SII-SWORD/CoKE huggingface dataset:
Nascent polypeptide-associated complex NAC domain (Nas_poly-pep-assoc_cplx_dom)
Type: Domain

In eukaryotes, the Nascent polypeptide-Associated Complex (NAC) is a heterodimeric cytosolic protein complex composed of NAC alpha (NACA) and NAC beta (BTF3) . NAC binds reversibly to the ribosome where it is in contact with nascent chains as they emerge from the ribosome. But the cellular function of NAC seems to be much more diverse as it is also involved in transcription regulation and mitochondrial translocation . Alpha and beta NACs share homology with each other, both contain a NAC A/B domain. In archaea no beta NAC proteins are found; the complex is an homodimer of NAC alpha .

The crystal structure of an archeal NAC has been solved . The NAC A/B domain consists of six strands arranged in a β-barrel structure similar to the OB fold. Various OB folds interact with ribosomal RNA which could suggest a similar role for the NAC A/B domain.
PIN domain (PIN_dom)
Type: Domain

PIN domains are small protein domains identified by the presence of three strictly conserved acidic residues. Apart from these three residues, there is poor sequence conservation . PIN domains are found in eukaryotes, eubacteria and archaea. In eukaryotes they are ribonucleases involved in nonsense mediated mRNA decay and in processing of 18S ribosomal RNA . In prokaryotes, they are the toxic components of toxin-antitoxin (TA) systems, their toxicity arising by virtue of their ribonuclease activity. The PIN domain TA systems are now called VapBC TAs(virulence associated proteins), where VapB is the inhibitor and VapC, the PIN-domain ribonuclease toxin .
Histone acetyltransferase domain, MYST-type (HAT_MYST-type)
Type: Domain

Histone acetyltransferases (HATs) fall into at least four different families based on sequence conservation within the HAT domain . The MYST family is the largest family of HATs and is named after the founding members: MOZ, Ybf2/ Sas3, Sas2 and Tip60. MYST proteins mediate many biological functions including gene regulation, DNA repair, cell-cycle regulation and development and have been shown to acetylate several non-histone substrates . MYST proteins are autoregulated by posttranslational modifications .

The MYST-type HAT domain contains three regions: a central region associated with acetyl-CoA cofactor binding and catalysis in addition to flanking N- and C-terminal regions harboring respectively a C2HC-type zinc finger and a helix- turn-helix DNA-binding motif. The N- and C-terminal segments directly flanking the catalytic core are likely to play an important role in histone substrate binding . The catalytic mechanism for the MYST-type HAT domain is still unresolved but seems to involve a conserved glutamate that functions to abstract a proton from lysine to promote the nucleophilic attack on the acetyl carbonyl carbon of acetyl-CoA .
Outer membrane protein, Helicobacter (OMP_Helicobacter)
Type: Family

Gram-negative bacterial outer membranes constitute a semi-permeable, size-dependent permeability barrier, for example to hydrolytic enzymes, detergents, dyes and hydrophobic anti-microbials. The outer membrane protein (OMP) profile of Helicobacter pylori differs from that of other Gram-negative bacteria, where the highly non-selective porins are absent and a number of less abundant protein species are observed . OMPs from H. pylori have been identified as porins, gastric epithelial cell adhesins and Lewis B binding adhesins . Extensive C-terminal sequence similarity between these OMPs has been used to define a much larger paralogous family.

