SII-SWORD/CoKE huggingface dataset:
HEPN domain (HEPN_dom)
Type: Domain

The HEPN (higher eukaryotes and prokaryotes nucleotide-binding) domain is a region of 110 residues found in the C terminus of sacsin, a chaperonin implicated in an early-onset neurodegenerative disease in human, and in many bacterial and archeabacterial proteins. There are three classes of proteins with HEPN domain:

Single-domain HEPN proteins found in many bacteria.

Two-domain proteins with N-terminal nucleotidyltransferase (NT) and C- terminal HEPN domains. This N-terminal NT domain belongs to a large family of NTs, which includes several classes of enzymes that are responsible for some types of bacterial resistance to aminoglycosides. These enzymes deactivate various antibiotics by transferring a nucleotidyl group to the drug.

A multidomain sacsin protein in genomes of fish and mammals. The HEPN domain is located at the C terminus of the protein, directly after the DnaJ domain (

).

The crystal structure of the HEPN domain from the TM0613 protein of Thermotoga maritima indicates that it is structurally similar to the C-terminal all- α-helical domain of kanamycin nucleotidyltransferases (KNTases). It is composed of five α helices, three of which form an up- and-down helical bundle, with a pair of short helices on the side. The distant structural similarity suggests that the HEPN domain might be involved in nucleotide binding .
AsmA (AsmA)
Type: Domain

The AsmA protein is involved in the assembly of outer membrane proteins in Escherichia coli . AsmA mutations were isolated as extragenic suppressors of an OmpF assembly mutant . AsmA may have a role in LPS biogenesis .
Haemin-degrading HemS/ChuX domain (HemS/ChuX_dom)
Type: Domain

The Yersinia enterocolitica O:8 periplasmic binding protein-dependent transport system consisted of four proteins: the periplasmic haemin-binding protein HemT, the haemin permease protein HemU, the ATP-binding hydrophilic protein HemV and the haemin-degrading protein HemS. The structure for HemS has been solved and consists of a tandem repeat of the domain represented in this entry.
RNA-recognition motif (RRM) Nup35-type domain (RRM_NUP35_dom)
Type: Domain

The nuclear pore complex (NPC) mediates the transport of macromolecules across the nuclear envelope (NE). The NPC is composed of a relatively small number of proteins (~30), termed nucleoporins or Nups. The vertebrate nuclear pore protein Nup35, the ortholog of Saccharomyces cerevisiae Nup53p, is suggested to interact with the NE membrane and to be required for nuclear morphology. The highly conserved region between vertebrate Nup35 and yeast Nup53p is predicted to contain an RNA-recognition motif (RRM) domain.

The sequences of the RRM Nup-35-type domain are highly conserved in all eucaryotes. The RRM Nup35-type domain adopts the characteristic BetaAlphaBeta BetaAlphaBeta topology of the secondary structure elements, with a four- stranded antiparallel β-sheet packed against two α helices. The RRM Nup35-type domain forms a homodimer and contains atypical rinonucleoprotein (RNP) motifs, which lack the conserved residues that typically bind RNA in canonical RRM domains. The dimer interface involves the β-sheet surface, with its atypical RNP motifs, which is generally used to bind RNA in typical RRM domains .

This entry represents the RRM Nup35-type domain.
Methyltransferase small domain (Small_mtfrase_dom)
Type: Domain

This domain is found in ribosomal RNA small subunit methyltransferase C and in other methyltransferases.
ATPase assembly factor ATP10 (ATP10)
Type: Family

This entry includes ATPase complex subunit ATP10, mostly from yeasts and plants. In budding yeasts, ATP10 is a mitochondria protein that is essential for the assembly of the mitochondrial F1-F0 complex . It assists assembly of Atp6 into the F0 unit of the yeast mitochondrial ATPase .
RCSD (RCSD)
Type: Domain

Proteins containing this region include Caenorhabditis elegans, UNC-89. This region is found repeated in UNC-89 and shows conservation in prolines, lysines and glutamic acids. Proteins with RCSD are involved in muscle M-line assembly, but the function of this region RCSD is not clear.
Cdc73/Parafibromin (Cdc73/Parafibromin)
Type: Family

This entry includes Cdc73 from budding yeasts and its animal homologue, parafibromin. They are part of the Paf1 complex involved in histone modifications, transcription elongation and other gene expression processes that include transcript site selection .

In budding yeasts, Paf1 is an RNA polymerase II-associated protein complex containing Paf1, Cdc73, Ctr9, Rtf1 and Leo1. It is required for full expression of a subset of yeast genes, particularly those responsive to signals from the Pkc1/MAP kinase cascade. The complex appears to play an essential role in RNA elongation .

