SII-SWORD/CoKE huggingface dataset:
E3 ubiquitin-protein ligase UBR4, N-terminal (E3_UBR4_N)
Type: Domain

This entry represents the N-terminal domain of E3 ubiquitin-protein ligases UBR4 (POE or PUSHOVER in Drosophila) from animals. UBR4 is a component of the N-rule pathway, identified as noncanonical N-recognins implicated in bulk lysosomal degradation and autophagy. Proteins containing this domain are extraordinarily large proteins that recognise and bind to proteins with N-terminal destabilising residues according to the N-end rule leading them to their ubiquitination and degradation. These proteins share a UBR box with others E3-ligases UBR box proteins, but UBR4 lacks the ubiquitylation domain, suggesting that it may interact with other catalytic proteins .
Protein furry, C-terminal (Fry_C)
Type: Domain

This entry represents the C-terminal domain of protein furry (Fry). Fry plays a crucial role in the structural integrity of mitotic centrosomes and in the maintenance of spindle bipolarity. This domain binds to polo-like kinase 1 (Plk1) through the polo-box domain (PBD) of Plk1 in a manner dependent on the cyclin-dependent kinase 1-mediated Fry phosphorylation, promoting Plk1 activity during early mitosis. Fry also binds to Aurora A and may function as a scaffold promoting the interaction between AURKA and PLK1, thereby enhancing AURKA-mediated PLK1 phosphorylation .
Transcription factor IND-like (IND-like)
Type: Family

This entry represents a group of bHLH transcription factors from plants, including IND, HEC1/2/3 and RHD6 from Arabidopsis. IND is required for seed dispersal , while HEC1/2/3 are required for the female reproductive tract development and fertility . IND interacts with another bHLH transcription factor SPATULA (SPT), and together they regulate genes involved in modulating auxin transport . RDH6 is a transcription factor that is specifically required for the development of root hairs. It integrates a jasmonate (JA) signaling pathway that stimulates root hair growth . This entry also includes LF (LATE FLOWERING) and LAX PANICLE 1 from rice. LF regulates flowering time , while LAX1 is a transcription factor that may regulate organogenesis in postembryonic development. It is involved in the regulation of shoot branching by controlling axillary meristem initiation .
Ist3-like, RNA recognition motif (RRM_Ist3-like)
Type: Domain

This entry represents the RNA recognition motif (RRM) of the Ist3 family that includes fungal Ist3 (also known as SNU17), X-linked 2 RNA-binding motif proteins (RBMX2) found in Metazoa and plants, and similar proteins. Ist3 is a novel yeast Saccharomyces cerevisiae protein required for the first catalytic step of splicing and for progression of spliceosome assembly . It binds specifically to the U2 snRNP and is an intrinsic component of prespliceosomes and spliceosomes .

Yeast Ist3 contains an atypical RNA recognition motif (RRM), also termed RBD (RNA binding domain) or RNP (ribonucleoprotein domain). In the yeast pre-mRNA retention and splicing complex, the atypical RRM of Ist3 functions as a scaffold that organizes the other two constituents, Bud13 (bud site selection 13) and Pml1 (pre-mRNA leakage 1) . The biological function of RBMX2 remains unclear. It shows high sequence similarity to yeast ist3 protein and harbours one RRM as well.
Serine/threonine-protein kinase BSK (BSK)
Type: Family

This entry represents a group of plant serine/threonine-protein kinases, including BSK1-12 from Arabidopsis. They are the substrates of BRI1 kinase that activate downstream BR (brassinosteroid) signal transduction . BSK1 has been shown to interact with the PAMP (pathogen-associated molecular pattern) receptor FLAGELLIN SENSING2 and regulate plant innate immunity .
DNA polymerase alpha catalytic subunit, catalytic domain (POLBc_alpha)
Type: Domain

Three DNA-dependent DNA polymerases type B (alpha, delta, and epsilon) have been identified as essential for nuclear DNA replication in eukaryotes. DNA polymerase (Pol) alpha is almost exclusively required for the initiation of DNA replication and the priming of Okazaki fragments during elongation. In most organisms no specific repair role, other than check point control, has been assigned to this enzyme. Pol alpha contains both polymerase and exonuclease domains, but lacks exonuclease activity suggesting that the exonuclease domain may be for structural purposes only .
Transcription factor AIG1-like (AIG1-like)
Type: Family

