SII-SWORD/CoKE huggingface dataset:
DNA repair Rad51/transcription factor NusA, alpha-helical (DNA_repair_Rad51/TF_NusA_a-hlx)
Type: Homologous_superfamily

This superfamily represents an α-helical bundle domain, which has a SAM domain-like fold. This compact domain consists of a 4-5 helical bundle of two orthogonally packed α-hairpins, and contains one classic and one pseudo HhH (helix-hairpin-helix) motif. This domain is found at N-terminal of the DNA repair protein Rad51, at the C-terminal of the transcription elongation protein NusA, and at the C-terminal of the hypothetical protein AF1548.

Human Rad51 protein is a homologue of Escherichia coli RecA protein, and functions in DNA repair and recombination . In higher eukaryotes, Rad51 protein is essential for cell viability. The N-terminal region of Rad51 is highly conserved among eukaryotic Rad51 proteins but is absent from RecA, suggesting a Rad51-specific function for this region. The-terminal domain is involved in interactions with DNA and proteins; DNA binding may be regulated via phosphorylation within the N-terminal domain.

NusA (N utilisation substance A) from E. coli is an essential transcription factor that associates with the RNA polymerase (RNAP) core enzyme, where it modulates transcriptional pausing, termination and anti-termination . The C-terminal of NusA consists of two repeat units, and is responsible for the interaction of NisA with the C-terminal of RNAP, and with its interaction with protein N from phage lambda during anti-termination .
Crossover junction endonuclease MUS81-like, HHH domain (HHH_MUS81)
Type: Domain

This helix-hairpin-helix (HHH) domain is found in Crossover junction endonuclease MUS81, DNA polymerase beta, as well as in other polymerases and DNA nucleotidylexotransferase (TdT).
HRDC-like superfamily (HRDC-like_sf)
Type: Homologous_superfamily

This superfamily represents the HRDC (helicase and RNaseD C-terminal) domain, which comprises two orthogonally packed α-hairpin subdomains, and is involved in interactions with DNA and protein.

The HRDC (helicase and RNaseD C-terminal) domain is found at the C terminus of many RecQ helicases, including the human Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN and RecQ-like DNA helicase BLM (previously known as Werner and Bloom syndrome proteins) . RecQ helicases have been shown to unwind DNA in an ATP-dependent manner. The structure of the HRDC domain consists of a 4-5 helical bundle of two orthogonally packed α-hairpins, and as such it resembles auxiliary domains in bacterial DNA helicases and other proteins that interact with nucleic acids. A positively charged region on the surface of the HRDC domain is able to interact with DNA.

The HRDC domain is also present in eukaryotic and archaeal RNA polymerase II subunit RBP4, the N-terminal of which forms a heterodimerisation α-hairpin .
Integrase/recombinase, N-terminal (Integrase_recombinase_N)
Type: Homologous_superfamily

Phage integrases are enzymes that mediate unidirectional site-specific recombination between two DNA recognition sequences, the phage attachment site, attP, and the bacterial attachment site, attB . Integrases may be grouped into two major families, the tyrosine recombinases and the serine recombinases, based on their mode of catalysis. Tyrosine family integrases, such as Bacteriophage lambda integrase, utilise a catalytic tyrosine to mediate strand cleavage, tend to recognise longer attP sequences, and require other proteins encoded by the phage or the host bacteria.

The 356 amino acid lambda integrase consists of two domains: an N-terminal domain (NTD) that includes residues 1 - 64 and is responsible for binding the arm-type sites of attP, and a C-terminal domain that binds the lower affinity core-type sites and contains the catalytic site. The NTD adopts a 4-5 helical bundle fold with two orthogonally packed α-hairpins.

The recombinases Cre from P1 phage, XerD from Escherichia coli, and Flp from yeast are members of the tyrosine recombinase family, and have a two-domain motif resembling that of lambda integrase, as well as sharing a conserved binding mechanism .
Retroviral matrix protein (Retrovr_matrix)
Type: Homologous_superfamily

Retroviral matrix proteins (or major core proteins) are components of envelope-associated capsids, which line the inner surface of virus envelopes and are associated with viral membranes . Matrix proteins are produced as part of Gag precursor polyproteins. During viral maturation, the Gag polyprotein is cleaved into major structural proteins by the viral protease, yielding the matrix (MA), capsid (CA), nucleocapsid (NC), and some smaller peptides. Gag-derived proteins govern the entire assembly and release of the virus particles, with matrix proteins playing key roles in Gag stability, capsid assembly, transport and budding. Although matrix proteins from different retroviruses appear to perform similar functions and can have similar structural folds which predominantly consist of four closely packed α-helices that are interconnected through loops, their primary sequences can be very different .

