SII-SWORD/CoKE huggingface dataset:
XRCC1, first (central) BRCT domain (BRCT_XRCC1_rpt1)
Type: Domain

XRCC1 plays a key role in multiple DNA repair pathways by acting as a scaffold that binds to both DNA single strand breaks and gaps, poly (ADP-ribose) and to numerous DNA repair enzymes. It forms homodimers and interacts with polynucleotide kinase (PNK), DNA polymerase-beta (POLB), DNA ligase III (LIG3), APTX, APLF, and APEX1 . XRCC1 contains an N-terminal XRCC1-specific domain and two BRCT domains. This entry corresponds to the first (central) BRCT domain . This domain has been shown to interact with poly(ADP-ribosyl)ated (PARylated) PARP1. Inactivation of the central X1BR1 domain results in DNA damage hypersensitivity due to a defect in S phase-dependent DNA repair .
Acidic leucine-rich nuclear phosphoprotein 32 (AN32)
Type: Family

The ANP32 family members of phosphoproteins are composed of a N-terminal evolutionarily conserved leucine-rich repeat (LRR) domain and a C-terminal variable anionic region. They are multifunctional proteins involved in the regulation of many processes including tumor suppression, apoptosis, cell cycle progression or transcription . ANP32A is one of the components of the INHAT (INHibitor of AcetylTransferases) complex, which contains the histone chaperone TAF-I (template-activating factor-I), directly binds the core histones, and inhibits the acetylation of the core histones H3 and H4. ANP32B has been shown to interact with the core histones H3-H4 through its acidic concave domain . ANP32E is an H2A.Z chaperone able specifically to remove H2A.Z from the nucleosome . It has been shown that ANP32A is an essential host partner coopted to support influenza virus vRNP polymerase activity and contributes to the influenza virus host range. Moreover, ANP32A and ANP32B have been shown to cooperate with CRM1 to support HIV-1 RNA nuclear export .
ATP synthase, F0 complex, subunit A, bacterial/chloroplast (ATP_syn_F0_a_bact/chloroplast)
Type: Family

Transmembrane ATPases are membrane-bound enzyme complexes/ion transporters that use ATP hydrolysis to drive the transport of protons across a membrane. Some transmembrane ATPases also work in reverse, harnessing the energy from a proton gradient, using the flux of ions across the membrane via the ATPase proton channel to drive the synthesis of ATP.

This entry represents the F0 subunit mostly found in bacteria and in plant chloroplasts.
ATP synthase, F0 complex, subunit A, bacterial/mitochondria (ATP_synth_F0_asu_bact/mt)
Type: Family

Transmembrane ATPases are membrane-bound enzyme complexes/ion transporters that use ATP hydrolysis to drive the transport of protons across a membrane. Some transmembrane ATPases also work in reverse, harnessing the energy from a proton gradient, using the flux of ions across the membrane via the ATPase proton channel to drive the synthesis of ATP.

This entry represents the F0 subunit mostly found in bacteria and mitochondria.
Transcription factor AIB/MYC-like (AIB/MYC-like)
Type: Family

This entry includes several bHLH transcription factors from plants, such as AIB and MYC proteins (MYC2, MYC3 and MYC4). AIB, also termed AtbHLH17, or EN 35, is a transcription activator that regulates positively abscisic acid (ABA) response . MYC2, also termed protein jasmonate insensitive 1, is a transcriptional activator involved in abscisic acid (ABA), jasmonic acid (JA), and light signaling pathways . MYC3 is a transcription factor involved in tryptophan, jasmonic acid (JA) and other stress-responsive gene regulation . MYC4 is a transcription factor involved in jasmonic acid (JA) gene regulation. MYC2, together with MYC3 and MYC4, controls additively subsets of JA-dependent responses .
DNA polymerase III, subunit gamma/tau, helical lid domain (HLD_clamp_pol_III_gamma_tau)
Type: Domain

