SII-SWORD/CoKE huggingface dataset:
Cystovirus, RNA-directed RNA polymerase (Cystovir_RNA-dir_pol)
Type: Family

RNA-directed RNA polymerase (RdRp) (

) is an essential protein encoded in the genomes of all RNA containing viruses with no DNA stage . It catalyses synthesis of the RNA strand complementary to a given RNA template, but the precise molecular mechanism remains unclear.
The postulated RNA replication process is a two-step mechanism. First, the initiation step of RNA synthesis begins at or near the 3' end of the RNA template by means of a primer-independent (de novo) mechanism. The de novo initiation consists in the addition of a nucleotide tri-phosphate (NTP) to the 3'-OH of the first initiating NTP. During the following so-called elongation phase, this nucleotidyl transfer reaction is repeated with subsequent NTPs to generate the complementary RNA product .

This entry represents RNA-directed RNA polymerase (also known as protein P2) from various Cystoviruses, such as Bacteriophage phi-6 and Bacteriophage phi-13 . The RdRp protein of Cystoviruses is capable of primer-independent initiation, as are many RNA polymerases. The structure of this polymerase revealed an initiation platform, composed of a loop in the C-terminal domain that was essential for de novo initiation, a similar element having been identified in Hepatitis C virus RNA-dependent RNA polymerase .
C-protein (C-protein)
Type: Family

This entry represents C protein. C protein is one of the proteins involved in the production and packaging of viral single-stranded DNA .
Bacteriophage phi-29, Gp1 (Phage_phi-29_Gp1)
Type: Family

This entry represents RNA-binding early protein Gp1 found in Bacillus phages phi-29 and PZA. Gp1 self-associates to form long filamentous structures, which appear to be necessary for efficient binding to RNA and for translational repression . Gp1 is required for viral DNA replication; it suppresses the synthesis of phi29 DNA polymerase and primer protein in the post-transcriptional process . It appears to be a component of a viral-encoded structure that associates with the bacterial membrane in order to provide an anchoring site for the viral DNA replication machinery.
Bacteriophage T4, Gp55.2 (Phage_T4_Gp55.2)
Type: Family

This entry is represented by Bacteriophage T4, Gp55.2; it is a family of uncharacterised viral proteins.
Bacteriophage-associated immunity protein (Phage_imm)
Type: Family

This entry contains proteins related to the phage/prophage-immunity proteins and includes the immunity (imm) gene of the Escherichia coli bacteriophage T4. The Imm protein affects the exclusion of phage superinfecting cells already infected with T4. Phage which were excluded upon infection of cells possessing a plasmid-encoded Imm protein ejected only about one-half of their DNA. Therefore, the Imm protein inhibited, directly or indirectly, DNA ejection .
Single-stranded DNA-binding protein, bacteriophage T7 (SSB_T7)
Type: Family

This group represents single-stranded DNA-binding proteins (SSB, also known as helix-destabilising proteins and gp2.5) from bacteriophage T7. It is expressed in the late stage of lytic development, binding preferentially to single-stranded DNA and is implicated in DNA replication, formation of concatemers, recombination and repair of double-stranded breaks . Together with DNA primase/helicase, promotes pairing of two homologous DNA molecules containing complementary single-stranded regions and mediates homologous DNA strand exchange . SSB disrupts loops, hairpins and other secondary structures present on ssDNA to reduce and eliminate pausing of viral DNA polymerase at specific sites during elongation . The C-terminal aromatic Phe and the overall acidic charge of this region are critical for its function .
RNA polymerase inhibitor (RNA_pol_inhibitor)
Type: Family

This entry represents RNA polymerase inhibitor, including Gp2 from T7-like viruses. Bacterial RNA polymerase inhibitor, which is expressed in the late stage of lytic development, is also essential for continuous synthesis of phage DNA and functions in the packaging of the viral genome into the mature phage particle . It inhibits the bacterial host RNA polymerase by interacting with the RpoC subunit and inhibiting the formation of a promoter complex .
Bacteriophage T4, DenA, endonuclease II (Phage_T4_DenA_endoDNaseII)
Type: Family

This entry represents endonuclease II from phage T4, encoded by gene danA, which catalyses the initial step in host DNA degradation allowing the scavenging of host-derived nucleotides for phage DNA synthesis. T4 phage DNA is protected from EndoII by hydroxymethylation and glucosylation of cytosine residues . EndoII belongs to the GIY-YIG family of enzymes and is able to cleave the two strands, independently of each other, of a long, asymmetric, and ambiguous DNA sequence. This cleavage is the result of concerted single-strand nicks, but many positions are only nicked, not cleaved. EndoII binds to two DNA substrates as an X-shaped tetrameric structure composed as a dimer of dimers .
Bacteriophage T4, Prohead assembly protein gp68 (Phage_T4_Gp68)
Type: Family