This entry represents a group of plant bHLH transcription factors, including AIG1 and related proteins from Arabidopsis. AIG1, also known as TARGET OF MOOPTEROS 5 or BHLH32, is required for MP (MONOPTEROS, an auxin-dependent transcription factor)-dependent root initiation .
YKT6, SNARE motif (R-SNARE_YKT6)
Type: Domain

YKT6 forms complexes with syntaxin-5 (Qa), GS28 (Qb) and either Bet1 (Qc) or GS15 (Qc). This complex regulates the early secretory pathway of eukaryotic cells at the level of the transport from the ER-Golgi intermediate compartment (ERGIC) to the cis-Golgi and transport from the trans-Golgi network to the cis-Golgi, respectively . YKT6 is a member of the R-SNARE subfamily of SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins which contain coiled-coil helices (called SNARE motifs) that mediate the interactions between SNARE proteins, and a transmembrane domain.

The SNARE complex mediates membrane fusion, important for trafficking of newly synthesized proteins, recycling of pre-existing proteins and organelle formation. SNARE proteins are classified into four groups, Qa-, Qb-, Qc- and R-SNAREs, depending on whether the residue in the hydrophilic centre layer of the four-helical bundle is a glutamine (Q) or arginine (R). Qa-, as well as Qb- and Qc-SNAREs, are localized to target organelle membranes, while R-SNARE is localized to vesicle membranes. They form unique complexes consisting of one member of each subgroup, that mediate fusion between a specific type of vesicles and their target organelle. Their SNARE motifs form twisted and parallel heterotetrameric helix bundles .
Inositol polyphosphate 5-phosphatase, plant (IP5P_plant)
Type: Family

This entry represents a group of plant inositol polyphosphate 5-phosphatases (IP5Ps), including IP5P1-10 from Arabidopsis. IP5P1 has phosphatase activity toward Ins(1,4,5)P3 and Ins(1,3,4,5)P4, but not toward Ins(1,4)P2, Ins1P . It can also hydrolyze PtdIns(4,5)P2 and PtdIns(3,4,5)P3 .
tRNA (uracil(54)-C(5))-methyltransferase, metazoa type (TRM2_met)
Type: Family

This entry represents a family of tRNA (uracil-5-)-methyltransferase homologues (

), mainly found in metazoa, including tRNA (uracil-5-)-methyltransferase homologue A (TRMT2A) and B (TRMT2B) from human. TRMT2A catalyses the formation of 5-methyl-uridine in tRNAs and some mRNAs . TRMT2A/B mainly catalyse the methylation of uridine at position 54 (m5U54) in cytosolic tRNAs . This family also includes the plant homologue AtC3H24 (also known as TRNA METHYLTRANSFERASE 2B) and putative RNA methyltransferases R405/407 from Acanthamoeba polyphaga mimivirus.

Methyltransferases (EC [ec:2.1.1.-]) constitute an important class of enzymes present in every life form. They transfer a methyl group most frequently from S-adenosyl L-methionine (SAM or AdoMet) to a nucleophilic acceptor such as oxygen leading to S-adenosyl-L-homocysteine (AdoHcy) and a methylated molecule . All these enzymes have in common a conserved region of about 130 amino acid residues that allow them to bind SAM . The substrates that are methylated by these enzymes cover virtually every kind of biomolecules ranging from small molecules, to lipids, proteins and nucleic acids . Methyltransferase are therefore involved in many essential cellular processes including biosynthesis, signal transduction, protein repair, chromatin regulation and gene silencing . More than 230 families of methyltransferases have been described so far, of which more than 220 use SAM as the methyl donor.
AMP-binding enzyme, C-terminal domain superfamily (AMP-bd_C_sf)
Type: Homologous_superfamily

This is a small domain that is found C-terminal to

in ATP-dependent AMP-binding enzymes from eukaryotes, bacteria and archaea, including Acetyl-coenzyme A synthetase (Acs). In Acs, this domain undergoes a large rotation to allow for both half-reaction to occur. It shows a central β-sheet core that is flanked by α-helices .
Protein UNC80, central region (UNC80_central)
Type: Domain

This entry represents the central region of protein UNC80 from eukaryotes, a component of the NALCN sodium channel complex. NALCN is a cation voltage-independent channel activated by substance P, neurotensin, acetylcholine and noradrenaline that controls neuronal excitability. UNC80 forms a complex with UNC79 and both are key regulators of the channel and required for the proper expression and axonal localisation of NALCN. UNC80 is required for NALCN control by GPCRs and essential for its sensitivity to extracellular calcium. This protein acts as a scaffold for Src family of tyrosine kinases (SFK) and UNC-79 to mediate interaction with NALCN . Proteins containing this domain also include some uncharacterised proteins from fungi.
Peptide chain release factor class I superfamily (Pep_chain_release_fac_I_sf)
Type: Homologous_superfamily

