SII-SWORD/CoKE huggingface dataset:
ER membrane protein complex subunit 6-like (EMC6-like)
Type: Family

This family consists of several Rab5-interacting proteins/factors (RABIF5 or Rab5ip) including ER membrane protein complex subunit 6 (EMC6, also known as RAB5IFL) and its homologue, GEL complex subunit OPTI (also known as RCAF1/RAB5IF) . The ras-related GTPase rab5 is rate-limiting for homotypic early endosome fusion. Rab5ip represents a novel rab5 interacting protein that may function on endocytic vesicles as a receptor for rab5-GDP and participate in the activation of rab5 . EMC6 interacts with Rab5A and BECN1/Beclin 1 and regulates autophagosome formation . EMC6 is part of the EMC complex, required for efficient folding of proteins in the ER and enables the energy-independent insertion into endoplasmic reticulum membranes of newly synthesized membrane proteins . RCAF1 is a component of the multi-pass translocon (MPT) complex that mediates insertion of multi-pass membrane proteins into the lipid bilayer of membranes and it also acts as an assembly factor for mitochondrial respiratory complexes .
Allosteric substrate binding domain superfamily (ASB_dom_sf)
Type: Homologous_superfamily

This superfamily represents a domain found at the N terminus of the L-serine dehydratases beta chain and in some but not all D-3-phosphoglycerate dehydrogenases (PGDH) and related enzymes.
ThuA-like domain (ThuA-like)
Type: Domain

The overall fold of this domain is very similar the class I glutamine amidotransferase (GAT) domain, but the putative active site has a different structure. The structure has been solved for ThuA-like protein from Bacillus Stearothermophilus

.
Helix hairpin bin domain superfamily (Helix_hairpin_bin_sf)
Type: Homologous_superfamily

This domain superfamily is found in uncharacterised protein whose genomic location within nitrogen fixation clusters suggests that they may play a role in this process. They consist of two α-helices. A four-residue linker between the helices allows them to form an anti-parallel bundle and cross over each other towards their termini . A similar domain is found in Sulfolobus spindle-shaped virus 1 (SSV1) protein D-63 . This domain is also present in eukaryotic proteins such as Golgi to ER traffic protein 1 (GET1), also known as tail-anchored protein insertion receptor WRB, Pre-mRNA-splicing factor ISY1 and Vacuolar protein sorting-associated protein 37.
HP0062-like domain superfamily (HP0062-like_sf)
Type: Homologous_superfamily

The HP0062 gene codes for a hypothetical small acidic protein in Helicobacter pylori (

). The HP0062 monomer has a helix-hairpin-helix structure. In the dimer, two monomers are held together by hydrophobic interactions in an antiparallel arrangement, forming a four helix bundle .
[NiFe]-hydrogenase, large subunit (NiFe-Hase_large)
Type: Homologous_superfamily

This domain superfamily is found in the large subunit of nickel-iron [NiFe] hydrogenase .

Hydrogenases catalyse the reversible oxidation of molecular hydrogen and play a vital role in anaerobic metabolism. Metal-containing hydrogenases are subdivided into three classes: Fe ('iron only') hydrogenases; Ni-Fe hydrogenases; and Ni-Fe-Se hydrogenases . Hydrogen oxidation is coupled to the reduction of electron acceptors (such as oxygen, nitrate, sulphate, carbon dioxide and fumarate), whereas proton reduction (hydrogen evolution) is essential in pyruvate fermentation or in the disposal of excess electrons.

The Ni-Fe hydrogenases, when isolated, are found to catalyse both hydrogen evolution and uptake, with low-potential multihaem cytochromes, such as cytochrome c3, acting as either electron donors or acceptors, depending on their oxidation state. Both periplasmic (soluble) and membrane-bound hydrogenases are known.

The Ni-Fe hydrogenases are heterodimeric proteins consisting of small (S) and large (L) subunits. The small subunit contains three iron-sulphur clusters (two [4Fe-4S] and one [3Fe-4S]); the large subunit contains a nickel ion . Small subunits of membrane-bound Ni-Fe hydrogenases contain a C-terminal domain of about 40 residues that is absent in periplasmic forms.
GAF-like domain superfamily (GAF-like_dom_sf)
Type: Homologous_superfamily

This superfamily represents the GAF domain and domains sharing protein structural similarity, such as the C-terminal domain of the transcription regulator IclR, the C-terminal domain of the heat-inducible transcription repressor HrcA, and the phytochrome chromophore attachment domain.

