SII-SWORD/CoKE huggingface dataset:
RelA/SpoT (RelA_SpoT)
Type: Domain

This entry includes the catalytic domains of Escherichia coli ppGpp synthetase (RelA), ppGpp synthetase/hydrolase (SpoT), and related proteins. The functions of Escherichia coli RelA and SpoT differ somewhat. RelA (

) produces pppGpp (or ppGpp) from ATP and GTP (or GDP) in response to amino-acid starvation and in association with ribosomes . SpoT (

) degrades ppGpp, but may also act as a secondary ppGpp synthetase under carbon limitation in a ribosome-independent manner . Gram-negative bacteria have two enzymes involved in (p)ppGpp metabolism while most Gram-positive organisms have a single Rel-Spo enzyme (Rel), which both synthesizes and degrades (p)ppGpp . The Arabidopsis thaliana Rel-Spo proteins, At-RSH1, At-RSH2, and At-RSH3 appear to regulate a rapid (p)ppGpp-mediated response to pathogens and other stresses . This catalytic domain is found in association with an N-terminal HD domain and a C-terminal metal dependent phosphohydrolase domain (TGS). Some Rel-Spo proteins also have a C-terminal regulatory ACT domain. This subgroup belongs to the Pol beta-like NT superfamily .

In the Pol beta-like NT superfamily , the majority of enzymes have two carboxylates, Dx[D/E], together with a third more distal carboxylate, which coordinate two divalent metal cations involved in a two-metal ion mechanism of nucleotide addition. These carboxylate residues are fairly well conserved in this family.
YutG/PgpA domain (YutG/PgpA)
Type: Domain

This domain consists of a bundle of six α-helices where one central helix is surrounded by five others. It is found in uncharacterised proteins, including YutG from Bacillus subtilis (

), putative phosphatidylglycerophosphatases and bacterial phosphatidylglycerophosphatase PgpA .
Methyl-coenzyme M reductase, protein C (Me_CoM_Rdtase_prot-C)
Type: Family

Members of this protein family are protein C, a non-structural protein, of the operon for methyl coenzyme M reductase , also called coenzyme-B sulfoethylthiotransferase (

). That enzyme, with alpha, beta, and gamma subunits, catalyzes the last step in methanogenesis; it has several modified sites, so accessory proteins are expected. Several methanogens have encode two such enzymes, designated I and II; this protein occurs only operons of type I. The precise function is unknown .
Plasmid conjugal transfer TrbL/VirB6 (Conjugal_tfr_TrbL/VirB6)
Type: Family

VirB proteins are suggested to act at the bacterial surface and there play an important role in directing t-DNA transfer to plant cells. VirB6 from Agrobacterium tumefaciens is an essential component of the type IV secretion machinery for T pilus formation and genetic transformation of plants. Absence of VirB6 leads to reduced cellular levels of VirB5 and VirB3, which were proposed to assist T pilus formation as minor component(s) or assembly factor(s), respectively .
A-alpha-Y mating type-dependent binding domain (AalphaY_mating_typ-dep-bd-dom)
Type: Domain

Mating-type protein A-alpha specifies the A-alpha-Y mating type. The A-alpha-Y protein binds to the AalphaZ protein of another mating type in Schizophyllum commune and may also regulate gene expression of the homokaryotic cell.
Type II secretion system protein GspM (T2SS_GspM)
Type: Family

GspM is part of the inner membrane component of the type II secretion system (T2SS). It consists of a short cytosolic N-terminal domain, a transmembrane domain, and a C-terminal periplasmic domain. The precise function of this protein is unknown . However, though in Vibrio cholerae, the EpsM protein interacts with the EpsL protein, and also forms homodimers .