This superfamily represents structurally homologous matrix proteins from different retroviruses, their structure consisting of four-five α helices in a right-handed superhelix. Retroviral matrix proteins bearing this structure have been isolated from Human immunodeficiency virus (HIV), Simian immunodeficiency virus (SIV-cpz), Human T-lymphotropic virus 1, Human T-cell leukemia virus 2 (HTLV-2), Mason-Pfizer monkey virus (MPMV) (Simian Mason-Pfizer virus), Rous sarcoma virus (RSV), Equine infectious anemia virus (EIAV), and Moloney murine leukemia virus (MoMLV). This entry also identifies matrix proteins from several eukaryotic endogenous retroviruses, which arise when one or more copies of the retroviral genome becomes integrated into the host genome .
Saposin-like (Saposin-like)
Type: Homologous_superfamily

The lysosomal degradation of several sphingolipids requires the presence of four small glycoproteins called saposins, generated by proteolytic processing of a common precursor, prosaposin . Saposins have three conserved disulphide bridges, and display a 5-helical, closed, folded leaf topology. Other proteins have been shown to have structures that closely resemble saposin, such as the antimicrobial peptides NK-lysin and granulysin . Some proteins contain saposin-like domains, such as prophytepsin, an acid protease from plants, and J3-crystallin, an eye-lens protein from jellyfish, both of which contain circularly permuted saposin motifs called swaposin . In some saposins and saposin-like domains, lipid-binding can promote conformational changes and oligomerization.
Flagellar motor switch protein FliG, alpha-helical (FliG_a-hlx)
Type: Homologous_superfamily

This superfamily represents an α-α superhelical domain found in the flagellar motor switch protein FliG. The flagellar motor switch regulates the direction of flagellar rotation and swimming behaviour in certain bacteria . The switch is a complex apparatus that responds to signals transduced by the chemotaxis sensory signalling system during chemotactic behaviour. CheY, the chemotaxis response regulator, is believed to act directly on the switch to induce tumbles in the swimming pattern .

The switch complex comprises at least three proteins - FliG, FliM and FliN. It has been shown that FliG interacts with FliM, FliM interacts with itself, and FliM interacts with FliN. Several residues within the middle third of FliG appear to be strongly involved in the FliG-FliM interaction, with residues near the N- or C-termini being less important. Such clustering suggests that FliG-FliM interaction plays a central role in switching.
Trimeric LpxA-like superfamily (Trimer_LpxA-like_sf)
Type: Homologous_superfamily

This domain superfamily is characterised by trimeric LpxA-like enzymes that display a single-stranded left-handed β-helix fold, composed of tandem repeats of a hexapeptide, as represented by the Bacterial transferase hexapeptide repeat, where the hexapeptide repeats correspond to individual strands. Many bacterial transferases contain this domain. The structures of several proteins with this domain have been determined, including UDP N-acetylglucosamine acyltransferase (LpxA,

) from Escherichia coli, the first enzyme in the lipid A biosynthetic pathway ; galactoside acetyltransferase (GAT, LacA,

) from E. coli, a gene product of the lac operon that may assist cellular detoxification ; gamma-class Archaeon carbonic anhydrase (

), a zinc-containing enzyme that catalyses the reversible hydration of carbon dioxide ; tetrahydrodipicolinate-N-succinlytransferase (DapD) from Mycobacterium bovis, an enzyme from the lysine biosynthetic pathway that contains an extra N-terminal 3-helical domain ; and the C-terminal domain of N-acetylglucosamine 1-phosphate uridyltransferase (GlmU,

