SII-SWORD/CoKE huggingface dataset:
Fido-like domain superfamily (Fido-like_dom_sf)
Type: Homologous_superfamily

This globular domain is named fido after the Fic and Doc proteins where it is found. It is approximately 125 to 150 residues long, and is present in proteins from all kingdoms of life , including:

Fic (filamentation induced by cAMP) from diverse bacteria. It contains a longer insert in the fido domain.

Doc (death on curing) proteins from phage P1 and several bacteria. All these proteins contain a minimal stand-alone version of the fido domain.

HypE (Huntingtin associated protein E) from animal. In humans, HypE is thought to interact with Huntingtin, one of the major proteins in the Huntington's disease protein interaction network. Proteins related to HypE are also found in several bacteria and some archaea. HypE proteins contain a longer insert in their fido domain and are typically multidomain proteins.

Type IV secretion system effector AnkX from Legionella.

VopS, a type III secretion system effector from Vibrio that causes eukaryotic cell cytotoxicity.

IbpA (virulence factor p76) from Haemophilus somnus. It includes an N-terminal haemagglutination activity domain, two fido domains and a peptidase C58 domain.

BepA, an anti-apoptotic bacterial effector protein, which is a type IV secretion system substrate.

The fido domain of Vibrio VopS covalently modifies Rho GTPase threonine with AMP to inhibit downstream signaling events in host cells. The AMPylation activity extends to a eukaryotic fido domain in Drosophila fic homologue CG9523. AMPylation represents a newly discovered posttranslational modification used to stably modify proteins with AMP. This signaling mechanism is predicted to be functionally similar to other posttranslation modifications such as phosphorylation, SUMOylation or acetylation, because the added moiety changes the activity of the modified protein. The covalent attachment of AMP by a phosphodiester bond is predicted to be reversible and is bulky enough to provide a docking site for a putative AMP binding domain .

The fido domain contains a central motif conserved in most sequences (H-x-F-x-[DE]-[AG]-N-[GK]-R), with the motif His contributing to fic AMPylation. The fido domain adopts an α-helical fold, arranged as a six-helix up and down bundle .
GOLD domain superfamily (GOLD_dom_sf)
Type: Homologous_superfamily

The GOLD (for Golgi dynamics) domain is a protein module found in several eukaryotic Golgi and lipid-traffic proteins. It is typically between 90 and 150 amino acids long. Most of the size difference observed in the GOLD-domain superfamily is traceable to a single large low-complexity insert that is seen in some versions of the domain. With the exception of the p24 proteins, which have a simple architecture with the GOLD domain as their only globular domain, all other GOLD-domain proteins contain additional conserved globular domains. In these proteins, the GOLD domain co-occurs with lipid-, sterol-or fatty acid-binding domains such as PH, CRAL-TRIO, FYVE oxysterol binding-and acyl CoA-binding domains, suggesting that these proteins may interact with membranes. The GOLD domain can also be found associated with a RUN domain, which may have a role in the interaction of various proteins with cytoskeletal filaments. The GOLD domain is predicted to mediate diverse protein-protein interactions . A secondary structure prediction for the GOLD domain reveals that it is likely to adopt a compact all-β-fold structure with six to seven strands. Most of the sequence conservation is centred on the hydrophobic cores that support these predicted strands. The predicted secondary-structure elements and the size of the conserved core of the domain suggests that it may form a β-sandwich fold with the strands arranged in two β-sheets stacked on each other .

Some proteins known to contain a GOLD domain are listed below:

Eukaryotic proteins of the p24 family.

Animal Sec14-like proteins. They are involved in secretion.

Human Golgi resident protein GCP60. It interacts with the Golgi integral membrane protein Giantin.

Yeast oxysterol-binding protein homologue 3 (OSH3).