The GAF domain is named after some of the proteins it is found in, including cGMP-specific phosphodiesterases, adenylyl cyclases and FhlA. It is also found in guanylyl cyclases and phytochromes . The structure of a GAF domain shows that the domain shares a similar fold with the PAS domain . Adenylyl and guanylyl cyclases catalyse ATP and GTP to the second messengers cAMP and cGMP respectively; these products up-regulate catalytic activity by binding to the regulatory GAF domain(s). The opposite hydrolysis reaction is catalysed by phosphodiesterase. cGMP-dependent 3',5'-cyclic phosphodiesterase catalyses the conversion of guanosine 3',5'-cyclic phosphate to guanosine 5'-phosphate. Here too, cGMP regulates catalytic activity by GAF-domain binding.

Phytochromes are regulatory photoreceptors in plants and bacteria which exist in two thermally stable states that are reversibly inter-convertible by light, the Pr state absorbs maximally in the red region of the spectrum, while the Pfr state absorbs maximally in the far-red region .
Enolase-like, N-terminal (Enolase-like_N)
Type: Homologous_superfamily

This superfamily represents the N-terminal of the enolase and similar structural domains found in several enzymes, such as D-glucarate dehydratases, muconate-lactonizing enzymes, mandelate racemases, d-galactonate dehydratase, O-succinylbenzoate synthases and chlormuconate cycloisomerases, l-Ala-d/l-Glu epimerases, 3-methylaspartate ammonia lyase, etc . These enzymes share a bidomain structure containing a capping domain and a C-terminal barrel domain. The N-terminal domain forms part of the capping domain .
Beta-hexosaminidase-like, domain 2 (Hex-like_dom2)
Type: Homologous_superfamily

This entry represents the domain 2 of bacterial beta-hexosaminidases. This domain can also be found in the N-terminal of alpha-glucuronidases, hyaluronoglucosaminidases and eukaryotic beta-hexosaminidases.
Beta-hexosaminidase, eukaryotic type, N-terminal (HEX_eukaryotic_N)
Type: Domain

This entry represents the N-terminal domain of the eukaryotic beta-hexosaminidases. There are 3 forms of beta-hexosaminidase: hexosaminidase A is a trimer, with one alpha, one beta-A and one beta-B chain; hexosaminidase B is a tetramer of two beta-A and two beta-B chains; and hexosaminidase S is a homodimer of alpha chains. The two beta chains are derived from the cleavage of a precursor.
Ammonium/urea transporter (Ammonium/urea_transptr)
Type: Homologous_superfamily

The entry represents the a structural domain found in ammonia and urea channels. The Amt/MEP/Rh ammonium transporters domain consists of a duplication of 2 structural repeats of five helices each plus one extra C-terminal helix . Similarly, the urea transporter fold contains two homologous halves with opposite orientations in the membrane, each half with five transmembrane helices .
Protein-tyrosine phosphatase-like (Prot-tyrosine_phosphatase-like)
Type: Homologous_superfamily

This superfamily represents a domain found in some protein-tyrosine phosphatases, including dual specificity phosphatases, myotubularin-like phosphatases , receptor-type tyrosine-protein phosphatases and non receptor-type tyrosine-protein phosphatases. This domain also shares structure similarity with the lipid phosphatase domain in tensin and tensin like proteins, such as cyclin G-associated kinase (GAK) and phoshphoinositide phosphatase PTEN (phosphatase and tensin homologue) .

Protein tyrosine (pTyr) phosphorylation is a common post-translational modification which can create novel recognition motifs for protein interactions and cellular localisation, affect protein stability, and regulate enzyme activity. Consequently, maintaining an appropriate level of protein tyrosine phosphorylation is essential for many cellular functions. Tyrosine-specific protein phosphatases (PTPase;

) catalyse the removal of a phosphate group attached to a tyrosine residue, using a cysteinyl-phosphate enzyme intermediate. These enzymes are key regulatory components in signal transduction pathways (such as the MAP kinase pathway) and cell cycle control, and are important in the control of cell growth, proliferation, differentiation and transformation . The PTP superfamily can be divided into four subfamilies :

(1) pTyr-specific phosphatases

(2) dual specificity phosphatases (dTyr and dSer/dThr)

(3) Cdc25 phosphatases (dTyr and/or dThr)

(4) LMW (low molecular weight) phosphatases

Based on their cellular localisation, PTPases are also classified as:

Receptor-like, which are transmembrane receptors that contain PTPase domains

Non-receptor (intracellular) PTPases

All PTPases carry the highly conserved active site motif C(X)5R (PTP signature motif), employ a common catalytic mechanism, and share a similar core structure made of a central parallel β-sheet with flanking α-helices containing a β-loop-α-loop that encompasses the PTP signature motif . Functional diversity between PTPases is endowed by regulatory domains and subunits.
Tensin-type phosphatase domain (Tensin_phosphatase)
Type: Domain

