SII-SWORD/CoKE huggingface dataset:
Rab geranylgeranyltransferase, alpha subunit, insert-domain superfamily (RabGGT_asu_insert-dom_sf)
Type: Homologous_superfamily

Rab geranylgeranyltransferase (RabGGT) catalyses the transfer of geranylgeranyl groups to the C-terminal cysteine residues of Rab proteins, Ras-related small GTPases that function in intracellular vesicular transport . RabGGT is only able to prenylate Rab when it is complexed to the Rab escort protein (REP), after which REP remains bound to the prenylated Rab and delivers it to its target membrane. RabGGT is a member of the protein prenyltransferase family, all of which are heterodimers consisting of alpha and beta subunits. RabGGT is distinct from other members of the prenyltransferase family because of the presence of an Ig-like insert domain in the alpha subunit that is folded into an eight-stranded sandwich between two helices in the helical domain.
YgfB-like superfamily (YgfB-like_sf)
Type: Homologous_superfamily

This group of proteins includes the Escherichia coli proteins YgfB and YecA, and similar proteins mainly found in gammaproteobacteria. The function of these proteins is unknown. The crystal structure is known for the member from Haemophilus influenzae YgfB (

), which folds into seven α-helices arranged into two domains: a four-helix bundle and a three-helix up-down bundle .
Mu1/VP4 superfamily (Mu1/VP4_sf)
Type: Homologous_superfamily

This entry includes outer capsid proteins Mu1 and VP4.

Mu1 is an outer capsid protein that acts as a reoviral penetration agent. Non-enveloped animal reoviruses must enter host cells by membrane penetration that does not involve membrane fusion, as they lack a viral membrane. Reoviruses are activated by proteolytic cleavage in the intestinal lumen, leading to infectious subviral particles. The core of the virus is coated by a layer of mu1 and sigma3 proteins. Proteases strip off sigma3 exposing mu1, which provides the membrane penetration machinery that perforates the membrane. In addition, N-terminal myristoylation of polypeptide Mu1 are required for site-specific cleavage to Mu1C in transfected cells . Mu1 forms a trimer, where the three mu1 molecules are coiled around one another with a right-handed twist. The mu1 chain fold consists of four distinct domains, three intertwined, predominantly α helical domains and a jelly-roll β-sandwich .
Cytochrome C oxidase subunit II, transmembrane domain superfamily (Cyt_c_oxidase_su2_TM_sf)
Type: Homologous_superfamily

Cytochrome c oxidase (

) is an oligomeric enzymatic complex which is a component of the respiratory chain and is involved in the transfer of electrons from cytochrome c to oxygen. In eukaryotes this enzyme complex is located in the mitochondrial inner membrane; in aerobic prokaryotes it is found in the plasma membrane. The enzyme complex consists of 3-4 subunits (prokaryotes) to up to 13 polypeptides (mammals).

Subunit 2 (CO II) transfers the electrons from cytochrome c to the catalytic subunit 1. It contains two adjacent transmembrane regions in its N terminus and the major part of the protein is exposed to the periplasmic or to the mitochondrial intermembrane space, respectively. CO II provides the substrate-binding site and contains a copper centre called Cu(A) (see

), probably the primary acceptor in cytochrome c oxidase. An exception is the corresponding subunit of the cbb3-type oxidase which lacks the copper A redox-centre. Several bacterial CO II have a C-terminal extension that contains a covalently bound haem c.

The N-terminal domain of cytochrome C oxidase contains two transmembrane α-helices .
Apyrase superfamily (Apyrase_sf)
Type: Homologous_superfamily

This superfamily contains several eukaryotic apyrase (or adenosine diphosphatase) proteins (

), and related nucleoside diphosphatases (

). The salivary apyrases of blood-feeding arthropods are nucleotide hydrolysing enzymes implicated in the inhibition of host platelet aggregation through the hydrolysis of extracellular adenosine diphosphate . Soluble calcium-activated nucleotidase 1 (CANT1) is the human homologue .
MFS transporter superfamily (MFS_trans_sf)
Type: Homologous_superfamily

This entry represents MFS transporter superfamily, characterised by twelve transmembrane helices. This superfamily includes, among others, the glycerol-3-phosphate transporter from Escherichia coli, which transports glycerol-3-phosphate into the cytoplasm and inorganic phosphate into the periplasm , and the E. coli proton/sugar transporter lactose permease (LacY), which acts to couple lactose and H+ translocation .