Plant Patellin 1-6. It may be involved in membrane-trafficking events .
DNA ligase, ATP-dependent, N-terminal domain superfamily (DNA_ligase_N_sf)
Type: Homologous_superfamily

DNA ligase (polydeoxyribonucleotide synthase) is the enzyme that joins two DNA fragments by catalysing the formation of an internucleotide ester bond between phosphate and deoxyribose. It is active during DNA replication, DNA repair and DNA recombination. There are two forms of DNA ligase, one requires ATP (

), the other NAD (

), the latter being restricted to eubacteria. Eukaryotic, archaebacterial, viral and some eubacterial DNA ligases are ATP-dependent. The first step in the ligation reaction is the formation of a covalent enzyme-AMP complex. The co-factor ATP is cleaved to pyrophosphate and AMP, with the AMP being covalently joined to a highly conserved lysine residue in the active site of the ligase. The activated AMP residue is then transferred to the 5'phosphate of the nick, before the nick is sealed by phosphodiester-bond formation and AMP elimination .

This domain superfamily is found in many but not all ATP-dependent DNA ligase enzymes (

). It is thought to be involved in DNA binding and in catalysis. In human DNA ligase I (

), and in Saccharomyces cerevisiae (Baker's yeast) (

), this region was necessary for catalysis, and separated from the amino terminus by targeting elements. In Vaccinia virus (

) this region was not essential for catalysis, but deletion decreases the affinity for nicked DNA and decreased the rate of strand joining at a step subsequent to enzyme-adenylate formation .
Paired amphipathic helix superfamily (PAH_sf)
Type: Homologous_superfamily

This entry represents the paired amphipathic helix (PAH) repeat. Sin3 proteins have at least three PAH domains (PAH1, PAH2, and PAH3) . They are components of a co-repressor complex that silences transcription, playing important roles in the transition between proliferation and differentiation. Sin3 proteins are recruited to the DNA by various DNA-binding transcription factors such as the Mad family of repressors, Mnt/Rox, PLZF, MeCP2, p53, REST/NRSF, MNFbeta, Sp1, TGIF and Ume6 . Sin3 acts as a scaffold protein that in turn recruits histone-binding proteins RbAp46/RbAp48 and histone deacetylases HDAC1/HDAC2, which deacetylate the core histones resulting in a repressed state of the chromatin . The PAH domains are protein-protein interaction domains through which Sin3 fulfils its role as a scaffold. The PAH2 domain of Sin3 can interact with a wide range of unrelated and structurally diverse transcription factors that bind using different interaction motifs. For example, the Sin3 PAH2 domain can interact with the unrelated Mad and HBP1 factors using alternative interaction motifs that involve binding in opposite helical orientations .

Structurally, PAH2 is composed of four helices arranged in an open up-and-down bundle fold which binds α-helical peptides.
CBM10 superfamily (CBM10_sf)
Type: Homologous_superfamily

Plant cell wall hydrolases from aerobic microorganisms generally have a modular structure consisting of a catalytic domain linked to one or more carbohydrate-binding modules (CBMs). CBMs function to attach the enzyme to the polymeric substrate, thereby increasing the catalytic activity. Most CBMs bind cellulose and are referred to as cellulose-binding domains (CBDs), while some can also bind xylan.
tRNA wybutosine-synthesizing-like superfamily (tRNA_yW-synthesising-like_sf)
Type: Homologous_superfamily

The methyltransferase TYW3 (tRNA-yW- synthesising protein 3) has been identified in yeast to be involved in wybutosine (yW) biosynthesis . yW is a complexly modified guanosine residue that contains a tricyclic base and is found at the 3'-position adjacent the anticodon of phenylalanine tRNA. TYW3 is an N-4 methylase that methylates yW-86 to yield yW-72 in an Ado-Met-dependent manner .
RNA polymerase, RBP11-like subunit (RBP11-like)
Type: Homologous_superfamily