H. pylori is the causative agent of gastritis and peptic ulceration in humans. Numerous subtypes of OMPs have also been identified. Attempts have been made to construct recombinant vectors that are able to express these OMPs in order to develop a vaccine protecting against Hp infection and a diagnostic reagent kit to quickly detect infection. OMPs were chosen as possible targets of vaccine development as they are H. pylori specific, surface exposed and highly antigenic.
Retinoblastoma-associated protein, B-box (RB_B)
Type: Domain

This entry includes retinoblastoma-associated protein (RB, also known as pRb, RB, p1051), retinoblastoma-like protein 1 (RBL1, also known as p107) and retinoblastoma-like protein 2 (RBL2, also known as RB2 or p130). Members of this entry contain a conserved domain named the 'pocket' that interacts with the LXCXE motif found in viral proteins, such as SV40 large T antigen . This pocket consists of A- and B-boxes which are found at the C-terminal end of the protein. This entry represents the B-box, that is on C-terminal side of the A-box. The crystal structure of the RB pocket bound to a nine-residue E7 peptide containing the LxCxE motif, shared by other RB-binding viral and cellular proteins, shows that the LxCxE peptide binds a highly conserved groove on the B-box portion of the pocket; the A-box portion (see

) appears to be required for the stable folding of the B box. Also highly conserved is the extensive A-B interface, suggesting that it may be an additional protein-binding site. The A and B boxes each contain the cyclin-fold structural motif, with the LxCxE-binding site on the B-box cyclin fold being similar to a Cdk2-binding site of cyclin A and to a TBP-binding site of TFIIB .

In humans, RB is a tumour suppressor linked to several major cancers . RB forms complexes with E2Fs and represses gene expression by recruiting chromatin remodeling factors, such as histone deacetylases (HDACs) to E2F-responsive promoters . Apart from E2Fs, RB also interacts with other transcription factors that govern cell differentiation .

RBL1 and RBL2 are the components of the DREAM complex, which represses cell cycle-dependent genes in quiescent cells and plays a role in the cell cycle-dependent activation of G2/M genes .
N(4)-bis(aminopropyl)spermidine synthase, C-terminal (BpsA_C)
Type: Domain

This domain is found in the C terminus of N(4)-bis(aminopropyl)spermidine synthase (BpsA) from hyperthermophiles and in uncharacterised proteins from bacteria and archaea.
Pyruvoyl-dependent arginine decarboxylase (Pyruvoyl-dep_arg_deCO2ase)
Type: Family

Arginine decarboxylase (

) catalyses the interconversion of arginine and agmatine plus carbon dioxide . It requires a pyruvoyl group for its activity. Archaeoglobus fulgidus contains three copies of this 80-residue domain, all of which are very closely related.
YgjP-like, metallopeptidase domain (YgjP-like_metallopeptidase)
Type: Domain

This is a conserved domain containing the catalytic zinc-metallopeptidase (HExxH) catalytic motif. Proteins containing this domain are found in some archaebacteria, as well as Helicobacter pylori. The proteins are 190-240 amino acids long, with the C terminus being the most conserved region, containing three conserved histidines . This domain is found in YgjP from E. coli , a predicted metal-dependent hydrolase that hydrolyses UTP to UMP and diphosphate in vitro; and in MJ0123 from Methanocaldococcus jannaschii (also referred to as projannalysin) .
CDP-archaeol synthase, archaea (CarS_archaea)
Type: Family

CarS (CDP-archaeol synthase) is a membrane protein that functions in the archaeal lipid biosynthetic pathway. It catalyses the transfer of the nucleotide to its specific archaeal lipid substrate, leading to the formation of a CDP-activated precursor (CDP-archaeol) to which polar head groups are attached .
Protein of unknown function DUF47 (DUF47)
Type: Family

This family includes prokaryotic proteins of unknown function, as well as a protein annotated as the pit accessory protein from Rhizobium meliloti (Sinorhizobium meliloti) (

). However, while it has been hypothesised that this protein may play a role in orthophosphate transport (Pit stands for phosphate transport), its exact function is unknown .

This entry represents a clade of the wider family described by

, excluding the Gram-positive bacterial family members.
CRISPR-associated protein Cas1 (CRISPR-assoc_Cas1)
Type: Family

This entry represents Cas1, which is a metal-dependent DNA-specific endonuclease . Cas1 may play a role in the recognition, cleavage, and/or integration of foreign nucleic acids into CRISPRs.