DNA polymerase III subunit gamma/tau is part of the DNA polymerase III holoenzyme. Gamma and tau subunits are isoforms, both containing the helical lid domain. Gamma interacts with the delta subunit to transfer the beta subunit on the DNA while tau serves as a scaffold to help in the dimerization of the core complex. Both are members of the clamp-loader clade of the AAA superfamily .
OBG-type GTPase (OBG_GTPase)
Type: Family

The P-loop guanosine triphosphatases (GTPases) control a multitude of biological processes, ranging from cell division, cell cycling, and signal transduction, to ribosome assembly and protein synthesis. GTPases exert their control by interchanging between an inactive GDP-bound state and an active GTP-bound state, thereby acting as molecular switches. The common denominator of GTPases is the highly conserved guanine nucleotide-binding (G) domain that is responsible for binding and hydrolysis of guanine nucleotides.

Within the translation factor-related (TRAFAC) class of P-loop GTPases, the OBG family comprises a group of high-molecular mass GTPases conserved from bacteria to eukaryotes. The OBG family consists of :

Obg from bacteria and eukaryotes .

DRG from eukaryotes and archaea. DRG proteins may regulate fundamental cellular processes through RNA binding .

Nog1 from eukaryotes and archaea. It is involved in the assembly of the large ribosomal subunit.

Yyaf/YchF from bacteria and eukaryotes. It consists of a central G domain, flanked by a coiled-coil domain and a TGS (ThrRS, GTPase, SpoT) domain. Members of this subfamily bind and hydrolyse ATP more efficiently than GTP .

Ygr210 from archaea and fungi.

The OBG-type G domain has a mononucleotide binding fold typical for the P-loop NTPases. A six-stranded mostly parallel β-sheet is flanked by α-helices on both sides. The OBG-type G domain contains five characteristic sequence motifs, termed G1-G5, involved in nucleotide binding and hydrolysis. The G1/Walker A motif (GXXXXGK(S/T)), also referred to as P-loop, helps to position the triphosphate moiety of the bound nucleotide. The G2 (X(T/S)X) and G3/Walker B (hhhDXXG) motifs are involved in the coordination of a Mg(2)+ ion that is required for nucleotide binding and hydrolysis. Specificity in nucleotide binding is conferred by the G4 motif, which has a (N/T)KXD signature in guanine nucleotide binding P-loop NTPases. The G5 motif ((T/G)(C/S)A) supports guanine base recognition .
Multicopper oxidase (Cu-oxidase_fam)
Type: Family

Copper is one of the most prevalent transition metals in living organisms and its biological function is intimately related to its redox properties. Since free copper is toxic, even at very low concentrations, its homeostasis in living organisms is tightly controlled by subtle molecular mechanisms. In eukaryotes, before being transported inside the cell via the high-affinity copper transporters of the CTR family, the copper (II) ion is reduced to copper (I). In blue copper proteins such as cupredoxin, the copper (I) ion form is stabilised by a constrained His2Cys coordination environment.

Multicopper oxidases oxidise their substrate by accepting electrons at a mononuclear copper centre and transferring them to a trinuclear copper centre; dioxygen binds to the trinuclear centre and, following the transfer of four electrons, is reduced to two molecules of water . There are three spectroscopically different copper centres found in multicopper oxidases: type 1 (or blue), type 2 (or normal) and type 3 (or coupled binuclear) . Multicopper oxidases consist of 2, 3 or 6 of these homologous domains, which also share homology to the cupredoxins azurin and plastocyanin. Structurally, these domains consist of a cupredoxin-like fold, a β-sandwich consisting of 7 strands in 2 β-sheets, arranged in a Greek-key β-barrel . Multicopper oxidases include:

Laccase (

) (urishiol oxidase), a 3-domain enzyme found in fungi and plants, which oxidises different phenols and diamines. CueO is a laccase found in Escherichia coli that is involved in copper-resistance .

Ascorbate oxidase (

), a 3-domain enzyme found in higher plants.

Nitrite reductase (

), a 2-domain enzyme containing type-1 and type-2 copper centres .

Fission yeast fio1 (also known as SpAC1F7.08), a multicopper oxidase that contains three cupredoxin domains and may function together with Frp1 in iron and copper uptakes in S. pombe .