Peptide chain release factors (RFs) are required for the termination of protein biosynthesis . At present two classes of RFs can be distinguished. Class I RFs bind to ribosomes that have encountered a stop codon at their decoding site and induce release of the nascent polypeptide. Class II RFs are GTP-binding proteins that interact with class I RFs and enhance class I RF activity. In prokaryotes there are two class I RFs that act in a codon specific manner : RF-1(gene prfA) mediates UAA and UAG-dependent termination while RF-2 (gene prfB) mediates UAA and UGA-dependent termination. RF-1 and RF-2 are structurally and evolutionary related proteins which have been shown to be part of a larger family .
Nitrite and sulphite reductase 4Fe-4S domain-like superfamily (NO2/SO3_Rdtase_4Fe4S_sf)
Type: Homologous_superfamily

Sulphite reductases (SiRs) and related nitrite reductases (NiRs) catalyse the six-electron reduction reactions of sulphite to sulphide, and nitrite to ammonia, respectively. The Escherichia coli SiR enzyme is a complex composed of two proteins, a flavoprotein alpha-component (SiR-FP) and a hemoprotein beta-component (SiR-HP) (

), and has an α(8)β(4) quaternary structure . SiR-FP contains both FAD and FMN, while SiR-HP contains a Fe(4)S(4) cluster coupled to a siroheme through a cysteine bridge. Electrons are transferred from NADPH to FAD, and on to FMN in SiR-FP, from which they are transferred to the metal centre of SiR-HP, where they reduce the siroheme-bound sulphite.

SiR-HP has a two-fold symmetry, which generates a distinctive three-domain α/β fold that controls assembly and reactivity . In the E. coli SiR-HP enzyme (

), the iron is bound to cysteine residues at positions 433, 439, 478 and 482, the latter also forming the siroheme ligand.
Oligo-1,6-glucosidase, domain 2 (O16G_dom_2)
Type: Homologous_superfamily

This superfamily represents the domain 2 of oligo-1,6-glucosidase MalL . This domain can be found in some glycosyl hydrolase 13 (

) family members, such as TreS from Mycobacterium smegmatis , YM304_32550 from Ilumatobacter coccineus , BbmA from Bacillus subtilis and YcjM from Escherichia coli .

Family GH13 is the major glycoside hydrolase family acting on substrates containing α-glucoside linkages. GH13 contains hydrolases, transglycosidases, and isomerases ; noticeably, animal amino acid transporters , which have no glycosidase activity , are also GH13 members. The enzymes are found in a very wide range of organisms from all kingdoms. The GH13 enzymes have a wide range of different preferred substrates and products. For example, the α-amylases prefer polysaccharides of the α-1,4-glucan type, such as amylose and amylopectin, but are also able to attack the supramolecular structures represented by starch granules and glycogen particles. Among thousands of sequences and ~30 different enzyme specificities many are closely related to each other; GH13 therefore has officially been subdivided into almost 40 subfamilies . In general, the GH13 members are multidomain proteins with catalytic (β/α)8-barrel (i.e. TIM-barrel) domain (called domain A) having a small domain B (usually varying in length and of irregular structure) . Some of these enzymes include:

α-amylase

oligo-1,6-glucosidase

α-glucosidase

pullulanase

cyclomaltodextrinase

maltotetraose-forming α-amylase

isoamylase

dextran glucosidase

trehalose-6-phosphate hydrolase

maltohexaose-forming α-amylase

)

maltotriose-forming α-amylase

maltogenic amylase

neopullulanase

malto-oligosyltrehalose trehalohydrolase

limit dextrinase

amylosucrase

sucrose phosphorylase

cyclomaltodextrin glucanotransferase (CGTase)

4-α-glucanotransferase

isomaltulose synthase

trehalose synthase

O-Glycosyl hydrolases (

) are a widespread group of enzymes that hydrolyse the glycosidic bond between two or more carbohydrates, or between a carbohydrate and a non-carbohydrate moiety. A classification system for glycosyl hydrolases, based on sequence similarity, has led to the definition of 85 different families . This classification is available on the CAZy (CArbohydrate-Active EnZymes) website.
Peroxisome biogenesis factor 2, HC subclass-RING finger domain (RING-HC_PEX2)
Type: Domain

This entry represents the RING finger domain, HC subclass, found exclusively in eukaryotic proteins such as the Peroxisome biogenesis factor 2 (PEX2) from Homo sapiens and Arabidopsis thaliana.