Transporters can be grouped into two classes, primary and secondary carriers. The primary active transporters drive solute accumulation or extrusion by using ATP hydrolysis, photon absorption, electron flow, substrate decarboxylation or methyl transfer. If charged molecules are unidirectionally pumped as a consequence of the consumption of a primary cellular energy source, electron chemical potential results. This potential can than be used to drive the active transport of additional solutes via secondary carriers.

Among the different transporters, the two largest families that occur ubiquitously in all classifications of organisms are the ATP-Binding Cassette (ABC) primary transporter superfamily (see

) and the Major Facilitator Superfamily (MFS). The MFS transporters are single-polypeptide secondary carriers capable only of transporting small solutes in response to chemiosmotic ion gradients . They function as uniporters, symporters or antiporters. In addition, their solute specificities are also diverse. MFS proteins contain 12 transmembrane regions (with some variations).

The 3D structure of human GLUT1, an archetype of the major facilitator superfamily, has been solved . Helices 1-5, 8, and 10-12 are arranged in a 9-member barrel-like manner, delimiting a hydrophilic central channel. Helix 7 is located in the centre of the channel, suggesting a role in regulating transport of solutes through the channel.
P40 nucleoprotein superfamily, Borna disease virus (P40_nucleoprot_sf_BD-vir)
Type: Homologous_superfamily

This entry represents P40 nucleoproteins from several Borna disease virus (BDV) strains. BDV is an RNA virus that is a member of the Mononegavirales family, which includes such members as Measles virus and Ebola virus sp.. BDV causes an infection of the central nervous system in a wide range of vertebrates, which can progress to an often fatal immune-mediated disease. Viral nucleoproteins are central to transcription, replication, and packaging of the RNA genome. P40 nucleoprotein from BDV is multi-helical in structure and can be divided into two subdomains, each of which has an α-bundle topology . The nucleoprotein assembles into a planar homotetramer, with the RNA genome either wrapping around the outside of the tetramer or possibly fitting within the charged central channel of the tetramer .
Ectatomin superfamily (Ectatomin_sf)
Type: Homologous_superfamily

Ectatomin is a toxin from the venom of the ant Ectatomma tuberculatum. Ectatomin can efficiently insert into the plasma membrane, where it can form channels. Ectatomin was shown to inhibit L-type calcium currents in isolated rat cardiac myocytes . In these cells, ectatomin induces a gradual, irreversible increase in ion leakage across the membrane, which can lead to cell death.

Ectatomin is comprised of two subunits, A and B, which are homologous. The structure of ectatomin reveals that each subunit consists of two α helices with a connecting hinge region, which form a hairpin structure that is stabilised by disulphide bridges. A disulphide bridge between the hinge regions of the two subunits links the heterodimer together, forming a closed bundle of four helices with a left-handed twist .
Resistin-like superfamily (Resistin-like_sf)
Type: Homologous_superfamily

This superfamily consists of several mammalian resistin proteins. Resistin is a 12.5kDa cysteine-rich secreted polypeptide first reported from rodent adipocytes. It belongs to a multigene family termed RELMs or FIZZ proteins. Plasma resistin levels are significantly increased in both genetically susceptible and high-fat-diet-induced obese mice. Immunoneutralisation of resistin improves hyperglycemia and insulin resistance in high-fat-diet-induced obese mice, while administration of recombinant resistin impairs glucose tolerance and insulin action in normal mice. It has been demonstrated that increases in circulating resistin levels markedly stimulate glucose production in the presence of fixed physiological insulin levels, whereas insulin suppressed resistin expression. It has been suggested that resistin could be a link between obesity and type 2 diabetes .

The resistin structure has a disulfide-rich six-stranded β-sandwich fold and jelly-roll topology.
Chorismate mutase type II superfamily (Chorismate_II_sf)
Type: Homologous_superfamily

Chorismate mutase (CM) is a regulatory enzyme (

) required for biosynthesis of the aromatic amino acids phenylalanine and tyrosine. CM catalyzes the Claisen rearrangement of chorismate to prephenate, which can subsequently be converted to precursors of either L-Phe or L-Tyr. In bifunctional enzymes the CM domain can be fused to a prephenate dehydratase (P-protein for Phe biosynthesis), to a prephenate dehydrogenase (T-protein, for Tyr biosynthesis), or to 3-deoxy-D-arabino-heptulosonate 7-phosphate (DAHP) synthase. Besides these prokaryotic bifunctional enzymes, monofunctional CMs occur in prokaryotes as well as in fungi, plants and nematode worms . The sequence of monofunctional chorismate mutase aligns well with the N-terminal part of P-proteins .