In addition to the above enzymes there are a number of other proteins that are similar to the multi-copper oxidases in terms of structure and sequence, some of which have lost the ability to bind copper. These include: copper resistance protein A (copA) from a plasmid in Pseudomonas syringae; domain A of (non-copper binding) blood coagulation factors V (Fa V) and VIII (Fa VIII) ; yeast FET3 required for ferrous iron uptake and yeast FET5 (YFL041w), which similarly to FET3 it is an iron transport multicopper oxidase required for Fe2 ion high affinity uptake . It is targeted to vacuole via AP-3 pathway . Ferroxidase HEPHL1, included in this entry, is a copper-binding glycoprotein with ferroxidase activity that oxidises Fe2 to Fe3 without releasing radical oxygen species . It may be involved in the regulation of intracellular iron content.
Aminotransferase ALAT1/2-like (ALAT1/2-like)
Type: Family

This entry represents a group of aminotransferases, including ALAT1/2 from humans. ALAT1/2 catalyzes the reversible transamination between alanine and 2-oxoglutarate to form pyruvate and glutamate . This entry also includes ALAT1/2 found in Arabidopsis mitochondria and GGAT1/2 found in Arabidopsis peroxisomes. GGAT1/2 catalyzes the Glu:glyoxylate aminotransferase (GGT), Ala:glyoxylate aminotransferase (AGT), Ala:2-oxoglutarate aminotransferase (AKT) and Glu:pyruvate aminotransferase (GPT) reactions in peroxisomes .
Prenyltransferase subunit beta (PGGT1B-like)
Type: Family

Prenyltransferases catalyze the covalent attachment of isoprenoid lipids (farnesyl or geranylgeranyl) to a cysteine near the C terminus of their substrates. This entry includes geranylgeranyl transferase type-1/2 subunit beta (Cdc43/Bet2) and farnesyltransferase subunit beta (Ram1). Cdc43/Bet2 catalyzes the transfer of a geranyl-geranyl moiety from geranyl-geranyl diphosphate to proteins having the C-terminal sequence Cys-Ile-Ile-Leu or Cys-Val-Leu-Leu . Ram1 catalyzes the transfer of a farnesyl moiety from farnesyl diphosphate to a cysteine at the fourth position from the C terminus of several proteins having the C-terminal sequence Cys-aliphatic-aliphatic-X where X is Ser, Ala, Met, Cys, or Gln .
Peptidase M3A/M3B (Pept_M3A_M3B)
Type: Family

This group of metallopeptidases belong to MEROPS peptidase family M3 (clan MA(E)), subfamilies M3A and M3B. The protein fold of the peptidase domain for members of this family resembles that of thermolysin, the type example for clan MA.

The Thimet oligopeptidase family, is a large family of archaeal, bacterial and eukaryotic oligopeptidases that cleave medium sized peptides. The group contains:

Mitochondrial intermediate peptidase (

)

Neurolysin, mitochondrial precursor, (

)

Thimet oligopeptidase (

)

Dipeptidyl carboxypeptidase (

)

Oligopeptidase A (

)

Oligoendopeptidase F
Mad2-like (Mad2-like)
Type: Family

This entry includes Mad2 and Mad2-like proteins, including Mad2/Rev7 from yeasts and MAD2A/B from animals. Mad2 is a central component of the spindle assembly checkpoint, which is a feedback control that prevents cells with incompletely assembled spindles from leaving mitosis . Rev7 (also known as MAD2L2 or MAD2B) is an accessory subunit of DNA polymerase zeta . It also acts as an interaction module in a broad array of cellular pathways, including translesion DNA synthesis, cell cycle control, and non-homologous end joining .
Exosome complex exonuclease Rrp6-like (Rrp6-like)
Type: Family

Rrp6 is a nuclear-specific catalytic component of the RNA exosome complex which has 3'->5' exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events . In animals is also known as exosome complex component 10 (EXOSC10). In contrast to yeast and humans where Rrp6 is encoded by a single gene, plants such as Arabidopsis thaliana, rice, and polar, have three homologues of Rrp6 .
Cullin (Cullin)
Type: Family