RNA polymerase (RNAP) II, which is responsible for all mRNA synthesis in eukaryotes, consists of 12 subunits. Subunits Rpb3 and Rpb11 form a heterodimer that is functionally analogous to the archaeal RNAP D/L heterodimer, and the prokaryotic RNAP alpha subunit homodimer. In each case, they play a key role in RNAP assembly by forming a platform on which the catalytic subunits (eukaryotic Rpb1/Rpb2, and prokaryotic beta/beta') can interact . These different subunits share regions of homology. Rpb11 contains a domain (Rpb11-like domain) that is required for dimerisation, and binds to a homologous region on Rpb3. The Rpb11-like domain in Rpb11 and archaeal L subunits is contiguous, whereas in Rpb3, archaeal D, and prokaryotic alpha subunits (

), the Rpb11-like domain is interrupted by an insert domain (

). In the prokaryotic RNAP alpha subunit, the Rpb11-like domain and the insert domain form two subregions of the N-terminal domain.

The structure of the Rpb11-like domain consists of a two-layer α/β fold consisting of β(2)-α-β(2)-α. Rpb3 and Rpb11 in yeast RNAP have been shown to share a high degree of sequence and structural similarity to the alpha subunit of bacterial RNAP .
Phosphoribosylformylglycinamidine synthase subunit PurS-like superfamily (PurS-like_sf)
Type: Homologous_superfamily

Phosphoribosylformylglycinamidine(FGAM) synthetase,

, catalyses the fourth step in the de novo purine biosynthetic pathway .

5-phosphoribosylformylglycinamide (FGAR) + glutamine + ATP = FGAM + glutamate + ADP + Pi

In eukaryotes and many bacterial systems (including Escherichia coli and Salmonella typhimurium), the FGAM synthetase is encoded by the large form of PurL (lgPurL), which contains an N-terminal ATPase domain and a C-terminal glutamine-binding domain. In archaeal and other bacterial systems, however, FGAM synthetase is encoded by separate genes, making it a multisubunit (rather than multidomain) enzyme. The protein is composed of the small form of PurL (smPurL), which is homologus to the ATPase domain of lgPurL, PurQ which is homologous to the glutamine-binding domain of of lgPurL, and PurS, whose function is not known.

This entry represents the PurS subunit (also known as YexA) of the multisubunit FGAM synthetase. Recent studies showed that disruption of the purS gene in Bacillus subtilis resulted in a purine auxotrophic phenotype, due to defective FGAM synthetase activity . Therefore, the PurS protein appears to be required for the function of the PurL and PurQ subunits of the FGAM synthetase, but the molecular mechanism for the functional role of PurS is currently not known.
Mago nashi superfamily (Mago_nashi_sf)
Type: Homologous_superfamily

This superfamily was originally identified in Drosophila and called mago nashi, it is a strict maternal effect, grandchildless-like, gene . The protein is an integral member of the exon junction complex (EJC). The EJC is a multiprotein complex that is deposited on spliced mRNAs after intron removal at a conserved position upstream of the exon-exon junction, and transported to the cytoplasm where it has been shown to influence translation, surveillance, and localization of the spliced mRNA. It consists of four core proteins (eIF4AIII, Barentsz [Btz], Mago, and Y14), mRNA, and ATP and is supposed to be a binding platform for more peripherally and transiently associated factors along mRNA travel. Mago and Y14 form a stable heterodimer that stabilizes the complex by inhibiting eIF4AIII's ATPase activity. Mago-Y14 heterodimer has been shown to interact with the cytoplasmic protein PYM, an EJC disassembly factor, and specifically binds to the karyopherin nuclear receptor importin 13 .

The human homologue has been shown to interact with an RNA binding protein, ribonucleoprotein rbm8 (

) . An RNAi knockout of the Caenorhabditis elegans homologue causes masculinization of the germ line (Mog phenotype) hermaphrodites, suggesting it is involved in hermaphrodite germ-line sex determination but the protein is also found in hermaphrodites and other organisms without a sexual differentiation.