The type II secretion system (T2SS) is one of several extracellular secretion systems in gram-negative bacteria. It delivers toxins and a range of hydrolytic enzymes including proteases, lipases and carbohydrate-active enzymes to the cell surface or extracellular space . T2SS systems are composed of 11 to 15 different proteins, which are generally called GspA to GspO and GspS. The T2SS spans the two bacterial membranes and ensures secretion of folded proteins across the outer membrane pore formed by GspD. The inner membrane complex contains GspC, GspL, GspM, and GspF. The cytoplasmic domains of GspL and GspF interact with an ATPase, GspE. GspE is thought to energize the formation of a short pseudopilus by several pilin-like proteins, GspG to GspK . GspD has been shown to interact with the inner membrane component GspC .
UDP-3-O-[3-hydroxymyristoyl] glucosamine N-acyltransferase LpxD (LpxD)
Type: Family

This entry represents LpxD, an enzyme for the biosynthesis of lipid A, a component oflipopolysaccharide (LPS) in the outer membrane outer leaflet of most Gram-negative bacteria. Some differences are found between lipid A of different species. This protein represents the third step from UDP-N-acetyl-D-glucosamine . The group added at this step generally is 14:0(3-OH) (myristate) but may vary; in Aquifex it appears to be 16:0(3-OH) (palmitate) .

Lipid A-like molecules in plants may serve as structural components of the outer membranes of mitochondria and/or chloroplasts, or may be involved in signal transduction or plant defense responses .
DNA helicase, DnaB type (DNA_helicase_DnaB)
Type: Family

This family includes the replicative DNA helicase DnaB, which exhibits DNA-dependent ATPase activity. Helicase DnaB is a homohexameric protein required for DNA replication. The homohexamer can form a ring around a single strand of DNA near a replication fork. An intein of more than 400 residues is found at a conserved location in DnaB of Synechocystis PCC6803, Rhodothermus marinus (both experimentally confirmed), and Mycobacterium tuberculosis. The intein removes itself by a self-splicing reaction. Replication protein, GP12 from Enterobacteria phage P22 also belongs to this family .
DNA helicase, DnaB-like, N-terminal (DNA_helicase_DnaB-like_N)
Type: Domain

The hexameric helicase DnaB unwinds the DNA duplex at the Escherichia coli chromosome replication fork. Although the mechanism by which DnaB both couples ATP hydrolysis to translocation along DNA and denatures the duplex is unknown, a change in the quaternary structure of the protein involving dimerization of the N-terminal domain has been observed and may occur during the enzymatic cycle. This N-terminal domain is required both for interaction with other proteins in the primosome and for DnaB helicase activity. This domain has a multi-helical structure that forms an orthogonal bundle .

It is also found in Replicative DNA helicase DnaC involved in the initiation and elongation during chromosome replication .
DNA helicase, DnaB-like, C-terminal (DNA_helicase_DnaB-like_C)
Type: Domain

This entry represents the C-terminal domain of DNAB-like helicases. DnaB helicase unwinds the DNA duplex at the Escherichia coli chromosome replication fork. The mechanism by which DnaB both couples ATP hydrolysis to translocation along DNA and denatures the duplex is unknown, however, a change in the quaternary structure of the protein involving dimerization of the N-terminal domain has been observed and may occur during the enzymatic cycle. This domain contains an ATP-binding site and is therefore probably the site of ATP hydrolysis .
DNA mismatch repair protein MutS-like, N-terminal (DNA_mismatch_repair_MutS-lik_N)
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 N-terminal domain of proteins in the MutS family of DNA mismatch repair proteins, as well as closely related proteins. The N-terminal domain of MutS is responsible for mismatch recognition and forms a 6-stranded mixed β-sheet surrounded by three α-helices, which is similar to the structure of tRNA endonuclease. Yeast MSH3 , bacterial proteins involved in DNA mismatch repair, and the predicted protein product of the Rep-3 gene of mouse share extensive sequence similarity. Human MSH has been implicated in non-polyposis colorectal carcinoma (HNPCC) and is a mismatch binding protein.
DNA mismatch repair protein MutS, core (DNA_mismatch_repair_MutS_core)
Type: Domain

This entry represents the core domain (domain 3) found in proteins of the MutS family. The core domain of MutS adopts a multi-helical structure comprised of two subdomains, which are interrupted by the clamp domain. Two of the helices in the core domain comprise the levers that extend towards the DNA. This domain is found associated with

,

,

and

. The aligned region corresponds with domain III, which is central to the structure of Thermus aquaticus MutS as characterised in .