Cullins are a family of hydrophobic proteins that act as scaffolds for ubiquitin ligases (E3). Cullins are found throughout eukaryotes. Humans express several cullins (Cul1, 2, 3, 4A, 4B, 5, 7 and 9), each forming part of a multi-subunit ubiquitin complex . Cullin-RING ubiquitin ligases (CRLs), such as Cul1 (SCF) , play an essential role in targeting proteins for ubiquitin-mediated destruction; as such, they are diverse in terms of composition and function, regulating many different processes from glucose sensing and DNA replication to limb patterning and circadian rhythms. The catalytic core of CRLs consists of a RING protein and a cullin family member. For Cul1, the C-terminal cullin-homology domain binds the RING protein. The RING protein appears to function as a docking site for ubiquitin-conjugating enzymes (E2s). Other proteins contain a cullin-homology domain, such as the APC2 subunit of the anaphase-promoting complex/cyclosome and the p53 cytoplasmic anchor PARC; both APC2 and PARC have ubiquitin ligase activity. The N-terminal region of cullins is more variable, and is used to interact with specific adaptor proteins .
Nicotinamide/nicotinate mononucleotide adenylyltransferase, eukaryotic (NMNAT_euk)
Type: Family

NMNAT represents the primary bacterial and eukaryotic adenylyltransferases for nicotinamide-nucleotide and for the deamido form, nicotinate nucleotide. It is an indispensable enzyme in the biosynthesis of NAD(+) and NADP(+). Nicotinamide-nucleotide adenylyltransferase synthesises NAD via the salvage pathway, while nicotinate-nucleotide adenylyltransferase synthesises the immediate precursor of NAD via the de novo pathway. Human NMNAT displays unique dual substrate specificity toward both NMN and NaMN, and can participate in both de novo and salvage pathways of NAD synthesis. This entry consists strictly of eukaryotic members and includes secondary structural elements not found in all NMNATs .
Ancient conserved domain protein family (ACDP)
Type: Family

Proteins containing the ancient conserved domain protein/cyclin M (CNNM) are integral membrane proteins that are conserved from bacteria to humans. CNNM family members influence metal ion homeostasis through mechanisms that may not involve direct membrane transport of the ions . Structurally, CNNMs contain large cytosolic regions composed of a CBS-pair and a cyclic nucleotide-binding homology (CNBH) domain . In mammals, the CNNM family consists of 4 integral membrane proteins (CNNM1-4). NNM-associated Mg2+ transport has been shown shown to be regulated by the binding of phosphatases of regenerating liver (PRLs). PRLs are potent oncogenes with strong association with metastatic cancers . In Caenorhabditis elegans, there are five CNNM family members that may work together to regulate Mg2+ homeostasis .
Protein ENHANCED DISEASE RESISTANCE 2-like (EDR2-like)
Type: Family

This entry includes EDR2 and EDR2L from Arabidopsis. They contain a pleckstrin homology and a StAR transfer (START) domain as well as a plant-specific domain of unknown function, DUF1336. EDR2 is a negative regulator of the salicylic acid- (SA-) mediated resistance to pathogens, including the biotrophic powdery mildew pathogens Golovinomyces cichoracearum and Blumeria graminis, and the downy mildew pathogen Hyaloperonospora parasitica, probably by limiting the initiation of cell death and the establishment of the hypersensitive response (HR) .
Thymidylate synthase/dCMP hydroxymethylase (Thymidate_synth/dCMP_Mease)
Type: Family

Thymidylate synthase (

) catalyzes the reductive methylation of dUMP to dTMP with concomitant conversion of 5,10-methylenetetrahydrofolate to dihydrofolate:
5,10-methylenetetrahydrofolate + dUMP = dihydrofolate + dTMP
This provides the sole
de novo
pathway for production of dTMP and is the only enzyme in folate metabolism in which the 5,10-methylenetetrahydrofolate is oxidised during one-carbon transfer . The enzyme is essential for regulating the balanced supply of the 4 DNA precursors in normal DNA replication: defects in the enzyme activity affecting the regulation process cause various biological and genetic abnormalities, such as thymineless death . The enzyme is an important target for certain chemotherapeutic drugs. Thymidylate synthase is an enzyme of about 30 to 35 Kd in most species except in protozoan and plants where it exists as a bifunctional enzyme that includes a dihydrofolate reductase domain . A cysteine residue is involved in the catalytic mechanism (it covalently binds the 5,6-dihydro-dUMP intermediate) . The sequence around the active site of this enzyme is conserved from phages to vertebrates.