The type II or AroQ class of CM has an all-helical 3D structure, represented by the CM domain of the bifunctional Escherichia coli P-protein. This type is named after the Enterobacter agglomerans monofunctional CM encoded by the aroQ gene . All CM domains from bifunctional enzymes as well as most monofunctional CMs belong to this class, including archaeal CM.

Eukaryotic CM from plants and fungi form a separate subclass of AroQ, represented by the Baker's yeast allosteric CM. These enzymes show only partial sequence similarity to the prokaryotic CMs due to insertions of regulatory domains, but the helix-bundle topology and catalytic residues are conserved and the 3D structure of the E. coli CM dimer resembles a yeast CM monomer . The E. coli P-protein CM domain consists of 3 helices and lacks allosteric regulation. The yeast CM has evolved by gene duplication and dimerization and each monomer has 12 helices. Yeast CM is allosterically activated by Trp and inhibited by Tyr .
Bacterial exopeptidase dimerisation domain (Bact_exopeptidase_dim_dom)
Type: Homologous_superfamily

This superfamily consists of a protein domain with four β strands and two α helices which make up the dimerisation surface of members of the MEROPS peptidase family M20 . This entry includes a range of zinc exopeptidases: carboxypeptidases, dipeptidases and specialised aminopeptidases .
HIT-like superfamily (HIT-like_sf)
Type: Homologous_superfamily

The histidine triad motif (HIT) consists of the conserved sequence HXHXHXX (where X is a hydrophobic amino acid) at the enzymatic catalytic centre, in which the second histidine is strictly conserved and participates in catalysis with the third histidine . Proteins containing HIT domains form a superfamily of nucleotide hydrolases and transferases that act on the alpha-phosphate of ribonucleotides . They are highly conserved from archaea to humans and are involved in galactose metabolism, DNA repair, and tumor suppression . HIT-containing proteins can be divided in five families based on catalytic specificities, sequence compositions, and structural similarities of its members:

Hint family of protein kinase-interacting proteins, the most ancient class in this superfamily. These include adenosine 5'-monophosphoramide hydrolases (e.g. HIT-nucleotide-binding protein, or HINT) . They also have a conserved zinc-binding motif C-X-X-C (where C is a cysteine residue and X is a hydrophobic residue), and a zinc ion is coordinated by these cysteine residues, together with the first histidine residue .

Fragile HIT protein, or FINT, whose name is due to its high rate of mutation at its locus on chromosome 3 in many cancers has been characterised as a tumor suppressor and plays a role in the hydrolysis of dinucleotide polyphosphates . HINT and FINT HIT domains have a topology similar to that found in the N-terminal of protein kinases .

GalT family. These include specific nucleoside monophosphate transferases (e.g. galactose-1-phosphate uridylyltransferase, diadenosine tetraphosphate phosphorylase, and adenylyl sulphate:phosphate adenylytransferase). These HIT domains are a duplication consisting of 2 HIT-like motifs. This family binds zinc and iron .

Aprataxin, which hydrolyses both dinucleotide polyphosphates and phophoramidates, and is involved in DNA repair systems .

mRNA decapping enzyme family. These include enzymes such as DcpS and Dcp2. The HIT-domain is usually C-terminal in these proteins .