The CRISPR-Cas system is a prokaryotic defence mechanism against foreign genetic elements. The key elements of this defence system are the Cas proteins and the CRISPR RNA.
Ribonuclease P protein subunit Rpp29/RNP1 (Rpp29/RNP1)
Type: Family

Ribonuclease P (Rnp) is a ubiquitous ribozyme that catalyzes a Mg2 -dependent hydrolysis to remove the 5'-leader sequence of precursor tRNA (pre-tRNA) in all three domains of life . In bacteria, the catalytic RNA (typically ~120kDa) is aided by a small protein cofactor (~14kDa) . Archaeal and eukaryote RNase P consist of a single RNA and archaeal RNase P has four or five proteins, while eukaryotic RNase P consists of 9 or 10 proteins. Eukaryotic and archaeal RNase P RNAs cooperatively function with protein subunits in catalysis .

Eukaryotic nuclear RNase P shares most of its protein components with another essential RNP enzyme, nucleolar RNase MRP . RNase MRP (mitochondrial RNA processing) is an rRNA processing enzyme that cleaves various RNAs, including ribosomal, messenger, and mitochondrial RNAs. It can cleave a specific site within precursor rRNA to generate the mature 5'-end of 5.8S rRNA . Despite its name, the vast majority of RNase MRP is localized in the nucleolus . RNase MRP has been shown to cleave primers for mitochondrial DNA replication and CLB2 mRNA. In yeast, RNase MRP possesses one putatively catalytic RNA and at least 9 protein subunits (Pop1, Pop3-Pop8, Rpp1, Snm1 and Rmp1) . Human RNase MRP complex consists of 267 nucleotides and supports the interaction with and among at least seven protein components: hPop1, hPop5, Rpp20, Rpp25, Rpp30, Rpp38, and Rpp40) and three additional proteins, hPop4, Rpp21 and Rpp14, have been reported to be associated with at least a subset of RNase MRP complexes .

This entry includes p29 subunit (also known as Rpp29 or Pop4) of the Ribonuclease P complex . Its homologues from eukaryotes are also a subunit of the RNase MRP complex. The structure of the RNase P subunit, Rpp29, from Methanobacterium thermoautotrophicum has been determined. Mth Rpp29 is a member of the oligonucleotide/oligosaccharide binding fold family. It contains a structured β-barrel core and unstructured N- and C-terminal extensions bearing several highly conserved amino acid residues that could be involved in RNA contacts in the protein-RNA complex . Rpp29 (

) catalyses the endonucleolytic cleavage of RNA, removing 5'-extranucleotides from tRNA precursor. It interacts with the Rpp25 and Pop5 subunits.
ATPase, BadF/BadG/BcrA/BcrD type (ATPase_BadF)
Type: Domain

This domain is found in the BadF (

) and BadG (

) proteins that are two subunits of Benzoyl-CoA reductase, that may be involved in ATP hydrolysis. The family also includes an activase subunit from the enzyme 2-hydroxyglutaryl-CoA dehydratase (

). The hypothetical protein AQ_278 from Aquifex aeolicus

contains two copies of this region suggesting that the family may structurally dimerise.
Holliday junction resolvase Hjc (Hjc)
Type: Family

This entry represents Holliday junction resolvases (hjc gene) and related proteins, primarily from archaeal species . The Holliday junction is an essential intermediate of homologous recombination. Holliday junctions are four-stranded DNA complexes that are formed during recombination and related DNA repair events. In the presence of divalent cations, these junctions exist predominantly as the stacked-X form in which the double-helical segments are coaxially stacked and twisted by 60 degrees in a right-handed direction across the junction cross-over. In this structure, the stacked arms resemble two adjacent double-helices, but are linked at the junction by two common strands that cross-over between the duplexes . During homologous recombination, genetic information is physically exchanged between parental DNAs via crossing single strands of the same polarity within the four-way Holliday structure. This process is terminated by the endonucleolytic activity of resolvases, which convert the four-way DNA back to two double strands.
AMMECR1 domain (AMMECR1_domain)
Type: Domain

Nuclear protein AMMECR1, presently a protein of unknown function, is encoded by one of the genes affected by an X-linked deletion that causes the association of Alport syndrome, midface hypoplasia, intellectual disability and elliptocytosis in humans .