Tensins constitute a eukaryotic family of lipid phosphatases that are defined by the presence of two adjacent domains: a lipid phosphatase domain and a C2-like domain. The tensin-type C2 lacks the canonical Ca(2+) ligands found in classical C2 domains, and in this respect it is similar to the C2 domains of PKC-type . The tensin-type C2 domain can bind phospholipid membranes in a Ca(2+) independent manner . In the tumour suppressor protein PTEN, the best-characterised member of the family, the lipid phosphatase domain was shown to specifically dephosphorylate the D3 position of the inositol ring of the lipid second messenger, phosphatidylinositol-3,4,5-triphosphate (PIP3). The lipid phosphatase domain contains the signature motif HCXXGXXR present in the active sites of protein tyrosine phosphatases (PTPs) and dual specificity phosphatases (DSPs). Furthermore, two invariant lysines are found only in the tensin-type phosphatase motif (HCKXGKXR) and are suspected to interact with the phosphate group at position D1 and D5 of the inositol ring .

The crystal structure of the PTEN tumour suppressor has been solved . The lipid phosphatase domain has a structure similar to the dual specificity phosphatase. However, PTEN has a larger active site pocket that could be important to accommodate PI(3,4,5)P3. The tensin-type C2 domain has a structure similar to the classical C2 domain that mediates the Ca2+-dependent membrane recruitment of several signalling proteins. However the tensin-type C2 domain lacks two of the three conserved loops that bind Ca2+.

Proteins known to contain a phosphatase and a C2 tensin-type domain are listed below:

Tensin, a focal-adhesion molecule that binds to actin filaments. It may be involved in cell migration, cartilage development and in linking signal transduction pathways to the cytoskeleton.

Phosphatase and tensin homologue deleted on chromosome 10 protein (PTEN). It antagonises PI 3-kinase signalling by dephosphorylating the 3-position of the inositol ring of PI(3,4,5)P3 and thus inactivates downstream signalling. It plays major roles both during development and in the adult to control cell size, growth, and survival.

Auxilin. It binds clathrin heavy chain and promotes its assembly into regular cages.

Cyclin G-associated kinase, or auxilin-2. It is a potential regulator of clathrin-mediated membrane trafficking.

PTEN homologues in fungi have the tensin phosphatase domain, but they lack the C2 domain.

This entry represents the phosphatase domain.
TerB-like (TerB-like)
Type: Homologous_superfamily

This multihelical domain can be found in the tellurium resistance protein TerB , uncharacterised protein PG1108 (

) and co-chaperone DjlA .
Type III secretion system substrate exporter, C-terminal (T3SS_substrate_exporter_C)
Type: Homologous_superfamily

Salmonella, and related proteobacteria, secrete large amounts of proteins into the culture media. The major secreted proteins are either flagellar proteins or virulence factors , secreted through the flagellar or virulence export structures respectively. Both secretion systems penetrate the inner and outer membranes and their components bear substantial sequence similarity. Both the flagellar and needle like pilus look fairly similar to each other .

The type III secretion system is of great interest, as it is used to transport virulence factors from the pathogen directly into the host cell and is only triggered when the bacterium comes into close contact with the host.

It is believed that the family of type III flagellar and pilus inner membrane proteins are used as structural moieties in a complex with several other subunits . One such set of inner membrane proteins, labeled "S" here for nomenclature purposes, includes the Salmonella and Shigella SpaS, the Yersinia YscU, Rhizobium Y4YO, and the Erwinia HrcU genes, Salmonella FlhB and Escherichia coli EscU .

This superfamily represent the C-terminal domain of the type III secretion system substrate exporters. Many of the proteins containing this domain undergo autocatalytic cleavage promoted by cyclisation of a conserved asparagine.
tRNA (guanine-N1-)-methyltransferase, N-terminal (tRNA_m1G_MTases_N)
Type: Homologous_superfamily

This entry represents the N-terminal domain of the tRNA (guanine-N1-)-methyltransferase. This domain forms a α/β knot structure that is extremely rare in protein structures as it poses a folding problem . This domain can also be found in the SPOUT superfamily members, including tRNA:Gm18 MTase TrmH .
Single alpha-helix domain superfamily (Single_a-helix_sf)
Type: Homologous_superfamily

This superfamily represents a single α-helix domain involved in coiled-coils or other helix-helix interfaces. It shares protein structural similarities with the cytochrome b-c1 complex subunit 10-like domain, which consists of single transmembrane helices .
Alpha/beta knot methyltransferases (Alpha/beta_knot_MTases)
Type: Homologous_superfamily

This entry represents a α/β knot structural domain that can be found in many RNA methyltransferases, including members from the SPOUT superfamily, EMG1/NEP1 methyltransferases and SAM-dependent RNA methyltransferases. The α/β knot structure is extremely rare in protein structures as it poses a folding problem .
Caspase-like domain superfamily (Caspase-like_dom_sf)
Type: Homologous_superfamily

This superfamily represents the caspase-like domain found in caspases, metacaspases and peptidases of the C25 family (gingipains).