Human parafibromin is a tumour suppressor that may facilitate association of 3' mRNA processing factors with actively-transcribed chromatin. It is a component of the human Paf1 complex (Paf1C), which consists of Paf1, Cdc73, Ctr9, Rtf1, Leo1 and Wdr61 (Ski8). As in yeast, the human Paf1C has a central role in co-transcriptional histone modifications .
Zinc finger, DNL-type (Znf_DNL-typ)
Type: Domain

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.

The DNL-type zinc finger is found in Tim15, a zinc finger protein essential for protein import into mitochondria. Mitochondrial functions rely on the correct transport of resident proteins synthesized in the cytosol to mitochondria. Protein import into mitochondria is mediated by membrane protein complexes, protein translocators, in the outer and inner mitochondrial membranes, in cooperation with their assistant proteins in the cytosol, intermembrane space and matrix. Proteins destined to the mitochondrial matrix cross the outer membrane with the aid of the outer membrane translocator, the tOM40 complex, and then the inner membrane with the aid of the inner membrane translocator, the TIM23 complex, and mitochondrial motor and chaperone (MMC) proteins including mitochondrial heat- shock protein 70 (mtHsp70), and translocase in the inner mitochondrial membrane (Tim)15. Tim15 is also known as zinc finger motif (Zim)17 or mtHsp70 escort protein (Hep)1. Tim15 contains a zinc-finger motif (CXXC and CXXC) of ~100 residues, which has been named DNL after a short C-terminal motif of D(N/H)L .

The DNL-type zinc finger is an L-shaped molecule. The two CXXC motifs are located at the end of the L, and are sandwiched by two- stranded antiparallel β-sheets. Two short α-helices constitute another leg of the L. The outer (convex) face of the L has a large acidic groove, which is lined with five acidic residues, whereas the inner (concave) face of the L has two positively charged residues, next to the CXXC motifs .

This entry represents the DNL-type zinc finger.
Pre-mRNA polyadenylation factor Fip1 domain (Fip1_dom)
Type: Domain

This short motif is about 40 amino acids in length and is found in the Fip1 protein that is a component of a Saccharomyces cerevisiae pre-mRNA polyadenylation factor that directly interacts with poly(A) polymerase . This region of Fip1 is needed for the interaction with the Yth1 subunit of the complex and for specific polyadenylation of the cleaved mRNA precursor .
RNA-dependent RNA polymerase, eukaryotic-type (RNA-dep_RNA_pol_euk-typ)
Type: Family

This entry represents various eukaryotic RNA-dependent RNA polymerases (RDRP;

), such as RCRP-1, RDRP-2 and RDRP-6. These enzymes are involved in the amplification of regulatory microRNAs during post-transcriptional gene silencing ; they are also required for transcriptional gene silencing. Double-stranded RNA has been shown to induce gene silencing in diverse eukaryotes and by a variety of pathways . These enzymes also play a role in the RNA interference (RNAi) pathway, which is important for heterochromatin formation, accurate chromosome segregation, centromere cohesion and telomere function during mitosis and meiosis. RDRP enzymes are highly conserved in most eukaryotes, but are missing in archaea and bacteria. The core catalytic domain of RDRP enzymes is structurally similar to the beta' subunit of DNA-dependent RNA polymerases (DDRP), however the other domains of DDRP show no similarity to those of RDRP.

This entry also includes QDE-1 from the filamentous fungus Neurospora. QDE-1 is both an RdRP and a DNA-dependent RNA polymerase (DdRP). It is able to synthesize RNA from both ssRNA and single-stranded DNA (ssDNA) .
Saposin-like type B, region 1 (SapB_1)
Type: Domain

Synonym(s):cerebroside sulphate activator, CSAct

Saposin B is a small non-enzymatic glycoprotein required for the breakdown of cerebroside sulphates (sulphatides) in lysosomes. Saposin B contains three intramolecular disulphide bridges, exists as a dimer and is remarkably heat, protease, and pH stable. The crystal structure of human saposin B reveals an unusual shell-like dimer consisting of a monolayer of α-helices enclosing a large hydrophobic cavity. Although the secondary structure of saposin B is similar to that of the known monomeric members of the saposin-like superfamily, the helices are repacked into a different tertiary arrangement to form the homodimer. A comparison of the two forms of the saposin B dimer suggests that extraction of target lipids from membranes involves a conformational change that facilitates access to the inner cavity .
Protein arginine N-methyltransferase PRMT5 (Arg_MeTrfase_PRMT5)
Type: Family