Thymidylate synthase also acts as a regulator of its own expression by binding and inactivating its own RNA. Due to its key role in the de novo pathway for thymidylate synthesis and, hence, DNA synthesis, it is one of the most conserved enzymes across species and phyla . Thymidylate synthase is a well-recognized target for anticancer chemotherapy, as well as a valuable new target against infectious diseases . Interestingly, in several protozoa, a single polypeptide chain codes for both dihydrofolate reductase (DHFR) and thymidylate synthase (TS), forming a bifunctional enzyme (DHFR-TS), possibly through gene fusion at a single evolutionary point. DHFR-TS is also active as a dimer .

This entry also includes dUMP hydroxymethylases and dCMP hydroxymethyltransferases from bacteriophages. dCMP-HMase catalyses the reversible conversion of dCMP and CH2THF to hydroxymethyl-dCMP and THF. dUMP hydroxymethylase is encoded by several bacteriophages that infect Bacillus subtilis and contain hydroxymethyl-dUMP instead of dTMP in their DNA, for their own protection against the host restriction system .

dCMP hydroxymethyltransferase has a subunit fold and a dimerisation pattern in common with thymidylate synthases .
Fyv10 family (Fyv10_fam)
Type: Family

This entry represents a group of Gid-type RING finger containing proteins, including Rmd5 and Fyv10 from budding yeasts. Rmd5 and Fyv10 form the heterodimeric E3 ligase unit of the Gid (glucose induced degradation deficient) complex, which is involved in the proteasome-dependent degradation of fructose-1,6-bisphosphatase .

This entry also includes animal MAEA and RMND5A/B, which are core components of the CTLH E3 ubiquitin-protein ligase complex that selectively accepts ubiquitin from UBE2H and mediates ubiquitination and subsequent proteasomal degradation of the transcription factor HBP1. MAEA and RMND5A are both required for catalytic activity of the CTLH E3 ubiquitin-protein ligase complex . The CTLH complex has been linked to several different functions like regulation of cell morphology, proteasome-dependent degradation of non-ubiquitinated alpha-catenin, or modulation of endosome/lysosome-dependent degradation of ubiquitinated proteins via interaction with HRS (hepatocyte growth factor-regulated tyrosine kinase substrate) .
PITH domain-containing protein 1-like (PITH1-like)
Type: Family

This entry represents a group of PITH domain-containing proteins, including PITHD1 from animals. PITHD1 acts as an activator of an internal ribosome entry site (IRES) element in the RUNX1 gene and enhances RUNX1 expression that subsequently promoted megakaryocyte differentiation .
Terminal uridylyltransferase 4/7, nucleotidyltransferase domain (TUT4/7_NTP_transf)
Type: Domain

This domain is found in terminal uridylyltransferases from animals, such as TUT4 and TUT7 . Uridylyltransferases mediate the terminal uridylation of mRNAs with short (less than 25 nucleotides) poly(A) tails, hence facilitating global mRNA decay .
PTEN, phosphatase domain (PTP_PTEN)
Type: Domain

This entry represents the phosphatase domain found in PTEN, which is a magnesium-dependent bifunctional phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase/dual-specificity protein phosphatase PTEN (

;

;

), which possesses the following catalytic activities:

Phosphatidylinositol 3,4,5-trisphosphate + H(2)O = phosphatidylinositol 4,5-bisphosphate + phosphate.

A phosphoprotein + H(2)O = a protein + phosphate.

Protein tyrosine phosphate + H(2)O = protein tyrosine + phosphate.