This entry represents the C-terminal region of AMMECR1 (approximately from residue 122 to 333), which is well conserved. Homologues appear in species ranging from bacteria and archaea to eukaryotes, including Protein PH0010 from Pyrococcus horikoshii . The high level of conservation of the AMMECR1 domain points to a basic cellular function, potentially in either the transcription, replication, repair or translation machinery . The AMMECR1 domain, which contains a 6-amino-acid motif (LRGCIG) that might be functionally important since it is strikingly conserved throughout evolution . The AMMECR1 domain consists of two distinct subdomains of different sizes. The large subdomain, which contains both the N- and C-terminal regions, consists of five α-helices and five β-strands. These five β-strands form an antiparallel β-sheet. The small subdomain consists of four α-helices and three β-strands, and these β-strands also form an antiparallel β-sheet. The conserved 'LRGCIG' motif is located at β(2) and its N-terminal loop, and most of the side chains of these residues point toward the interface of the two subdomains. The two subdomains are connected by only two loops, and the interaction between the two subdomains is not strong. Thus, these subdomains may move dynamically when the substrate enters the cleft. The size of the cleft suggests that the substrate is large, e.g., the substrate may be a nucleic acid or protein. However, the inner side of the cleft is not filled with positively charged residues, and therefore it is unlikely that negatively charged nucleic acids such as DNA or RNA interact at this site .
Bacterial bifunctional deaminase-reductase, C-terminal (RibDG_C)
Type: Domain

This domain is found in the C terminus of the bifunctional deaminase-reductase of Escherichia coli, Bacillus subtilis and other bacteria in combination with

that catalyses the second and third steps in the biosynthesis of riboflavin, i.e., the deamination of 2,5-diamino-6-ribosylamino-4(3H)-pyrimidinone 5'-phosphate (deaminase) and the subsequent reduction of the ribosyl side chain (reductase) . The domain is also present in some HTP reductases from archaea and fungi.
Translation initiation factor IF2/IF5 domain (Transl_init_fac_IF2/IF5_dom)
Type: Domain

The beta subunit of archaeal and eukaryotic translation initiation factor 2 (IF2beta) and the N-terminal domain of translation initiation factor 5 (IF5) show significant sequence homology . Archaeal IF2beta contains two independent structural domains: an N-terminal mixed α/β core domain (topological similarity to the common core of ribosomal proteins L23 and L15e), and a C-terminal domain consisting of a zinc-binding C4 finger . Archaeal IF2beta is a ribosome-dependent GTPase that stimulates the binding of initiator Met-tRNA(i)(Met) to the ribosomes, even in the absence of other factors . The C-terminal domain of eukaryotic IF5 is involved in the formation of the multi-factor complex (MFC), an important intermediate for the 43S pre-initiation complex assembly. IF5 interacts directly with IF1, IF2beta and IF3c, which together with IF2-bound Met-tRNA(i)(Met) form the MFC .

This entry represents both the N-terminal and zinc-binding domains of IF2, as well as a domain in IF5.
Triphosphoribosyl-dephospho-CoA protein (CitG)
Type: Family

This entry represents the triphosphoribosyl-dephospho-CoA synthases CitG and MdcB. CitG and MdcB are closely related and produce the same molecule, triphosphoribosyl-dephospho-CoA, which becomes the prosthetic group of acyl carrier protein subunits of citrate lyase and malonate decarboxylase respectively .
MEMO1 family (MEMO1_fam)
Type: Family

This entry is composed of Memo 1 (mediator of ErbB2-driven cell motility 1) and related proteins from eukaryotes, archaea and bacteria whose molecular function is unclear.