) from E. coli, a trimeric bifunctional enzyme that catalyses the last two sequential reactions in the de novo biosynthetic pathway for UDP-N-acetylglucosamine, an essential precursor for many biomolecules .
Dihydropteroate synthase-like superfamily (Dihydropteroate_synth-like_sf)
Type: Homologous_superfamily

All organisms require reduced folate cofactors for the synthesis of a variety of metabolites. The enzyme 7,8-dihydropteroate synthase (DHPS) (

) catalyses the condensation of para-aminobenzoic acid (pABA) with 6-hydroxymethyl-7, 8-dihydropterin-pyrophosphate to form 7,8-dihydropteroate and pyrophosphate. DHPS is essential for the de novo synthesis of folate in prokaryotes, lower eukaryotes, and in plants, but is absent in mammals . By contrast, higher vertebrates possess an active transport system that enables them to use dietary folates. DHPS is the target of sulphonamides, which are substrate analogues that compete with pABA, but which do not affect vertebrates as they lack the DHPS enzyme. DHPS is a single domain protein that forms an eight-stranded TIM α/β barrel, where the 7,8-dihydropterin pyrophosphate substrate binds in a deep cleft in the barrel . In the lower eukaryote Pneumocystis carinii, DHPS is the C-terminal domain of a multifunctional folate synthesis enzyme (gene fas) .

Other proteins contain a DHPS-like domain, including members of the methyltetrahydrofolate (corrinoid iron-sulphur protein methyltransferase (MeTr)) family. MeTr catalyses a key step in the Wood-Ljungdahl pathway of carbon dioxide fixation . Other members of this family that contain a DHPS-like domain include methionine synthase and methanogenic enzymes that activate the methyl group of methyltetrahydromethano(or -sarcino)pterin.
CheY-like superfamily (CheY-like_superfamily)
Type: Homologous_superfamily

CheY is a member of the response regulator family in bacterial two-component signalling systems, where CheY receives the signal from the sensor partner, usually a histidine protein kinase. Signal transduction involves phosphotransfer, whereby the histidine kinase phosphorylates a conserved aspartate in the response regulator to activate responses to environmental signals . CheY is a single domain protein that folds into a compact globular unit with a flavodoxin-like fold consisting of three-layer α/β/α sandwich with 21345 β topology, where the phosphorylation region lies in a cavity.

Other members of the response regulator family contain a CheY-like receiver domain, which is often found N-terminal to a DNA-binding effector domain. Examples include NarL (nitrate/nitrite response regulator), NtrC (nitrogen regulatory protein C), Spo0A and Spo0F (sporulation response) from Bacillus, PhoA and PhoB cyclin-dependent kinases from Aspergillus, among others.

AmiR, the positive regulator of the amidase operon in Psuedomonas, is an unusual member of the bacterial response regulator family; AmiR is able to bind RNA and uses ligand-regulated activation rather than phopho-activation. It has a CheY-like fold at its N terminus, but contains two subdomains in a C-terminal extension, one forming a coiled-coil and the other a long α-helix. As such AmiR may represent a new family of RNA-binding response regulators .

CheY-like domains can be found in other protein families as well. Examples include the receiver domain of the ethylene receptor (ETR1) from Arabidopsis, which is involved in ethylene detection and signal transduction ; the N-terminal wing' domain of ornithine decarboxylase from Lactobacilli, which catalyses the conversion of ornithine to putrescine at the beginning of the polyamine pathway . The N-terminal domain of the Circadian clock oscillator protein KaiA, from cyanobacteria, acts as a psuedo-receiver domain, but lacks the conserved aspartyl residue required for phosphotransfer in response regulators .
Dimeric alpha-beta barrel (Dimeric_a/b-barrel)
Type: Homologous_superfamily

Dimeric α-β barrel domains exhibit an α+β sandwich fold with an antiparallel β-sheet that forms a closed barrel. These domains dimerise through the β-sheet, and in some cases these dimers may assemble into higher oligomers. Domains with this structure are found in proteins from several different families, including bacterial actinorhodin biosynthesis monooxygenase (ActVa-Orf6), which catalyses the oxidation of an aromatic intermediate of the actinorhodin biosynthetic pathway ; bacterial muconalactone isomerase, a decamer composed of five dimers ; and the C-terminal domain of archaeal LprA, a member of the Lrp/AqsnC family of transcription regulators .
Protein kinase-like domain superfamily (Kinase-like_dom_sf)
Type: Homologous_superfamily