This entry represents a group of arginine N-methyltransferases, including Skb1 from S. pombe , Hsl7 from S. cerevisiae and their homologues PRMT5 from animals and plants . Skb1 is a mediator of hyperosmotic stress response in Schizosaccharomyces pombe . Plant PMRT15 is involved in the post-transcriptional regulation of the circadian clock . Human PRMT5 is a component of multiple protein complexes and contributes to essential cellular processes, such as RNA transport and splicing, cell cycle regulation, tumour growth, and chromatin remodelling, leading to either gene silencing or activation .
Dpy-30 motif (Dpy-30_motif)
Type: Conserved_site

This motif is about 40 residues long and is probably formed of two α-helices. It is found in the Dpy-30 proteins, hence the motifs name. Dpy-30 from
Caenorhabditis elegans is an essential component of dosage compensation machinery and loss of dpy-30 activity results in XX-specific lethality; in XO animals, Dpy-30 is required for developmental processes other than dosage compensation . In yeast, the homologue of DPY-30, Saf19p, functions as part of the Set1 complex that is necessary for the methylation of histone H3 at lysine residue 4; Set1 is a key part of epigenetic developmental control . There is also a human homologue of Dpy-30 . This Dpy-30 region may be a dimerisation motif analogous that found in the cAMP-dependent protein kinase regulator, type II PKA, R subunit

.
ETF-QO/FixX, C-terminal domain (ETF-QO/FixX_C)
Type: Domain

This domain is found at the C-terminal of Electron-transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO), which accepts electrons from a electron-transfer flavoprotein that is located in the mitochondrial matrix and reduces ubiquinone in the mitochondrial membrane. The two redox centres in the protein, FAD and a [4Fe4S] cluster, are present in a 64kDa monomer .

This entry also includes some ferredoxin-like proteins, such as FixX from bacteria.
DNA mismatch repair protein MutS, connector domain (DNA_mmatch_repair_MutS_con_dom)
Type: Domain

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

This entry represents the connector domain (domain 2) found in proteins of the MutS family. The structure of the MutS connector domain consists of a parallel β-sheet surrounded by four α helices, which is similar to the structure of the Holliday junction resolvase ruvC.
DNA mismatch repair protein MutS, clamp (DNA_mismatch_repair_MutS_clamp)
Type: Domain

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

This entry represents the clamp domain (domain 4) found in proteins of the MutS family. The clamp domain is inserted within the core domain at the top of the lever helices. It has a β-sheet structure .
Adenylate kinase, active site lid domain (Adenylate_kinase_lid-dom)
Type: Domain

Adenylate kinases (ADK;

) are phosphotransferases that catalyse the Mg-dependent reversible conversion of ATP and AMP to two molecules of ADP, an essential reaction for many processes in living cells. In large variants of adenylate kinase, the AMP and ATP substrates are buried in a domain that undergoes conformational changes from an open to a closed state when bound to substrate; the ligand is then contained within a highly specific environment required for catalysis. Adenylate kinase is a 3-domain protein consisting of a large central CORE domain flanked by a LID domain on one side and the AMP-binding NMPbind domain on the other . The LID domain binds ATP and covers the phosphates at the active site. The substrates first bind the CORE domain, followed by closure of the active site by the LID and NMPbind domains.

Comparisons of adenylate kinases have revealed a particular divergence in the active site lid. In some organisms, particularly the Gram-positive bacteria, residues in the lid domain have been mutated to cysteines and these cysteine residues (two CX(n)C motifs) are responsible for the binding of a zinc ion. The bound zinc ion in the lid domain is clearly structurally homologous to Zinc-finger domains. However, it is unclear whether the adenylate kinase lid is a novel zinc-finger DNA/RNA binding domain, or that the lid bound zinc serves a purely structural function .
Peptidase M16, C-terminal (Peptidase_M16_C)
Type: Domain

These metallopeptidases belong to MEROPS peptidase family M16 (clan ME). They include proteins, which are classified as non-peptidase homologues either have been found experimentally to be without peptidase activity, or lack amino acid residues that are believed to be essential for the catalytic activity.