This superfamily also includes CDP-diacylglycerol pyrophosphatases, CDH, which play a role in phospholipid metabolism and regulates phosphatidylinositol levels , the C-terminal CwfJ domains of CWF19-like protein DRN1 from Saccharomyces cerevisiae (

) which is involved branched RNA metabolism, modulating the turnover of lariat-intron pre-mRNAs by the lariat-debranching enzyme DBR1 and its homologues. This C-terminal Cwfj domains contain evolutionarily conserved cysteine and histidine residues in an arrangement similar to the CCCH-class of zinc fingers .
SecA, Wing/Scaffold superfamily (SecA_Wing/Scaffold_sf)
Type: Homologous_superfamily

SecA protein binds to the plasma membrane where it interacts with proOmpA to support translocation of proOmpA through the membrane. SecA protein achieves this translocation, in association with SecY protein, in an ATP-dependent manner. This domain is composed of two C-terminal α helical subdomains: the wing and scaffold subdomains.
RuvA, C-terminal domain superfamily (RuvA_C_sf)
Type: Homologous_superfamily

In prokaryotes, RuvA, RuvB, and RuvC process the universal DNA intermediate of homologous recombination, termed Holliday junction. The tetrameric DNA helicase RuvA specifically binds to the Holliday junction and facilitates the isomerization of the junction from the stacked folded configuration to the square-planar structure . In the RuvA tetramer, each subunit consists of three domains, I, II and III, where I and II form the major core that is responsible for Holliday junction binding and base pair rearrangements of Holliday junction executed at the crossover point, whereas domain III regulates branch migration through direct contact with RuvB.

The domain represents the C-terminal domain III of RuvA. This domain plays a significant role in the ATP-dependent branch migration of the hetero-duplex through direct contact with RuvB . Within the Holliday junction, this domain makes no interaction with the DNA.
ZapD domain superfamily (ZapD_sf)
Type: Homologous_superfamily

Cell division protein ZapD enhances FtsZ-ring assembly. It directly interacts with FtsZ and promotes bundling of FtsZ protofilaments, with a reduction in FtsZ GTPase activity .
Rho termination factor, N-terminal domain superfamily (Rho_N_sf)
Type: Homologous_superfamily

The Rho termination factor disengages newly transcribed RNA from its DNA template at certain, specific transcripts. It is thought that two copies of Rho bind to RNA and that Rho functions as a hexamer of protomers . This domain is found to the N terminus of the RNA binding domain (

).
UPF0358 superfamily (UPF0358_sf)
Type: Homologous_superfamily

This entry consists of several hypothetical bacterial proteins of around 90 residues in length. The function of the UPF035 family is unknown; however they form α helical bundles and are thought to be involved in control of cell shape .
Tetracyclin repressor-like, C-terminal domain superfamily (Tet_transcr_reg_TetR-rel_C_sf)
Type: Homologous_superfamily

This entry represents the C-terminal domain found in a number of different TetR transcription regulator proteins. TetR regulates the expression of the membrane-associated tetracycline resistance protein, TetA, which exports the tetracycline antibiotic out of the cell before it can attach to the ribosomes and inhibit protein synthesis . TetR blocks transcription from the genes encoding both TetA and TetR in the absence of antibiotic. The C-terminal domain is multi-helical and is interlocked in the homodimer with the helix-turn-helix (HTH) DNA-binding domain. Other members of the TetR family of transcriptional regulators carry this C-terminal domain. These include:

QacR from Staphylococcus aureus, a multidrug binding protein that represses transcription of the qacA multidrug transporter gene

Ethr, a repressor from Mycobacterium tuberculosis implicated in ethionamide drug resistance

CprB, a gamma-butyrolactone autoregulator/receptor from Streptomyces coelicolor that acts as a DNA-binding protein

YcdC, a hypothetical transcriptional regulator from Escherichia coli

YsiA, YfiR, and YxaF, hypothetical transcriptional regulators from Bacillus subtilis

YbiH, a hypothetical transcriptional regulator from Salmonella typhimurium
Methuselah, N-terminal domain superfamily (Methuselah_N_sf)
Type: Homologous_superfamily

Drosophila Methuselah (Mth) mutants have a 35% increase in average lifespan and increased resistance to several forms of stress, including heat, starvation, and oxidative damage. The protein affected by this mutation is related to G protein-coupled receptors of the secretin receptor family. Mth, like secretin receptor family members, has a large N-terminal ectodomain, which may constitute the ligand binding site .