Caspases (Cysteine-dependent ASPartyl-specific proteASE) are cysteine peptidases . They are tightly regulated proteins that require zymogen activation to become active, and once active can be regulated by caspase inhibitors. Caspases are mainly involved in mediating cell death (apoptosis) . They have two main roles within the apoptosis cascade: as initiators that trigger the cell death process, and as effectors of the process itself. Caspases can have roles other than in apoptosis, such as caspase-1 (interleukin-1 beta convertase) (

), which is involved in the inflammatory process. The activation of apoptosis can sometimes lead to caspase-1 activation, providing a link between apoptosis and inflammation, such as during the targeting of infected cells. Caspases may also be involved in cell differentiation .

Metacaspases are arginine/lysine-specific, in contrast to caspases, which are aspartate-specific. They are found only in plants , fungi and lower eukaryotes, including the protozoa . While plant metacaspases have been shown to be involved in cell death pathways, in other organisms they have evolved alternative functions .
Gingipain, N-terminal superfamily (Gingipain_N_sf)
Type: Homologous_superfamily

This superfamily represents a domain found at the N terminus of cysteine peptidases belonging to MEROPS peptidase family C25 (gingipain). Gingipains are cysteine proteinases acting as key virulence factors of the bacterium Porphyromonas gingivalis (Bacteroides gingivalis), a Gram-negative anaerobic bacterial species strongly associated with adult periodontitis . The gingipain subgroup contains extracellular Arg- and Lys-specific proteinases called Arg-gingipain (RgpA and RgpB) and Lys-gingipain (Kgp) , which are the major virulence factors of P. gingivalis .
AhpD-like (AhpD-like)
Type: Homologous_superfamily

This superfamily represents the α-helical domain found in alkyl-hydroperoxide reductase AhpD . AhpD is a component of alkyl-hydroperoxide reductase participating in defense against ROS (reactive oxygen species) . The C-terminal α-helical domain of the AhpD protein from Mycobacterium tuberculosis shares protein sequence and structural similarity with the N-terminal of Sesns from animals . Sestrins (Sesns) are involved in ROS (reactive oxygen species) regulation .
Histidine phosphatase superfamily (His_PPase_superfam)
Type: Homologous_superfamily

The histidine phosphatase superfamily is a large and functionally diverse group of proteins. They share a conserved catalytic core centred on a histidine which becomes phosphorylated during the course of the reaction. The superfamily is mainly composed of phosphatases, but the best-studied member is dPGM (cofactor-dependent phosphoglycerate mutase). The superfamily contains two branches sharing very limited sequence similarity: histidine phosphatase clade-1 and clade-2 .

The larger clade-1 contains a wide variety of catalytic functions, the best known being fructose 2,6-bisphosphatase (found in a bifunctional protein with 2-phosphofructokinase) and cofactor-dependent phosphoglycerate mutase. The latter is an unusual example of a mutase activity in the superfamily: the vast majority of members appear to be phosphatases. The bacterial regulatory protein phosphatase SixA is also in clade-1 and has a minimal, and possible ancestral-like structure, lacking the large domain insertions that contribute to binding of small molecules in clade-1 members.

The smaller clade-2 is composed mainly of acid phosphatases and phytases. Acid phosphatases are a heterogeneous group of proteins that hydrolyse phosphate esters, optimally at low pH. The catalytic functions of these proteins include phytase, glucose-1-phosphatase and multiple inositol polyphosphate phosphatase. Fungal phytases are histidine acid phosphatases that catalyse the hydrolysis of phytate (myo-inositol hexakisphosphate) to myo-inositol and inorganic phosphate .
Cystine-knot cytokine (Cystine-knot_cytokine)
Type: Homologous_superfamily

This cystine-knot cytokine domain is a disulfide-rich, all-β core domain that is found in glycoprotein hormones , in members of the TGF-beta family , IL-17 family and VEGF growth factor family among others.
DHS-like NAD/FAD-binding domain superfamily (DHS-like_NAD/FAD-binding_dom)
Type: Homologous_superfamily

This superfamily represents a domain which adopts a Rossmann fold, similar to the FAD/NAD(P)-binding Rossmann fold domain. However, there are differences between these two domains. Proteins with this DHS-like NAD/FAD-binding domain bind cofactor in the opposite direction and lack the conserved GxGxxG motif found in classical NADP binding Rossmann folds. It also forms an internal hydrogen bond in the FAD molecule .