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.
Alanine dehydrogenase/pyridine nucleotide transhydrogenase, NAD(H)-binding domain (AlaDH/PNT_NAD(H)-bd)
Type: Domain

Alanine dehydrogenase catalyses the NAD-dependent reversible reductive amination of pyruvate into alanine. Pyridine nucleotide transhydrogenase catalyses the reduction of NADP
+
to NADPH with the concomitant oxidation of NADH to NAD
+
. This enzyme is located in the plasma membrane of prokaryotes and in the inner membrane of the mitochondria of eukaryotes. The transhydrogenation between NADH and NADP is coupled with the translocation of a proton across the membrane. In prokaryotes the enzyme is composed of two different subunits, an alpha chain (gene pntA) and a beta chain (gene pntB), while in eukaryotes it is a single chain protein.

The sequence of alanine dehydrogenase from several bacterial species is related with that of the alpha subunit of bacterial pyridine nucleotide transhydrogenase and the N-terminal half of the eukaryotic enzyme. The two most conserved regions correspond respectively to the N-terminal domain of these proteins, and to a central glycine-rich region which is part of the NAD(H)-binding site . This entry represents a domain found in alanine dehydrogenase and pyridine nucleotide transhydrogenase, containing the glycine-rich region. This domain is also found in lysine 2-oxoglutarate reductases .
SGS domain (SGS_dom)
Type: Domain

The SGT1-specific (SGS) domain is a module of ~90 amino acids, which was initially identified in eukaryotic Sgt1 proteins . It was latter also found in calcyclin-binding proteins . The SGS domain has been shown to bind to proteins of the S100 family, which are thought to function as sensors of calcium ion concentration in the cell .

In budding yeasts, Sgt1 is required for both SCF (Skp1p/Cdc53p-Cullin-F-box)-mediated ubiquitination, cyclic AMP pathway activity and kinetochore function . Its Schizosaccharomyces pombe homologue, Git7, is required for glucose and cyclic AMP signaling, cell wall integrity, and septation . Its two homologues in Arabidopsis, SGT1a and SGT1b, can complement two yeast temperature-sensitive sgt1 mutant alleles, suggesting that fundamental cellular function(s) of yeast SGT1in SCF-mediated protein ubiquitylation. Moreover, SGT1a and SGT1b can act as cochaperones with HSP90 and HSC70 and function in regulating multiple resistance (R) genes and environmental responses . The SGS domain of SGT1 is a key determinant of the HSC70-SGT1 association .

Calcyclin (S100A6) is a member of the S100A family of calcium binding proteins and appears to play a role in cell proliferation .
Domain of unknown function DUF668 (DUF668)
Type: Domain

This entry represents the C-terminal domain of PSI proteins from Arabidopsis. This domain is found associated with DUF3475 (

).

PSI1 was identified as a gene that is co-expressed with the phytosulfokine (PSK) receptor genes PSKR1 and PSKR2 in Arabidopsis thaliana. PSI proteins are plant-specific and promote growth .
Interferon-related developmental regulator, N-terminal (Interferon-rel_develop_reg_N)
Type: Domain

This entry represents the N-terminal domain of IFRD1 and similar eukaryotic sequences.

Interferon-related developmental regulator (IFRD1) is the human homologue of the Rattus norvegicus early response protein PC4 and its murine homologue TIS7 . IFRD1 is a transcriptional coactivator/repressor controlling patterns of gene expression by interacting with transcription factors or histone deacetylase (HDAC) complexes . This entry also contains IFRD2 and its murine equivalent SKMc15, which are highly expressed soon after gastrulation and in the hepatic primordium, suggesting an involvement in early hematopoiesis . Members of this group are generally described as transcriptional regulators implicated in cellular differentiation and various human diseases .
Janus (Janus)
Type: Family

This family is comprised of the 14kDa phosphohistidine phosphatase from mammals and Janus-A/Janus-B proteins from Drosophila melanogaster. Janus-A and Janus-B regulate somatic sex differentiation and have been found to be testes specific . 14kDa phosphohistidine phosphatase is a histidine phosphatase that may play a role of reversible histidine phosphorylation in neuronal functions .
Per os infectivity factor 3 (PIF3)
Type: Family