Structurally, Mago nashi has a β(4)-α-β(2)-α fold arranged into two layers (α/β) with an antiparallel β-sheet.
EhaM-like superfamily (EhaM-like_sf)
Type: Homologous_superfamily

Energy converting hydrogenase A (eha) and B (ehb) encode putative multisubunit membrane-bound [NiFe] hydrogenases in Methanobacterium thermoautotrophicum. Eha and Ehb hydrogenases contain extra subunits in addition to those shared by other energy-converting [NiFe] hydrogenases (or [NiFe]-hydrogenase-3-type). Eha contains a 6[4Fe-4S] polyferredoxin, a 10[4F-4S] polyferredoxin, ten other predicted integral membrane proteins and four Hydrophilic subunits (EhaM, EhaR, EhS, EhT) . Eha and Ehb catalyse the reduction of low-potential redox carriers (e.g. ferredoxins or polyferredoxins), which then might function as electron donors to oxidoreductases.

This superfamily describes the hydrophilic EhaM subunit of Eha-type energy-converting [NiFe] hydrogenase complexes.
Glucosidase 2 subunit beta-like (PRKCSH)
Type: Domain

The sequences found in this entry are similar to a region found in the beta-subunit of glucosidase II (

), which is also known as protein kinase C substrate 80K-H (PRKCSH). The enzyme catalyses the sequential removal of two alpha-1,3-linked glucose residues in the second step of N-linked oligosaccharide processing . The beta subunit is required for the solubility and stability of the heterodimeric enzyme, and is involved in retaining the enzyme within the endoplasmic reticulum . The beta-subunit confers substrate specificity for di- and monoglucosylated glycans on the glucose-trimming activity of the alpha-subunit .
MTH777-like superfamily (MTH777-like_sf)
Type: Homologous_superfamily

The structure of the Methanothermobacter thermautotrophicus (Methanobacterium thermoformicicum) protein MT0777 has been determined (

) and consists of a 3-layer(α-β-α) sandwich. No evidence for the function of this protein or its homologues is available yet.
LCCL domain superfamily (LCCL_sf)
Type: Homologous_superfamily

The LCCL domain has been named after the best characterised proteins that were found to contain it, namely Limulus factor C, Coch-5b2 and Lgl1. It is an about 100 amino acids domain whose C-terminal part contains a highly conserved histidine in a conserved motif YxxxSxxCxAAVHxGVI. The LCCL module is thought to be an autonomously folding domain that has been used for the construction of various modular proteins through exon-shuffling. It has been found in various metazoan proteins in association with complement B-type domains, C-type lectin domains, von Willebrand type A domains, CUB domains, discoidin lectin domains or CAP domains. It has been proposed that the LCCL domain could be involved in lipopolysaccharide (LPS) binding . Secondary structure prediction suggests that the LCCL domain contains six β strands and two α helices . The structure of the LCCL domain from human Coch-5b2 has been solved. It has an unusual fold, where a centrally located helix is wrapped by extended polypeptide segments of mostly irregular secondary structure .

Some proteins known to contain a LCCL domain include Limulus factor C, a LPS endotoxin-sensitive trypsin type serine protease which serves to protect the organism from bacterial infection; vertebrate cochlear protein cochlin or coch-5b2 (Cochlin is probably a secreted protein, mutations affecting the LCCL domain of coch-5b2 cause the deafness disorder DFNA9 in humans); and mammalian late gestation lung protein Lgl1, contains two tandem copies of the LCCL domain .
PEBP-like superfamily (PEBP-like_sf)
Type: Homologous_superfamily