This entry represents the N-terminal domain superfamily of the Methuselah protein. The structure of this domain contains two similar sub domains connected by a structured linker.
CRAL/TRIO, N-terminal domain superfamily (CRAL/TRIO_N_dom_sf)
Type: Homologous_superfamily

This all-α domain is often found N-terminal to CRAL-TRIO domains (

). Its function is unknown.
HR1 repeat superfamily (HR1_rpt_sf)
Type: Homologous_superfamily

HR1 was first described as a three times repeated homology region of the N-terminal non-catalytic part of protein kinase PRK1(PKN) . The first two of these repeats were later shown to bind the small G protein rho known to activate PKN in its GTP-bound form. Similar rho-binding domains also occur in a number of other protein kinases and in the rho-binding proteins rhophilin and rhotekin. Recently, the structure of the N-terminal HR1 repeat complexed with RhoA has been determined by X-ray crystallography. This domain contains two long α helices forming a left-handed antiparallel coiled-coil fold termed the antiparallel coiled- coil (ACC) finger domain. The two long helices encompass the basic region and the leucine repeat region, which are identified as the Rho-binding region .
YdgH-like superfamily (YdgH-like_sf)
Type: Homologous_superfamily

This domain is found in several Enterobacterial proteins of around 90 residues in length, including E. coli YdgH, YhcN, BhsA and McbA, which play a role in stress response, biofilm formation, and pathogenesis . BhsA (also known as ComC) reduces the permeability of the outer membrane to copper and may decrease biofilm formation by repressing cell-cell interaction and cell surface interaction . Members of this entry have one copy of this domain with the exception of YdgH, which has three. The function of this domain is unknown, however, it is suggested to be directly involved in host-pathogen interaction .

The structure of YdgH has a dodecin subunit-like fold, which consists of a β-α-β(2) fold, divided into two layers (α/β) and an antiparallel β-sheet topology.
T4 RNase H, C-terminal (T4_RNaseH_C)
Type: Domain

The C-terminal region of T4 RNaseH ribonuclease adopts a SAM domain-like fold, consisting of a bundle of four/five helices. These residues may have a role in providing a docking site for other proteins or enzymes in the replication fork .
SMCs flexible hinge superfamily (SMC_hinge_sf)
Type: Homologous_superfamily

This entry represents the hinge region superfamily of the SMC (Structural Maintenance of Chromosomes) family of proteins. The hinge region is responsible for formation of the DNA interacting dimer. It is also possible that its precise structure is an essential determinant of the specificity of the DNA-protein interaction .

The structure of this hinge region consists of two different α+β subdomains and forms subdomain-swapped dimers.
Sialidase superfamily (Sialidase_sf)
Type: Homologous_superfamily

Sialidases (neuraminidases) hydrolyse the non-reducing, terminal sialic acid linkage in various natural substrates, such as glycoproteins, glycolipids, gangliosides, and polysaccharides . In mammals, sialidases occur in the lysosome, the cytosol, and associated with the plasma membrane. Sialidases have also been implicated in the pathogenesis of many diseases. For example, in viruses neuraminidases enable the transport of the virus through mucin, the eruption of the virus from the infected host cell, and the prevention of self-aggregation of virus particles through the destruction of the host cell receptor recognised by the virus . Eukaryotic, bacterial and viral sialidases share highly conserved regions of β-sheet motifs. Bacterial sialidases often possess domains in addition to the catalytic sialidase domain, for instance the sialidase from Micromonospora viridifaciens contains three domains, of which the catalytic domain described here is the N-terminal domain . Similarly, leech sialidase is a multidomain protein, where the catalytic domain is the C-terminal domain . In several paramyxoviruses, sialidase forms part of the multi-functional haemagglutinin-sialidase glycoprotein found on the viral envelope .
5'-3' exonuclease, C-terminal domain superfamily (5-3_exonuclease_C_sf)
Type: Homologous_superfamily

This entry represents the C-terminal domain of 5' to 3' exonucleases. The 5'-3' exonucleases are conserved in organisms as diverse as bacteriophage and mammals. It adopts a SAM fold consisting of 4-5 helices packed into a bundle of two orthogonally packed α-hairpins. This domain is involved in interactions with DNA and proteins. 5' to 3' exonucleases that contain this domain include:

Bacteriophage T4 RNase H, which has sequence similarity to the RAD2 family of eukaryotic proteins .

5' to 3' exonuclease domain of DNA polymerase Taq, which is homologous to Escherichia coli DNA polymerase I (pol I) .

Bacteriophage T5 5'-exonuclease, which are structure-specific endonucleases .

Flap endonuclease-1 (Fen-1 nuclease), a structure specific nuclease that is an essential enzyme for eukaryotic DNA replication and repair .