The peptidases in this group of sequences include:

Insulinase, insulin-degrading enzyme (

)

Mitochondrial processing peptidase alpha subunit, (Alpha-MPP,

)

Pitrlysin, Protease III precursor (

)

Nardilysin, (

)

Ubiquinol-cytochrome C reductase complex core protein I,mitochondrial precursor (

)

Coenzyme PQQ synthesis protein F (

)

These proteins do not share many regions of sequence similarity; the most noticeable is in the N-terminal section. This region includes a conserved histidine followed, two residues later by a glutamate and another histidine. In pitrilysin, it has been shown that this H-x-x-E-H motif is involved in enzymatic activity; the two histidines bind zinc and the glutamate is necessary for catalytic activity. The mitochondrial processing peptidase consists of two structurally related domains. One is the active peptidase whereas the other, the C-terminal region, is inactive. The two domains hold the substrate like a clamp .
Urease accessory protein UreE, C-terminal domain (UreE_C_dom)
Type: Domain

Urease and other nickel metalloenzymes are synthesised as precursors devoid of the metalloenzyme active site. These precursors then undergo a complex post-translational maturation process that requires a number of accessory proteins.

Members of this family are nickel-binding proteins required for urease metallocentre assembly . They are believed to function as metallochaperones to deliver nickel to urease apoprotein . It has been shown by yeast two-hybrid analysis that UreE forms a dimeric complex with UreG in Helicobacter pylori . The UreDFG-apoenzyme complex has also been shown to exist and is believed to be, with the addition of UreE, the assembly system for active urease . The complexes, rather than the individual proteins, presumably bind to UreB via UreE/H recognition sites.

The structure of Klebsiella aerogenes UreE reveals a unique two-domain architecture.The N-terminal domain is structurally related to a heat shock protein, while the C-terminal domain shows homology to the Atx1 copper metallochaperone . Significantly, the metal-binding sites in UreE and Atx1 are distinct in location and types of residues despite the relationship between these proteins and the mechanism for UreE activation of urease is proposed to be different from the thiol ligand exchange mechanism used by the copper metallochaperones.

The C-terminal domain of this protein is the metal-binding region, which can bind up to six Ni molecules per dimer. Most members of this group contain a histidine-rich C-terminal motif that is involved in, but not solely responsible for, binding nickel ions in K. aerogenes UreE . However, internal ligands, not the histidine residues at the C terminus, are necessary for UreE to assist in urease activation in K. aerogenes , even though the truncated protein lacking the His-rich region binds two nickel ions instead of six. In H. pylori and some other organisms, the terminal histidine-rich binding sites are absent, but the internal histidine sites are present, and the latter probably function as nickel donors. Deletion analysis shows that this domain alone is sufficient for metal-binding and activation of urease .
Aminopeptidase P, N-terminal (Aminopep_P_N)
Type: Domain

This entry represents the N-terminal domain of aminopeptidase P (X-Pro aminopeptidase I,II and III

) and related sequences belonging to the peptidase M24B family. The domain is structurally very similar to the creatinase N-terminal domain (

).
TRIC channel (TRIC_channel)
Type: Family

TRIC (trimeric intracellular cation) channels are differentially expressed in intracellular stores in animal cell types. TRIC subtypes contain three proposed transmembrane segments, and form homo-trimers with a bullet-like structure. Electrophysiological measurements with purified TRIC preparations identify a monovalent cation-selective channel .
Glucose-methanol-choline oxidoreductase, C-terminal (GMC_OxRtase_C)
Type: Domain

The glucose-methanol-choline (GMC) oxidoreductases are FAD flavoproteins oxidoreductases . These enzymes include a variety of proteins; choline dehydrogenase (CHD), methanol oxidase (MOX) and cellobiose dehydrogenase (

) which share a number of regions of sequence similarities. The function of this C-terminal conserved domain is not yet known.
Hom-end-associated Hint (Hom_end_hint)
Type: Domain

Homing endonucleases are encoded by mobile DNA elements that are found inserted within host genes in all domains of life. The crystal structure of the homing nuclease PI-Sce revealed two domains: an endonucleolytic centre resembling the C-terminal domain of Drosophila melanogaster Hedgehog protein, and a second domain containing the protein-splicing active site. This domain corresponds to the protein-splicing domain.
Homing endonuclease PI-Sce (Homing_endonuc_PI-Sce)
Type: Domain

Homing endonucleases are encoded by mobile DNA elements that are found inserted within host genes in all domains of life. The crystal structure of the homing nuclease PI-Sce revealed two domains: an endonucleolytic centre resembling the C-terminal domain of Drosophila melanogaster Hedgehog protein, and a second domain containing the protein-splicing active site.
Methyltransferase TRM13 (Methyltransferase_TRM13)
Type: Domain

This entry consists of eukaryotic and bacterial proteins that specifically methylates guanosine-4 in various tRNAs with a Gly(CCG), His or Pro signatures . The alignment contains some conserved cysteines and histidines that might form a zinc binding site.