The PEBP (PhosphatidylEthanolamine-Binding Protein) superfamily is a highly conserved group of proteins that have been identified in numerous tissues in a wide variety of organisms, including bacteria, yeast, nematodes, plants, drosophila and mammals. The various functions described for members of this family include lipid binding, neuronal development , serine protease inhibition , the control of the morphological switch between shoot growth and flower structures , and the regulation of several signalling pathways such as the MAP kinase pathway , and the NF-kappaB pathway . The control of the latter two pathways involves the PEBP protein RKIP, which interacts with MEK and Raf-1 to inhibit the MAP kinase pathway, and with TAK1, NIK, IKKalpha and IKKbeta to inhibit the NF-kappaB pathway. Other PEBP-like proteins that show strong structural homology to PEBP include Escherichia coli YBHB and YBCL, the Rattus norvegicus (Rat) neuropeptide HCNP, and Antirrhinum majus (Garden snapdragon) protein centroradialis (CEN).
Trigger factor ribosome-binding domain superfamily (Trigger_fac_ribosome-bd_sf)
Type: Homologous_superfamily

In the Escherichia coli cytosol, a fraction of the newly synthesised proteins requires the activity of molecular chaperones for folding to the native state. The major chaperones implicated in this folding process are the ribosome-associated Trigger Factor (TF), and the DnaK and GroEL chaperones with their respective co-chaperones. Trigger Factor is an ATP-independent chaperone and displays chaperone and peptidyl-prolyl-cis-trans-isomerase (PPIase) activities
in vitro
. It is composed of at least three domains, an N-terminal domain which mediates association with the large ribosomal subunit, a central substrate binding and PPIase domain with homology to FKBP proteins, and a C-terminal domain of unknown function. The positioning of TF at the peptide exit channel, together with its ability to interact with nascent chains as short as 57 residues renders TF a prime candidate for being the first chaperone that binds to the nascent polypeptide chains . This group of sequences contain the ribosomal subunit association domain.
K Homology domain, type 1 superfamily (KH_dom_type_1_sf)
Type: Homologous_superfamily

The K homology (KH) domain was first identified in the human heterogeneous nuclear ribonucleoprotein (hnRNP) K. It is a domain of around 70 amino acids that is present in a wide variety of quite diverse nucleic acid-binding proteins . It has been shown to bind RNA . Like many other RNA-binding motifs, KH motifs are found in one or multiple copies (14 copies in chicken vigilin) and, at least for hnRNP K (three copies) and FMR-1 (two copies), each motif is necessary for
in vitro
RNA binding activity, suggesting that they may function cooperatively or, in the case of single KH motif proteins (for example, Mer1p), independently .

According to structural analysis the KH domain can be separated in two groups. The first group or type-1 contain a β-α-α-β-β-α structure, whereas in the type-2 the two last β-sheet are located in the N-terminal part of the domain (α-β-β-α-α-β). Sequence similarity between these two folds are limited to a short region (VIGXXGXXI) in the RNA binding motif. This motif is located between helices 1 and 2 in type-1 and between helices 2 and 3 in type-2. Proteins known to contain a type-1 KH domain include bacterial polyribonucleotide nucleotidyltransferase (

); vertebrate Fragile X messenger ribonucleoprotein 1 (FMR1); eukaryotic heterogeneous nuclear ribonucleoprotein K (hnRNP K), one of at least 20 major proteins that are part of hnRNP particles in mammalian cells; mammalian poly(rC) binding proteins; Artemia salina glycine-rich protein GRP33; yeast PAB1-binding protein 2 (PBP2); vertebrate vigilin; and human high-density lipoprotein binding protein (HDL-binding protein).
MHC class II-associated invariant chain, trimerisation domain superfamily (MHCII_invariant_trimer_sf)
Type: Homologous_superfamily

Newly synthesized MHCII proteins associate with a chaperone protein called the invariant chain (Ii) and form a nonameric complex (alpha3beta3Ii3) in the endoplasmic reticulum . Ii plays a critical role in the assembly of the MHC, as well as in MHC II antigen processing by stabilising peptide-free class II alpha/beta heterodimers in a complex soon after their synthesis and directing transport of the complex from the endoplasmic reticulum to compartments where peptide loading of class II takes place . In antigen-presenting cells (APCs), loading of MHC II molecules with peptides is regulated by Ii, which blocks MHC II antigen-binding sites in pre-endosomal compartments . Several molecules then act upon MHC II molecules in endosomes to facilitate peptide loading: Ii-degrading proteases, the peptide exchange factor, human leukocyte antigen-DM (HLA-DM), and its modulator, HLA-DO (DO).