PEX2 is an integral peroxisomal membrane protein with two transmembrane regions and a C3HC4-type RING-HC finger within its cytoplasmically exposed C terminus. It may be involved in the biogenesis of peroxisomes, as well as in peroxisomal matrix protein import . Mutations in the PEX2 gene are the primary defect in a subset of patients with Zellweger syndrome and related peroxisome biogenesis disorders . Moreover, PEX2 functions as an E3-ubiquitin ligase that mediates the UBC4-dependent polyubiquitination of PEX5, a key player in peroxisomal matrix protein import, to control PEX5 receptor recycling or degradation .
Snake toxin-like superfamily (Snake_toxin-like_sf)
Type: Homologous_superfamily

This domain superfamily is predominantly found in venomous neurotoxins and cytotoxins from snakes, but also structurally similar (non-snake) toxin-like proteins (TOLIPs) such as Lymphocyte antigen 6D and Ly6/PLAUR domain-containing protein. Snake toxins are short proteins with a compact, disulphide-rich structure. TOLIPs have similar structural features (abundance of spaced cysteine residues, a high frequency of charge residues, a signal peptide for secretion and a compact structure) . This structure can be found in the extracellular domain of TGF-beta-family receptors. This domain can also be found in BMP and activin membrane-bound inhibitor (BAMBI), which is a regulator related to TGF-beta-family type I receptors but lacks an intracellular kinase domain .
CorA, cytoplasmic domain (CorA_cytoplasmic_dom)
Type: Homologous_superfamily

This superfamily represents the N-terminal cytoplasmic domain of the Mg2+ transporter protein CorA. Thermotoga maritima CorA is an efflux system that forms funnel-shaped homopentamers, the tip of the funnel is formed from two C-terminal transmembrane (TM) helices from each monomer, and the large opening of the funnel from the N-terminal cytoplasmic domains . This domain can also be found in zinc transport protein ZntB .

Thermotoga maritima CorA (TmCorA) has 2 TM domains,TM1 and TM2 . The loop connecting TM1 and TM2 contains the conserved CorA signature motifs YGMNF and MPEL. With its N- and C-terminal ends face the cytosol and its similarity to the class II CorA (a CorA group lacking the MPEL motif and may transport divalent cations out of the cell), TmCorA is predicted to be primarily involved in ion efflux . It forms a pentameric membrane protein channel featuring a possible ion discriminating aspartate ring at the cytoplasmic entrance of the pore and two distinct cytoplasmic metal binding sites per monomer, which could have regulatory roles .
Nucleotidyltransferase Trf4-like (Trf4-like)
Type: Family

This protein family includes nucleotidyltransferases that use nuclear RNA as substrate, such as Trf4 (also known as Poly(A) RNA polymerase protein 2, PAP2) from S. cerevisiae and its homologues Terminal nucleotidyltransferase 4A/B from humans (TENT4A and TENTB, also known as PAPD7/TRF4-1 and PAPD5/TRF4-2, respectively), Poly(A) RNA polymerase protein 1 from Saccharomyces cerevisiae (TRF5), and Poly(A) RNA polymerase cid12 from Schizosaccharomyces pombe (Cid12 or PAP). These proteins function as subunits of the TRAMP-like complexes, which have a poly(A) RNA polymerase activity and are involved in a post-transcriptional quality control mechanism limiting inappropriate expression of genetic information .

TRF4 from humans catalyses preferentially the transfer of ATP and GTP on RNA 3' poly(A) tail creating a heterogeneous 3' poly(A) tail leading to mRNAs stabilization by protecting mRNAs from active deadenylation .

In S. cerevisiae, TRF5 polyadenylates RNA processing and degradation intermediates of snRNAs, snoRNAs and mRNAs that accumulate in strains lacking a functional exosome. TRF5 is also required for proper nuclear division in mitosis and sister chromatid cohesion. It is involved in the regulation of histone mRNA levels .