This entry represents Prohead assembly protein gp68 from Enterobacteria phage T4 (Bacteriophage T4) and similar proteins found in the viral family Myoviridae. Gp68 plays a role in the phage head size determination. About ten copies of this protein are found in the mature phage head . It is predicted to have a secondary structure that consists of α-helical hairpins similar to supersecondary-structure-forming domains such as tetratricopeptide and HEAT repeats .
Bacteriophage T4, Gp31, chaperonin-GroEL (Phage_T4_Gp31_GroEL)
Type: Family

This group represents a bacteriophage-encoded co-chaperonin analogous to bacterial GroES. This protein is essential for proper capsid assembly and functions as a co-chaperonin with the host GroEL protein .
Spanin, inner membrane subunit, T7likevirus-type (I-spanin_T7likevirus)
Type: Family

The lysis of Gram-negative hosts by double-strand DNA bacteriophages requires, in addition to the actions of a holin and endolysin, a third step involving the spanin complex. This complex consists of a small outer membrane lipoprotein and an integral cytoplasmic membrane protein, designated as o-spanins and i-spanins, respectively. The spanin complex is involved in the disruption of the outer membrane. Without the spanin function, lysis is blocked and progeny virions are trapped in dead spherical cells .

This entry represents the i-spanin subunit, mainly from T7-like viruses.
Uncharacterised conserved protein UCP004509, Rem (UCP004509_Rem)
Type: Family

This group represents a Rem protein.
Prepilin peptidase-dependent protein B, predicted (Prepilin_Pept-dep_B_prd)
Type: Family

This group represents a predicted prepilin peptidase-dependent protein B.
Uncharacterised conserved protein UCP004546 (UCP004546)
Type: Family

This group represents an uncharacterised conserved protein.
Transposition, TnsE (Transposition_TnsE)
Type: Family

This group represents a transposition protein TnsE.
Replication-associated protein RepA4 (Rep_assoc_RepA4)
Type: Family

This group represents a replication-associated protein RepA4.
Resolvase, Rsv (Resolvase_Rsv)
Type: Family

This group represents a resolvase, Rsv type.
Cytochrome B pre-mRNA-processing protein 2 (Cbp2)
Type: Family

Cytochrome B pre-mRNA-processing protein 2 (Cbp2) is required for splicing of the group I intron bI5 of the COB pre-mRNA . It can also stimulate the splicing of the omega intron of the precursor of large ribosomal RNA .
4-hydroxy-3-methylbut-2-en-1-yl diphosphate synthase, bacterial (IspG_bac)
Type: Family

This protein previously of unknown biochemical function is essential in Escherichia coli. It has now been characterised as 1-hydroxy-2-methyl-2-(E)-butenyl 4-diphosphate synthase, which converts 2C-methyl-D-erythritol 2,4-cyclodiphosphate (ME-2,4CPP) into 1-hydroxy-2-methyl-2-(E)-butenyl 4-diphosphate in the sixth step of nonmevalonate terpenoid biosynthesis. The family is largely restricted to bacteria, where it is widely but not universally distributed. No homology can be detected between this family and other proteins.
L-aspartate semialdehyde sulfurtransferase MA1821-like (MA1821-like)
Type: Family

In Methanosarcina acetivorans, MA1821 is a L-aspartate semialdehyde sulfurtransferase required for O-acetylhomoserine sulfhydrylase (OAHS)-independent homocysteine (Hcy) biosynthesis . It contains two C-terminal cystathionine beta-synthase (CBS) domains. The CBS domains bind S-adenosyl-l-methionine (SAM) and 5'-methylthioadenosine (MTA), which induce a conformational change consistent with regulatory function. Another protein in the same pathway, MA1822, is involved in the reduction of the disulfide formed in MA1821 during the conversion of Asa (aspartate semialdehyde) to Hcy .
Uncharacterised conserved protein UCP004699, CBS/ParB-like (UCP004699_CBS/ParB)
Type: Family

This group represents an uncharacterised protein with CBS and ParB-like domains.
NADPH-dependent 7-cyano-7-deazaguanine reductase, QueF type 2 (QueF_type2)
Type: Family

This group represents QueF-like proteins, closely related to

(QueF/YkvM) but containing an additional N-terminal domain. They are predicted to function as NADPH-dependent nitrile oxidoreductase based on sequence similarity to

, and to catalyse the NADPH-dependent reduction of 7-cyano-7-deazaguanineto7-aminomethyl-7-deazaguanine, a late step in the biosynthesis of queuosine, a 7-deazaguanine modified nucleoside found in tRNA(GUN) of bacteria and eukaryotes.