Ii first assembles into a trimer and then associates with three class II alpha/beta MHC heterodimers. This entry represents the trimerisation domain of Ii. Its structure has been determined by NMR .
Holliday junction resolvase RusA-like superfamily (RusA-like_sf)
Type: Homologous_superfamily

This superfamily consists of several bacterial and phage Holliday junction resolvase (RusA) like proteins. The RusA protein of Escherichia coli is an endonuclease that can resolve Holliday intermediates and correct the defects in genetic recombination and DNA repair associated with inactivation of RuvAB or RuvC .
Mur ligase, C-terminal domain superfamily (Mur_ligase_C_dom_sf)
Type: Homologous_superfamily

This entry represents the C-terminal domain superfamily from all four stage 2 Mur enzymes: UDP-N-acetylmuramate-L-alanine ligase (MurC), UDP-N-acetylmuramoylalanine-D-glutamate ligase (MurD), UDP-N-acetylmuramoylalanyl-D-glutamate-2,6-diaminopimelate ligase (MurE), and UDP-N-acetylmuramoyl-tripeptide-D-alanyl-D-alanine ligase (MurF). This entry also includes the C-terminal domain of folylpolyglutamate synthase that transfers glutamate to folylpolyglutamate and cyanophycin synthetase that catalyses the biosynthesis of the cyanobacterial reserve material multi-L-arginyl-poly-L-aspartate (cyanophycin) .

The C-terminal domain superfamily is almost always associated with the cytoplasmic peptidoglycan synthetases, N-terminal domain superfamily (see

).

The bacterial cell wall provides strength and rigidity to counteract internal osmotic pressure, and protection against the environment. The peptidoglycan layer gives the cell wall its strength, and helps maintain the overall shape of the cell. The basic peptidoglycan structure of both Gram-positive and Gram-negative bacteria is comprised of a sheet of glycan chains connected by short cross-linking polypeptides. Biosynthesis of peptidoglycan is a multi-step (11-12 steps) process comprising three main stages:

(1) formation of UDP-N-acetylmuramic acid (UDPMurNAc) from N-acetylglucosamine (GlcNAc).

(2) addition of a short polypeptide chain to the UDPMurNAc.

(3) addition of a second GlcNAc to the disaccharide-pentapeptide building block and transport of this unit through the cytoplasmic membrane and incorporation into the growing peptidoglycan layer.

Stage two involves four key Mur ligase enzymes: MurC (

) , MurD (

) , MurE (

) and MurF (

) . These four Mur ligases are responsible for the successive additions of L-alanine, D-glutamate, meso-diaminopimelate or L-lysine, and D-alanyl-D-alanine to UDP-N-acetylmuramic acid . All four Mur ligases are topologically similar to one another, even though they display low sequence identity. They are each composed of three domains: an N-terminal Rossmann-fold domain responsible for binding the UDPMurNAc substrate; a central domain (similar to ATP-binding domains of several ATPases and GTPases); and a C-terminal domain (similar to dihydrofolate reductase fold) that binds the incoming amino acid . Residues found in the three domains (the Asp50, Lys130 (GKT motif), and Glu174 residues, MurC numbering) are involved in the catalytic process . The conserved sequence motifs found in the four Mur enzymes also map to other members of the Mur ligase family, including folylpolyglutamate synthetase, cyanophycin synthetase and the capB enzyme from Bacillales .