This domain can be found in deoxyhypusine synthase (DHS), the C-terminal domain of the electron transfer flavoprotein alpha subunit, the central domain of the pyruvate oxidase and decarboxylase, transhydrogenase domain III (dIII), Sir2 family of transcriptional regulators and the CO dehydrogenase beta subunit/acetyl-CoA synthase epsilon subunit.
Pyrroline-5-carboxylate reductase, dimerisation domain (P5CR_dimer)
Type: Domain

Pyrroline-5-carboxylate reductase consists of two domains, an N-terminal catalytic domain and a C-terminal dimerisation domain. This entry represents the dimerisation domain .
DUF1407/YfgJ-like superfamily (DUF1407/YfgJ-like_sf)
Type: Homologous_superfamily

This entry represents a structural domain composed of two rubredoxin-like subdomains, interlocked together. It is found in uncharacterised protein YfgJ from E. coli (

) and DUF1407 family members.
Methionyl-tRNA synthetase, Zn-domain (MetRS_Zn)
Type: Homologous_superfamily

All methionyl-tRNA synthetases (MetRS) display a highly conserved catalytic core with a Rossmann fold, the two halves of which are linked by a connective peptide (CP) . In E. coli MetRS, a tightly bound zinc ion was shown to play a role in the folding of the CP region . This entry represents the CP region.
Flavoprotein-like superfamily (Flavoprotein-like_sf)
Type: Homologous_superfamily

Proteins in this entry contain a flavodoxin-like fold, which is characterised by an open twisted/α β structure consisting of five parallel β-sheets connected by α-helices which surround the sheet. Flavodoxins are electron-transfer proteins that function in various electron transport systems. They bind one FMN molecule, which serves as a redox-active prosthetic group and are functionally interchangeable with ferredoxins .
RNA polymerase subunit RPABC4/transcription elongation factor Spt4 (RPABC4/Spt4)
Type: Homologous_superfamily

This superfamily represents a domain which consists of a metal (zinc or iron)-bound fold. Its sequence contains two CX(n)C motifs. It is found in transcription elongation factor Spt4, and in RNA polymerase archaeal subunit P and eukaryotic subunit RPABC4.
FAD-linked oxidoreductase-like (FAD-linked_oxidoreductase-like)
Type: Homologous_superfamily

This superfamily represents a domain found in bacterial 5,10-methylenetetrahydrofolate reductases and eukaryotic Proline dehydrogenase 1 and Hydroxyproline dehydrogenases. It is also found at the N-terminal domain of the eukaryotic enzyme Methylenetetrahydrofolate reductase (NADPH) and the bacterial bifunctional protein putA.

Both eukaryotic and prokaryotic methylenetetrahydrofolate reductases generate 5-methyltetrahydrofolate from 5,10-methylenetetrahydrofolate, a cosubstrate for homocysteine remethylation to methionine . In humans, there are several clinically significant mutations in MTHFR that result in hyperhomocysteinemia, which is a risk factor for the development of cardiovascular disease .
Glycine cleavage T-protein/YgfZ, C-terminal (GcvT/YgfZ_C)
Type: Homologous_superfamily

This superfamily represents a β-barrel domain found at the C-terminal of the glycine cleavage T-protein (aminomethyltransferase) and in tRNA-modifying protein YgfZ. YgfZ binds folate and is likely to be a folate-dependent regulatory protein .
Nucleotide-diphospho-sugar transferases (Nucleotide-diphossugar_trans)
Type: Homologous_superfamily

The biosynthesis of disaccharides, oligosaccharides and polysaccharides involves the action of hundreds of different glycosyltransferases. These enzymes catalyse the transfer of sugar moieties from activated donor molecules to specific acceptor molecules, forming glycosidic bonds. A classification of glycosyltransferases using nucleotide diphospho-sugar, nucleotide monophospho-sugar and sugar phosphates ([ec:2.4.1.-]) and related proteins into distinct sequence based families has been described . This classification is available on the CAZy (CArbohydrate-Active EnZymes) web site. The same three-dimensional fold is expected to occur within each of the families. Because 3-D structures are better conserved than sequences, several of the families defined on the basis of sequence similarities may have similar 3-D structures and therefore form 'clans'.