Queuosine (Q) is an example of a highly modified nucleoside located in the anticodon wobble position 34 of tRNAs specific for Tyr, His, Asp, and Asn. With few exceptions (such as yeast and mycoplasma), it is widely distributed in most prokaryotic and eukaryotic phyla . Q is based on a very unusual 7-deazaguanosine core, which is further modified by addition of a cyclopentendiol ring .

This group of proteins belongs to the T fold structural superfamily and is related to GTP cyclohydrolase FolE. QueF-like proteins form two groups, type I proteins exemplified by Bacillus subtilis YkvM (

) and type II proteins exemplified by Escherichia coli YqcD (

). The type I proteins are comparable in size with bacterial and mammalian FolE, whereas the type II proteins are larger and are predicted to be comprised of two domains, similar to plant FolE .

In members of this entry, the N-terminal domain has often been annotated as a membrane-spanning domain, but transmembrane prediction programs run on YqcD do not detect any transmembrane segments . Instead, the QueF motif can be easily detected in this domain, whereas the flanking and invariant cysteine and glutamate residues (Cys-190 and Glu-230 in E. coli YqcD) are only present in the C-terminal domain. The splitting of active-site residues between the two domains of YqcD is very similar to that seen in two-domain FolE, in which neither domain contains the full set of active site residues nor is active when expressed separately. Further, the pattern of active-site splitting is the same in both proteins, with a similarly located conserved central sequence motif split from two flanking sequences, which are 40 residues apart. The splitting of the YqcD active site suggests that a gene duplication occurred, with each domain retaining some of the residues of the putative active site . As in two-domain FolE, such a duplication event and redistribution of active-site residues could allow the YqcD proteins to evolve a simpler quaternary structure than the QueF proteins .
NAD biosynthesis/regulator protein NadR (NAD_NadR)
Type: Family

NadR functions as a transcriptional regulator in Salmonella enterica . When NAD+ is available, NadR is bound with its corepressor, NAD+, and this leads to DNA binding activity that acts as a repressor for several genes needed for de novo NAD+ biosynthesis . NadR also possesses both NMN adenylyltransferase (NMNAT) and nicotinamide ribonucleoside kinase (RNK) activity . Haemophilus influenzae lacks de novo biosynthetic pathways for NAD+ and also lacks a helix-turn-helix DNA binding domain present in NadR of S. enterica. H. influenzae NadR does not function as a repressor, but has enzymatic activity. Nicotinamide riboside (NR) enters the NAD+ resynthesis pathway after uptake, it is phosphorylated to obtain NMN by a nicotinamide RNK activity, and subsequently, NAD+ is synthesized from NMN and ATP via an NMNAT activity . NadR is a multifunctional biosynthesis/regulator protein.
Cytadherence high molecular weight protein 2 (Cytadherence_Hmw2)
Type: Family

This group represents cytadherence high molecular weight protein 2. It is a component of the cytoskeleton-like structure which stabilises the shape of the wall-less Mycoplasma . This cytoskeleton-like network of accessory proteins containing HMW proteins 1 to 5 allows the proper anchoring of cytadhesin proteins in the mycoplasmal membrane at the attachment organelle .
Pyruvate-formate lyase-activating enzyme, predicted (Pyrv-formate_lyase-activ_prd)
Type: Family

This group represents a predicted pyruvate-formate lyase-activating enzyme.
Ribonuclease P subunit RNP4 (RNP4)
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 .

This entry represents ribonuclease P (Rnp) subunit RNP4 (also known as Rpp21) mostly from archaea. In the hyperthermophilic archaeon Pyrococcus horikoshii OT3, RNase P is composed of the RNase P RNA (pRNA) and five proteins (PhoPop5, PhoRpp38, PhoRpp21, PhoRpp29, and PhoRpp30) .
Small GTPase superfamily, Uncharacterized protein MJ1339 (Small_GTPase_MJ1339)
Type: Family

This entry represents the Uncharacterized protein MJ1339 from Methanocaldococcus jannaschii, thought to be part of the wider small GTPase superfamily.