This protein acts as a dual-specificity protein phosphatase, dephosphorylating tyrosine-, serine- and threonine-phosphorylated proteins . It also acts as a lipid phosphatase, removing the phosphate in the D3 position of the inositol ring from phosphatidylinositol 3,4,5-trisphosphate, phosphatidylinositol 3,4-diphosphate, phosphatidylinositol 3-phosphate and inositol 1,3,4,5-tetrakisphosphate. The lipid phosphatase activity is critical for its tumour suppressor function . PTEN antagonizes the PI3K-AKT/PKB signalling pathway by dephosphorylating phosphoinositides and thereby modulating cell cycle progression and cell survival. The unphosphorylated form of PTEN cooperates with AIP1 to suppress AKT1 activation. PTEN dephosphorylates tyrosine-phosphorylated focal adhesion kinase and inhibits cell migration and integrin-mediated cell spreading and focal adhesion form .
TPTE, protein tyrosine phosphatase-like catalytic domain (PTP_VSP_TPTE)
Type: Domain

Proteins containing this domain are a family of phosphoinositide phosphatases with substrates that include phosphatidylinositol-4,5-diphosphate and phosphatidylinositol-3,4,5-trisphosphate. This family is conserved in deuterostomes; VSP was first identified as a sperm flagellar plasma membrane protein in Ciona intestinalis . Gene duplication events in primates resulted in the presence of paralogs, transmembrane phosphatase with tensin homology (TPTE) and TPTE2, that retain protein domain architecture but, in the case of TPTE, have lost catalytic activity. TPTE, also called cancer/testis antigen 44 (CT44), may play a role in the signal transduction pathways of the endocrine or spermatogenic function of the testis. TPTE2, also called TPTE and PTEN homologous inositol lipid phosphatase (TPIP), occurs in several differentially spliced forms; TPIP alpha displays phosphoinositide 3-phosphatase activity and is localized on the endoplasmic reticulum, while TPIP beta is cytosolic and lacks detectable phosphatase activity . VSP/TPTE proteins contain an N-terminal voltage sensor consisting of four transmembrane segments, a protein tyrosine phosphatase (PTP)-like phosphoinositide phosphatase catalytic domain, followed by a regulatory C2 domain .
E3 ubiquitin-protein ligase RNF5/RNF185-like (RNF5/RNF185-like)
Type: Family

This entry represents a group of RING membrane-anchor proteins, including RNF5/RNF185 from humans and AtRMA1/AtRMA2/AtRMA3 from Arabidopsis. They contain a RING finger motif and a C-terminal membrane-anchoring domain. RNF5 and RNF185 are E3 ubiquitin-protein ligases .

AtRMA1, AtRMA2, and AtRMA3, are endoplasmic reticulum (ER)-localized Arabidopsis homologues of human outer membrane of the ER-anchor E3 ubiquitin-protein ligase, RING finger protein 5 (RNF5) . AtRMAs possess E3 ubiquitin ligase activity, and may play a role in the growth and development of Arabidopsis. The AtRMA1 and AtRMA3 genes are predominantly expressed in major tissues, such as cotyledons, leaves, shoot-root junction, roots, and anthers, while AtRMA2 expression is restricted to the root tips and leaf hydathodes. AtRma1 probably functions with the Ubc4/5 subfamily of E2. AtRMA2 is likely involved in the cellular regulation of ABP1 expression levels through interacting with auxin binding protein 1 (ABP1). AtRMA proteins contain an N-terminal C3HC4-type RING-HC finger and a trans-membrane-anchoring domain in their extreme C-terminal region .
Alfin (Alfin)
Type: Family

The Alfin family includes PHD finger protein Alfin1 and Alfin1-like proteins. They contain a conserved N domain at the N terminus, a PHD finger domain with conserved C4HC3 residues at the C terminus and a variable V region between the two conserved domains . Alfin1 is a histone-binding component that specifically recognises H3 tails trimethylated on 'Lys-4' (H3K4me3), which marks transcription start sites of virtually all active genes . Alfin1-like proteins have been shown to play roles in root growth and abiotic stress response .