Memo 1 is an effector of the ErbB2 receptor tyrosine kinase involved in breast carcinoma cell migration . Its increased expression is associated with cancer aggressiveness. In breast cancer it regulates insulin-like growth factor-I receptor-dependent signaling pathway . It binds to a specific ErbB2-derived phosphopeptide . It regulates the localisation of the small G protein RhoA and its effector mDia1 at the plasma membrane, and thereby coordinates the organisation of the lamellipodial actin network, adhesion site formation, and MT outgrowth within the cell leading edge to sustain cell motility . In yeast, the homologue is known as Mho1, and inhibits haploid invasive growth when overexpressed .
RNase P subunit p30 (RNase_P_p30)
Type: Family

Members of this protein family are part of the ribonuclease P complex (

) that takes part in endonucleolytic cleavage of RNA, removing 5'-extra-nucleotide from tRNA precursor. This process is essential for tRNA processing.
RNA-binding protein PAB1135-like (PAB1135-like)
Type: Family

This entry represents a family of archaeal proteins, including RNA-binding protein PAB1135 from Pyrococcus abyssi, UPF0201 protein PH1010 from Pyrococcus horikoshii and UPF0201 protein SSO1042 from Saccharolobus solfataricus. While PAB1135 has been reported to bind efficiently double-stranded RNAs in vitro in a non-sequence specific manner , other members of this family such as PH1010 are unlike to have rRNA-binding ability despite its structural similarity to the RRM-type RNA-binding domain of the ribosomal L5 protein as the residues involved in RNA-binding in the L5 protein are not conserved in members of this family .

PH1010 is composed of six β-strands that form a slightly twisted antiparallel β-sheet and face five α-helices on one side and two additional β-strands forming an antiparallel β-sheet in the C terminus. PH1010 forms a characteristic homodimer structure in the crystal. Dimerisation of the molecule is crucial for function .
EVE domain (EVE_domain)
Type: Domain

The EVE domain is part of the wider PUA domain superfamily. The function of this domain is not known but, given the structural similarities to PUA, is likely to involve RNA binding .
Desulfoferrodoxin, ferrous iron-binding domain (Desulfoferrodoxin_Fe-bd_dom)
Type: Domain

Desulfoferrodoxins contains two types of iron: an Fe-S4 site very similar to that found in desulfoferrodoxin from Desulfovibrio gigas, and an octahedral coordinated high-spin ferrous site most probably with nitrogen/oxygen-containing ligands. Due to this rather unusual combination of active centres, this novel protein is named desulfoferrodoxin .
MIP18 family-like (MIP18-like)
Type: Domain

This domain (previously known as DUF59) is found in proteins that are mostly defined as members of the MIP18 family. This includes iron-sulfur cluster carrier proteins, where the domain is found in the N terminus. This domain is also found in protein AE7 from Arabidopsis and its homologues. Protein AE7 is thought to be a central member of the cytosolic iron-sulfur (Fe-S) protein assembly (CIA) pathway, however protein AE7-like 1 and 2 (also containing this domain) are probably not involved in this pathway . MIP18 family protein YHR122W (CIA2) from S. cerevisiae is a component of the CIA machinery, and acts at a late step of Fe-S cluster assembly . The SufT protein from Staphylococcus aureus is composed of this domain solely and is involved in the maturation of FeS proteins .
Phosphotransferase KptA/Tpt1 (Ptrans_KptA/Tpt1)
Type: Family

This entry includes Tpt1 and its homologues from all domains of life. Tpt1 was first discovered as an essential component of the fungal tRNA splicing pathway, which characteristically generates a 2'-PO4, 3'-5' phosphodiester splice junction during the tRNA ligation reaction . It is an enzyme that catalyzes the transfer of an internal RNA 2'-monophosphate (2'-PO4) to NAD+ to form a 2'-OH RNA, ADP-ribose 1"-2" cyclic phosphate, and nicotinamide .