Small GTPases form an independent superfamily within the larger class of regulatory GTP hydrolases. This superfamily contains proteins that control a vast number of important processes and possess a common, structurally preserved GTP-binding domain . Sequence comparisons of small G proteins from various species have revealed that they are conserved in primary structures at the level of 30-55% similarity .

Crystallographic analysis of various small G proteins revealed the presence of a 20kDa catalytic domain that is unique for the whole superfamily . The domain is built of five α helices (A1-A5), six β-strands (B1-B6) and five polypeptide loops (G1-G5). A structural comparison of the GTP- and GDP-bound forms allows one to distinguish two functional loop regions: switch I and switch II that surround the gamma-phosphate group of the nucleotide. The G1 loop (also called the P-loop) that connects the B1 strand and the A1 helix is responsible for the binding of the phosphate groups. The G3 loop provides residues for Mg2 and phosphate binding and is located at the N terminus of the A2 helix. The G1 and G3 loops are sequentially similar to Walker A and Walker B boxes that are found in other nucleotide binding motifs. The G2 loop connects the A1 helix and the B2 strand and contains a conserved Thr residue responsible for Mg2 binding. The guanine base is recognised by the G4 and G5 loops. The consensus sequence NKXD of the G4 loop contains Lys and Asp residues directly interacting with the nucleotide. Part of the G5 loop located between B6 and A5 acts as a recognition site for the guanine base .

The small GTPase superfamily can be divided into at least 8 different families, including:

Arf small GTPases. GTP-binding proteins involved in protein trafficking by modulating vesicle budding and uncoating within the Golgi apparatus.

Ran small GTPases. GTP-binding proteins involved in nucleocytoplasmic transport. Required for the import of proteins into the nucleus and also for RNA export.

Rab small GTPases. GTP-binding proteins involved in vesicular traffic.

Rho small GTPases. GTP-binding proteins that control cytoskeleton reorganisation.

Ras small GTPases. GTP-binding proteins involved in signalling pathways.

Sar1 small GTPases. Small GTPase component of the coat protein complex II (COPII) which promotes the formation of transport vesicles from the endoplasmic reticulum (ER).

Mitochondrial Rho (Miro). Small GTPase domain found in mitochondrial proteins involved in mitochondrial trafficking.

Roc small GTPases domain. Small GTPase domain always found associated with the COR domain.
Ribonuclease P protein subunit Rnp2, archaea (Rnp2_archaea)
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 .

In the hyperthermophilic archaeon Pyrococcus horikoshii OT3, RNase P is composed of the RNase P RNA (pRNA) and five proteins (PhoPop5, PhoRpp38, PhoRpp21, PhoRpp29, and PhoRpp30) . This entry represents protein component 2 (Rnp2, also known as Pop5) of ribonuclease (RNase) P (

).
Diphthamide synthesis DPH1/DPH2 (DPH1/DPH2)
Type: Family

Archaeal and eukaryotic translation elongation factor 2 contain a unique posttranslationally modified histidine residue called diphthamide, the target of the diphtheria toxin. Diphtheria toxin inhibits eukaryotic protein synthesis by ADP-ribosylating diphthamide in EF2 .

Members of this family include 2-(3-amino-3-carboxypropyl)histidine synthase subunit 1/2 (also known as Diphtheria toxin resistance protein 1/2, DPH 1/2), which are involved in the first step of diphthamide synthesis . Archaeal DPHs are more similar to eukaryotic DPH1 than to DPH2 .
Uncharacterised conserved protein UCP005063, CBS-type (UCP005063_CBS)
Type: Family

This group represents an uncharacterised protein with CBS domain pair, MJ1232 type.
MCT-1/Tma20 (MCT-1/Tma20)
Type: Family

This entry includes malignant T-cell-amplified sequence 1 (MCT-1) from animals and translation machinery-associated protein 20 (Tma20) from fungi. MCT-1 is an oncogene that plays a role in cell cycle regulation . The function of Tma20 is not clear. This entry also includes some uncharacterised proteins from archaea.
ATP-dependent RNA helicase SKI2-like (SKI2-like)
Type: Family

This family represents a group of ATP-dependent RNA helicases and their homologues, including Superkiller complex protein 2 (SKI2) and RNA helicase Mtr4 (also known as Dob1). SKI2 is a RNA helicase that forms Ski complex, which participates in many cytoplasmic pathways of the exosome in both yeast and metazoan cells, including 3'-to-5' mRNA turnover . Mtr4 is a ATP-dependent 3'-5' RNA helicase involved in nuclear RNA processing and degradation . This entry also includes Arabidopsis AtMTR4 (AT1G59760) and HEN2 (AT2G06990), which target specific subsets of nuclear transcripts for degradation by the nuclear exosome .
Sphingosine N-acyltransferase Lag1/Lac1-like (Lag1/Lac1-like)
Type: Family

Yeast ceramide synthase component Lag1 has a paralog, Lac1. This entry includes Lac1, Lag1 and their homologues from plants and animals , involved in sphingolipid synthesis.