Protein kinases (

) modify other proteins by chemically adding phosphate groups to them. This process is fundamental to most signalling and regulatory processes in the eukaryotic cell .
DNA breaking-rejoining enzyme, catalytic core (DNA_brk_join_enz)
Type: Homologous_superfamily

Phage integrases are enzymes that mediate unidirectional site-specific recombination between two DNA recognition sequences, the phage attachment site, attP, and the bacterial attachment site, attB . Integrases may be grouped into two major families, the tyrosine recombinases and the serine recombinases, based on their mode of catalysis. Tyrosine family integrases, such as Bacteriophage lambda integrase, utilise a catalytic tyrosine to mediate strand cleavage, tend to recognise longer attP sequences, and require other proteins encoded by the phage or the host bacteria.

The 356 amino acid lambda integrase consists of two domains: an N-terminal domain that includes residues 1-64 and is responsible for binding the arm-type sites of attP, and a C-terminal domain (CTD) that binds the lower affinity core-type sites and contains the catalytic site. The CTD can be further divided into the core-type binding domain (residues 65-169) and the catalytic core domain (170-356), the later representing this entry. The catalytic core adopts an α3-β3-α4 fold, where one side of the β sheet is exposed.

The recombinases Cre from phage P1, XerD from Escherichia coli and Flp from yeast are members of the tyrosine recombinase family, and have a two-domain motif resembling that of lambda integrase, as well as sharing a conserved binding mechanism . The structural fold of their catalytic core domains resemble that of Lambda integrase.

The catalytic core of the eukaryotic DNA topoisomerase I shares significant structural similarity with the bacteriophage family of DNA integrases . Topoisomerases I promote the relaxation of DNA superhelical tension by introducing a transient single-stranded break in duplex DNA and are vital for the processes of replication, transcription and recombination.
Zinc finger, FYVE/PHD-type (Znf_FYVE_PHD)
Type: Homologous_superfamily

The FYVE zinc finger domain is conserved from yeast to man, and is named after four proteins that it has been found in: Fab1, YOTB/ZK632.12, Vac1, and EEA1. It functions in the membrane recruitment of cytosolic proteins by binding to phosphatidylinositol 3-phosphate (PI3P), which is found mainly on endosomes .

The plant homeodomain (PHD) zinc finger domain has a C4HC3-type motif, and is widely distributed in eukaryotes, being found in many chromatin regulatory factors .

Both the FYVE and the PHD zinc finger motifs display strikingly similar dimetal(zinc)-bound α+β folds.

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.
Longin-like domain superfamily (Longin-like_dom_sf)
Type: Homologous_superfamily

VAMPs (and its homologue synaptobrevins) define a group of SNARE proteins that contain a C-terminal coiled-coil/SNARE motif, in combination with variable N-terminal domains that are used to classify VAMPs: those containing longin N-terminal domains (~150 aa) are referred to as longins, while those with shorter N-termini are referred to as brevins . Longins are the only type of VAMP protein found in all eukaryotes, suggesting that their longin domain is essential. The longin domain is thought to exert a regulatory function. Longin domains have been shown to share the same structural fold, a profilin-like globular domain consisting of a five-stranded antiparallel β-sheet that is sandwiched by an α-helix on one side, and two α-helices on the other (β(2)-α-β(3)-α(2)).

Other families have been shown to contain domains that structurally resemble the VAMP longin domain. An example is the eukaryotic conserved protein, SEDL, which is a component of the transport protein particle (TRAPP), critically involved in endoplasmic reticulum-to-Golgi vesicle transport; mutations in the SEDL gene are associated with an X-linked skeletal disorder, spondyloepiphyseal dysplasia tarda . Another example is the assembly domain of clathrin coat proteins, such as Mu2 adaptin (AP50) and Sigma2 adaptin (AP17), which structurally resemble the longin domain. AP50 and AP17 are two of the proteins that make up the core of AP2, a complex that functions in clathrin-mediated endocytosis .
Galactose mutarotase-like domain superfamily (Gal_mutarotase_sf_dom)
Type: Homologous_superfamily