Interestingly, many Tpt1 homologues have no obvious need for an RNA 2'-phosphotransferase because: (i) they lack tRNA introns; and/or (ii) they are not known to have an enzymatic pathway that generates 2'-PO4, 3'-5' phosphodiester RNA structures. There are more evidence showing that Tpt1 homologues are not limited to the canonical activity of Tpt1 healing the 2'-PO4, 3'-5' phosphodiester RNA splice junction formed during fungal and plant tRNA splicing . Instead, the ADP-ribosyl transfer to a phosphorylated substrate is the unifying mechanistic feature of Tpt1-catalyzed reactions. For instance, some Tpt1 homologues have been shown to catalyze the transfer of ADP-ribose from NAD+ to a 5'-monophosphate end of RNA or DNA to install a 5'-phospho-ADP-ribose cap structure .
Uncharacterised protein family UPF0216 (UPF0216)
Type: Family

This Domain of unknown function 61 (DUF61) family of proteins are widely distributed in archaea. In crenarchaea, the genes of DUF61 proteins are in an operon containing two genes of box C/D RNA protein complexes. The NMR structure of a DUF61 family member from the hyperthermophilic archaeon Sulfolobus solfataricus revealed a rigid core structure and flexible N- and C-terminal regions, including a negatively-charged independent C-terminal helix. The core structure consists of N- and C-terminal subdomains, in which the C-terminal subdomain shows significant structural similarity with several nucleic acid binding proteins .
S-adenosyl-l-methionine hydroxide adenosyltransferase (SAM_OH_AdoTrfase)
Type: Family

The S-adenosyl-L-methionine (SAM) hydroxide adenosyltransferase family groups several fluorinase and chlorinase enzymes whose common feature is that they mediate nucleophilic reactions of their respective halide ions to the C-5' carbon of SAM . These enzymes utilise a rigorously conserved amino acid side chain triad (Asp-Arg-His) which may have a role in activating water to hydroxide ion. Structural studies indicate that the protein is a homotrimer, with each monomer being composed of N- and C-terminal domains . The N-terminal domain has a central seven-stranded β-sheet, which combines parallel and antiparallel strands sandwiched between α-helices. The C-terminal domain forms a β-barrel with a greek-key topology. SAM is bound at the interface between the C-terminal domain of one monomer and the N-terminal domain of the neighbouring monomer, with a total of three molecules bound by the trimer. This group of proteins, which are predominantly found in prokaryotes, used to be known as DUF62 .
Cobalt-precorrin-5B C(1)-methyltransferase CbiD (CbiD)
Type: Family

CbiD is a SAM-dependent methyltransferase essential for cobalamin biosynthesis in both Salmonella typhimurium and Bacillus megaterium . A deletion mutant of CbiD suggests that this enzyme is involved in C-1 methylation and deacylation reactions required during the ring contraction process in the anaerobic pathway to cobalamin (similar role as CobF) . The CbiD protein has a putative S-AdoMet binding site . CbiD has no counterpart in the aerobic pathway.

Cobalamin (vitamin B12) is a structurally complex cofactor, consisting of a modified tetrapyrrole with a centrally chelated cobalt. Cobalamin is usually found in one of two biologically active forms: methylcobalamin and adocobalamin. Most prokaryotes, as well as animals, have cobalamin-dependent enzymes, whereas plants and fungi do not appear to use it. In bacteria and archaea, these include methionine synthase, ribonucleotide reductase, glutamate and methylmalonyl-CoA mutases, ethanolamine ammonia lyase, and diol dehydratase . In mammals, cobalamin is obtained through the diet, and is required for methionine synthase and methylmalonyl-CoA mutase .
Protein of unknown function DUF63 (DUF63)
Type: Family

This entry represents probable transmembrane proteins with unknown function from archaea.