LAG1 and LAC1 contain multiple membrane-spanning domains and are localised to the endoplasmic reticulum (ER) . They are essential subunits of the acyl-CoA-dependent ceramide synthase that is involved in synthesis of ceramide from C26(acyl)-coenzyme A and dihydrosphingosine or phytosphingosine .

Human Lac1/Lag1 homologue CERS2 (ceramide synthase 2) is a tumour metastasis suppressor that can inhibit breast cancer cell invasion .
Rubredoxin-oxygen oxidoreductase (Rubredoxin-O_OxRdtase)
Type: Family

This entry represents rubredoxin-oxygen oxidoreductases. This includes enzymes such as the flavorubredoxin oxidoreductase NorV (or nitric oxide reductase flavorubredoxin) that contains one rubredoxin domain and binds FMN as a cofatror, acting to sense nitric oxide (NO) by formation of a mono-nitrosyl iron complex. NorV uses NADH to detoxify nitric oxide under anaerobic conditions, thereby protecting several 4Fe-4S NO-sensitive enzymes . NorV has at least two reductase partners, one of which is NorW (flavorubredoxin reductase). NorV can also function as an aerobic oxygen reductase.

Other enzymes include the metalloflavoprotein FprA (also known as F420H2 oxidase) that functions as a low-potential electron donor to a number of redox enzymes , it catalyses the oxidation of two coenzymes F420H2 with one O2 to two coenzyme F420 and two H2O . There is also FpaA (flavoprotein A) that probably functions as an electron acceptor for a hydrogenase .
TEL2-interacting protein 1 (Tti1)
Type: Family

This entry includes yeast TEL2-interacting protein 1 (TTI1) and its homologues from animals.

TTI1 binds to TELO2 and TTI2 proteins to form the TTT complex, which plays a role in the assembly and stability of all phosphatidylinositol 3-kinase-related protein kinases (PIKKs) , pivotal proteins in various pathways related to cell metabolism, proliferation and differentiation . The TTT complex is involved in the cellular resistance to DNA damage stresses, like ionizing radiation (IR), ultraviolet (UV) and mitomycin C (MMC) . Budding yeast TTI1 is a subunit of the ASTRA complex, which is involved in chromatin remodelling .
tRNA-splicing endonuclease, archaeal short subfamily (tRNA_splic_arch_short)
Type: Family

tRNA-splicing endonucleases (

) catalyse the endonucleolytic cleavage of pre tRNA at the 5' and 3' splice sites to release the intron and produces two half tRNA molecules bearing 5' hydroxyl and 2', 3'-cyclic phosphate termini . The genes encoding these proteins are homologous in eukaryotes and archea. The eukaryotic tRNA-splicing endonucleases are heterotetrameric while the archaeal endonucleases can be split into homodimeric and homotetrameric subgroups.

This group represents a tRNA-splicing endonuclease belonging to the archaeal short subfamily .
RNA 3'-terminal phosphate cyclase type 2 (RNA3'_term_phos_cyc_type_2)
Type: Family

This entry represents the type 2 RNA 3'-terminal phosphate cyclases, also known as RNA'-terminal-phosphate-cyclase-like (Rcl) proteins .

RNA cyclases are a family of RNA-modifying enzymes that are conserved in eukaryotes, bacteria and archaea. Type 1 RNA 3'-terminal phosphate cyclases (

) catalyse the conversion of 3'-phosphate to a 2',3'-cyclic phosphodiester at the end of RNA:

ATP + RNA 3'-terminal-phosphate = AMP + diphosphate + RNA terminal-2',3'-cyclic-phosphate

The physiological function of the cyclase is not known, but the enzyme could be involved in the maintenance of cyclic ends in tRNA splicing intermediates or in the cyclisation of the 3' end of U6 snRNA .

A second subfamily of RNA 3'-terminal phosphate cyclases (type 2) that do not have cyclase activity have been identified in eukaryotes. They are localised to the nucleolus and are involved in ribosomal modification .