Proteins with this domain belong to the galactose mutarotase-like structural superfamily.
The domain has a distorted supersandwich structure consisting of 18 strands in two sheets, and probably functions to bind carbohydrates in enzymes that act on sugars. Domains with this structure occur in several protein families, including galactose mutarotase (

) ; domain 5 of beta-galactosidase (

); domain 2 of Isomaltosyltransferase (

); the central domain of hyaluronate lyase-like enzymes, such as chondroitinase AC (

), xanthan lyase (

), chrondroitin ABC lyase I, and hyaluronate lyase (

) itself ; the N-terminal domain of lactobacillus maltose phosphorylase (

), 6-glucosyltransferase (

) and bacterial glucoamylase (

) ; the C-terminal domain of eukaryotic alpha-mannosidase (

) and archaeon 4-alpha-glucanotransferase (

) .
Mechanosensitive ion channel MscS, transmembrane-2 (MscS_channel_TM-2)
Type: Homologous_superfamily

MscS is a mechanosensitive channel present in the membrane of bacteria, archaea and eukarya that responds both to stretching of the cell membrane and to membrane depolarisation . MscS folds as a homo-heptamer with a cylindrical shape, and can be divided into transmembrane and extramembrane regions: an N-terminal periplasmic region, a transmembrane region, and a C-terminal cytoplasmic region. The MscS family of channels shows diversity in size and sequence between its members; most of the diversity occurs in the size of the transmembrane region, which ranges from three to eleven transmembrane helices, although the three C-terminal helices are conserved. This domain superfamily covers the core transmembrane region, which consists of three transmembrane helices per subunit in an oligomeric fold.
LEM/LEM-like domain superfamily (LEM/LEM-like_dom_sf)
Type: Homologous_superfamily

The LEM domain is a ~40-residue motif found in nuclear membrane-associated proteins, including lamino-associated polypeptide 2 (LAP2), emerin, MAN1, otefin and Lem-3 . Defects in the emerin gene are a cause of Emery-Dreifuss muscular dystrophy, an X-linked disorder characterised by early contractures, muscle wasting, weakness and cardiomyopathy. The N-terminal LEM domain in emerin mediates binding to BAF (barrier-to-autointegration factor).

All LAP2 isoforms also share an N-terminal segment composed of a LEM domain that is connected to a highly divergent LEM-like domain by a highly flexible 60-residue linker. The LEM-like globular domain has the same size and structural fold as the LEM domain, but has been shown to bind directly to DNA .
TRASH domain (TRASH_dom)
Type: Domain

TRASH domain contains a well-conserved cysteine motif that may be involved in metal coordination. TRASH is encoded by multiple prokaryotic genomes and is present in transcriptional regulators, cation-transporting ATPases and hydrogenases, and is also present as a stand-alone module. The observed domain associations and conserved genome context of TRASH-encoding genes in prokaryotic genomes suggest that TRASH constitutes a novel component in metal trafficking and heavy-metal resistance. The precise role of the multiple copies of TRASH that are present in vertebrate proteins remains to be elucidated .
KIND domain (KIND_dom)
Type: Domain

The KIND (kinase non-catalytic C-lobe domain) is a putative protein interaction domain, which has been identified as being similar to the C-terminal protein kinase catalytic fold (C lobe) (see

).

The presence of the KIND domain at the N terminus of signalling proteins and the absence of the active site residues in the catalytic and activation loops suggest that it folds independently and is likely to be non-catalytic. The occurrence of the domain only in metazoa implies that it has evolved from the catalytic protein kinase domain into an interaction domain possibly by keeping the substrate-binding features . In SPIRE1 (protein spire homologue 1) this domain interacts with FMN2 (formin-2) .
HTTM-like (HTTM-like)
Type: Domain

Sequence analysis of vitamin K dependent gamma-carboxylases (VKGC) revealed the presence of a novel domain, HTTM (Horizontally Transferred TransMembrane). In contrast to most known domains, HTTM contains four transmembrane regions. Its occurrence in eukaryotes, bacteria and archaea is more likely caused by horizontal gene transfer than by early invention. The conservation of VKGC catalytic sites indicates an enzymatic function also for the other family members.