This family contains viral proteins, and includes Baculovirus Per os infectivity factor 3 (PIF3). PIF3 forms a complex on the occlusion-derived virus surface with PIF1, PIF2, and P74 which has an essential function in the initial stages of baculovirus oral infection .
GPI mannosyltransferase 1 (PIG-M)
Type: Family

PIG-M has a DXD motif. The DXD motif is found in many glycosyltransferases that utilise nucleotide sugars. It is thought that the motif is involved in the binding of a manganese ion that is required for association of the enzymes with nucleotide sugar substrates .
Vesicle transport v-SNARE, N-terminal (Vesicle_trsprt_v-SNARE_N)
Type: Domain

v-SNARE proteins are required for protein traffic between eukaryotic organelles. The v-SNAREs on transport vesicles interact with t-SNAREs on target membranes in order to facilitate this . This domain is the N-terminal half of the v-Snare proteins.
Epstein-Barr virus nuclear antigen 3/4/6 (EBNA-3/4/6)
Type: Family

This family contains EBNA-3A (EBNA-3), -3B (EBNA-4), and -3C (EBNA-6) which are latent infection nuclear proteins important for Epstein-Barr virus (strain GD1) (HHV-4) (Human herpesvirus 4)-induced B-cell immortalisation and the immune response to EBVG infection .
Transforming acidic coiled-coil-containing protein, C-terminal (TACC_C)
Type: Domain

This entry represents a C-terminal domain found in the the proteins TACC 1, 2 and 3 (TACC1-3). TACC1 is found concentrated in the centrosomes of eukaryotes which may play a conserved role in organising centrosomal microtubules. The human TACC proteins have been linked to cancer and TACC2 has been identified as a possible tumour suppressor (AZU-1) . TACC 3 from Xenopus laevis, also known as maskin, associates XMAP215 and promotes efficient microtubule elongation during mitosis . Maskin is also found to bind CPEB and elF-4E . Interestingly, the functional homologue (Alp7) in Schizosaccharomyces pombe (not included in this entry) has been shown to be required for organisation of bipolar spindles .
Lariat debranching enzyme, C-terminal (DBR1_C)
Type: Domain

This presumed domain is found at the C terminus of lariat debranching enzyme. This domain is always found in association with a metallo-phosphoesterase domain

. RNA lariat debranching enzyme is capable of digesting a variety of branched nucleic acid substrates and multicopy single-stranded DNAs. The enzyme degrades intron lariat structures during splicing.
N-formylglutamate amidohydrolase (N-FG_amidohydro)
Type: Family

Formylglutamate amidohydrolase (FGase, also known as N-formylglutamate deformylase) catalyses the terminal reaction in the five-step pathway for histidine utilization in Pseudomonas putida. By this action, N-formyl-L-glutamate (FG) is hydrolysed to produce L-glutamate plus formate .
Nucleoside 2-deoxyribosyltransferase (Nucleoside_deoxyribTrfase)
Type: Family

Nucleoside 2-deoxyribosyltransferase (NDT) (

) catalyses the cleavage of the glycosidic bonds of 2-deoxyribonucleosides. Nucleoside 2-deoxyribosyltransferases can be divided into two groups based on their substrate specificity: class I enzymes are specific for the transfer of deoxyribose between two purines, while class II enzymes will transfer the deoxyribose between either purines or pyrimidines. The structure of the class I and class II enzymes are very similar. In class I enzymes, the purine base shields the active site from solvent, which the smaller pyrimidine base cannot do, while in class II enzymes the active site is shielded by a loop (residues 48-62). Both classes of enzymes are found in various Lactobacillus species and participate in nucleoside recycling in these microorganisms. This entry represents both classes of enzymes.

