the aaRS family. Bacterial and mitochondrial PheRSs share a ferredoxin-fold anticodon binding (FDX-ACB) domain, which represents a canonical double split α+β motif having no insertions. The FDX-ACB domain displays a typical RNA recognition fold (RRM) (see

) formed by the four-stranded antiparallel β sheet, with two helices packed against it .
Endonuclease/exonuclease/phosphatase superfamily (Endo/exonu/phosph_ase_sf)
Type: Homologous_superfamily

This domain superfamily is found in a large number of proteins including magnesium dependent endonucleases and phosphatases involved in intracellular signalling . This domain is found in many proteins including AP endonuclease proteins (DNA-(apurinic or apyrimidinic site) lyase

), deoxyribonuclease-1 (DNase I;

), synaptojanin an inositol-1,4,5-trisphosphate phosphatase (

) and sphingomyelinase (

).

The DNase I domain structure contains a β-sandwich fold and a duplication of the α+β motif.
Shew3726-like superfamily (Shew3726-like_sf)
Type: Homologous_superfamily

This superfamily consists of several hypothetical bacterial proteins. The structure of Shewanella Shew3726 has been solved (

).
Transcription factor LuxR-like, autoinducer-binding domain superfamily (TF_LuxR_autoind-bd_dom_sf)
Type: Homologous_superfamily

This domain superfamily binds N-acyl homoserine lactones (AHLs), which are also known as autoinducers. These are small, diffusible molecules used as communication signals in a large variety of proteobacteria. It is almost always found in association with the DNA-binding LuxR domain (

). The autoinducer binding domain forms the N-terminal region of the protein, while the DNA-binding domain forms the C-terminal region. In most cases, binding of AHL by this N-terminal domain leads to unmasking of the DNA-binding domain, allowing it to bind DNA and activate transcription . In rare cases, some LuxR proteins such as EsaR, act as repressors . In these proteins binding of AHL to this domain leads to inactivation of the protein as a transcriptional regulator. A large number of processes have been shown to be regulated by LuxR proteins, including bioluminescence, production of virulence factors in plant and animal pathogens, antibiotic production and plasmid transfer.

Structural studies of TraR from Agrobacterium tumefaciens show that the functional protein is a homodimer. Binding of the cognate AHL is required for protein folding, resistance to proteases and dimerisation. The autoinducer binding domain binds its cognate AHL in an α/β/α sandwich and provides an extensive dimerisation surface, though residues from the C-terminal region also make some contribution to dimerisation. The autoinducer binding domain is also required for interaction with RpoA, allowing transcription to occur .

There are some proteins which consist solely of the autoinducer binding domain. The function of these is not known, but TrlR from Agrobacterium has been shown to inhibit the activity of TraR by the formation of inactive heterodimers .