This entry also includes the related enzyme deoxynucleoside 5-monophosphate N-glycosidase (DNPH1), also known as 5-hydroxymethyl-dUMP N-hydrolase (

). DNPH1 is related to NDT in structure and enzymatic activity, but in contrast to NDT catalyses the hydrolysis of 2'-deoxyribonucleoside 5'-monophosphate to yield a free nucleobase and 2-deoxyribose 5-phosphate . DNPH1 is a potential proto-oncogene .
Toxin HigB-1 (HigB-1)
Type: Family

Bacterial toxin-antitoxin loci consist of two genes in an operon encoding a 'toxin' and an 'antitoxin' respectively. Ectopic expression of the toxins severely reduces cell growth and prevents colony formation. This entry includes HigB-1, one of the toxins found in Vibrio cholerae. It inhibits translation by sequence-specific cleavage of mRNA. It prefers either in-frame or out-of-frame 5'-AAA-3' codons (lysine) .
Toxin-antitoxin system, RelE/ParE toxin family (RelE/ParE_toxin)
Type: Family

The RelE/ParE family encompasses several toxin components of toxin-antitoxin modules. RelE is a sequence-specific, ribosome-dependent mRNA endoribonuclease which inhibits translation during amino acid starvation . ParE is involved in plasmid partition. ParE acts by inhibiting DNA gyrase, converting supercoiled plasmid DNA into a singly cleaved linear form in an ATP-dependent fashion .
TMP repeat (TMP_rpt)
Type: Repeat

This short repeat consists of the motif WXXh where X can be any residue and h is a hydrophobic residue. The repeat is named TMP after its occurrence in the tape measure protein (TMP). Tape measure protein is a component of phage tail and probably forms a β-helix. Truncated forms of TMP lead to shortened tail fibres . This repeat is also found in non-phage proteins where it may play a structural role.
CFA20 domain (CFA20_dom)
Type: Domain

This domain is characteristic of cilia- and flagella-associated protein 20 (CFA20). CFA20 is a cilium- and flagellum-specific protein that plays a role in axonemal structure organisation and motility . In Chlamydomonas reinhardtii, it stabilises outer doublet microtubules (DMTs) of the axoneme and may work as a scaffold for intratubular proteins, such as tektin and PACRG, to produce the beak structures in DMT1 .

Other proteins contain a domain with homology to CFA20. WDR90/POC16 contains such a domain in its N terminus, followed by a large C-terminal domain with multiple WD40 repeats . This domain is also present in the N terminus of uncharacterised protein C3orf67.
Ubiquinone biosynthesis protein Coq4 (Coq4)
Type: Family

Coq4 is a component of a multi-subunit COQ enzyme complex, which plays a role in the coenzyme Q (ubiquinone) biosynthetic pathway . In budding yeasts, Coq4 plays an essential role in organising the COQ enzyme complex and is required for steady-state levels of Coq3, Coq6, Coq7 and Coq9 .
NPL4, zinc-binding putative (NPL4_Zn-bd_put)
Type: Domain

The HRD4 gene is identical to NPL4, a gene previously implicated in nuclear transport. Using a diverse set of substrates and direct ubiquitination assays, analysis revealed that HRD4/NPL4 is required for a poorly characterised step in ER-associated degradation after ubiquitination of target proteins but before their recognition by the 26S proteasome . This region of the protein contains possibly two zinc binding motifs. Npl4p physically associates with Cdc48p via Ufd1p to form a Cdc48p-Ufd1p-Npl4p complex. The Cdc48-Ufd1-Npl4 complex functions in the recognition of several polyubiquitin-tagged proteins and facilitates their presentation to the 26S proteasome for processive degradation or even more specific processing.
Nuclear pore localisation protein NPL4, C-terminal (NPL4_C)
Type: Domain

The HRD4 gene is identical to NPL4, a gene previously implicated in nuclear transport. Using a diverse set of substrates and direct ubiquitination assays, analysis revealed that HRD4/NPL4 is required for a poorly characterised step in ER-associated degradation following ubiquitination of target proteins but preceding their recognition by the 26S proteasome . Npl4p physically associates with Cdc48p via Ufd1p to form a Cdc48p-Ufd1p-Npl4p complex. The Cdc48-Ufd1-Npl4 complex functions in the recognition of several polyubiquitin-tagged proteins and facilitates their presentation to the 26S proteasome for processive degradation or even more specific processing .