Cid12 from S. pombe, has a role in the RNA interference (RNAi) pathway which is important for heterochromatin formation and accurate chromosome segregation. It is a member of the RNA-directed RNA polymerase complex (RDRC) which is involved in the generation of small interfering RNAs (siRNAs) and mediate their association with the RNA-induced transcriptional silencing (RITS) complex .
CorA, transmembrane region (CorA_TM1_TM2)
Type: Homologous_superfamily

This superfamily represents the transmembrane region (including TM1 and TM2) of the Mg2 transporter protein CorA. Thermotoga maritima CorA is an efflux system that forms funnel-shaped homopentamers, the tip of the funnel is formed from two C-terminal transmembrane (TM) helices from each monomer, and the large opening of the funnel from the N-terminal cytoplasmic domains . This domain can also be found in zinc transport protein ZntB and plant magnesium transporter MRS2 .

Thermotoga maritima CorA (TmCorA) has 2 TM domains,TM1 and TM2 . The loop connecting TM1 and TM2 contains the conserved CorA signature motifs YGMNF and MPEL. With its N- and C-terminal ends face the cytosol and its similarity to the class II CorA (a CorA group lacking the MPEL motif and may transport divalent cations out of the cell), TmCorA is predicted to be primarily involved in ion efflux . It forms a pentameric membrane protein channel featuring a possible ion discriminating aspartate ring at the cytoplasmic entrance of the pore and two distinct cytoplasmic metal binding sites per monomer, which could have regulatory roles .
Class II Aminoacyl-tRNA synthetase/Biotinyl protein ligase (BPL) and lipoyl protein ligase (LPL) (aa-tRNA-synth_II/BPL/LPL)
Type: Homologous_superfamily

This superfamily represents the fold comprising the seven β-strands found in the catalytic domain of Class II of aminoacyl-tRNA synthetases (aaRS), the lipoyl protein ligase (LPL) and the biotinyl protein ligase (BPL), which structurally homologous . Interestingly, Class II of aaRSs has a two-step reaction mechanism analogous to that of BPL. It first catalyses the ATP-dependent formation of an aminoacyl-AMP intermediate and then transfer the activated aminoacyl moiety to an acceptor tRNA .

The aminoacyl-tRNA synthetases (also known as aminoacyl-tRNA ligases) catalyse the attachment of an amino acid to its cognate transfer RNA molecule in a highly specific two-step reaction . These proteins differ widely in size and oligomeric state, and have limited sequence homology . The 20 aminoacyl-tRNA synthetases are divided into two classes, I and II. Class I aminoacyl-tRNA synthetases contain a characteristic Rossman fold catalytic domain and are mostly monomeric . Class II aminoacyl-tRNA synthetases share an antiparallel β-sheet fold flanked by α-helices , and are mostly dimeric or multimeric, containing at least three conserved regions . However, tRNA binding involves an α-helical structure that is conserved between class I and class II synthetases. In reactions catalysed by the class I aminoacyl-tRNA synthetases, the aminoacyl group is coupled to the 2'-hydroxyl of the tRNA, while, in class II reactions, the 3'-hydroxyl site is preferred. The synthetases specific for arginine, cysteine, glutamic acid, glutamine, isoleucine, leucine, methionine, tyrosine, tryptophan, valine, and some lysine synthetases (non-eukaryotic group) belong to class I synthetases. The synthetases specific for alanine, asparagine, aspartic acid, glycine, histidine, phenylalanine, proline, serine, threonine, and some lysine synthetases (non-archaeal group), belong to class-II synthetases. Based on their mode of binding to the tRNA acceptor stem, both classes of tRNA synthetases have been subdivided into three subclasses, designated 1a, 1b, 1c and 2a, 2b, 2c .

BPLs and LPLs are evolutionarily related protein families, with a homologous catalytic module (seven-stranded mixed β-sheet on one side and four α-helices on the other side) that must have evolved from a common ancestor . Amino acid sequence conservation between the catalytic modules of biotinyl protein ligases (BPLs) and lipoyl protein ligases (LPLs) is very low, and mainly affects residues that are important for the scaffold of the structure, such as those contributing to the hydrophobic core. Despite the poor overall sequence similarity, a single lysine residue is strictly conserved in all LPL and BPL sequences. This lysine residue is likely to bind specifically to the carbonyl oxygen of the carboxyl group of biotin or at the end of the hydrogen-carbon tail of the lipoyl moiety .
ACT-like domain (ACT-like_dom_sf)
Type: Homologous_superfamily

The ACT domain is found in a variety of contexts and is proposed to be a conserved regulatory binding fold. ACT domains, named after the proteins Aspartate kinase, Chorismate mutase and TyrA (prephenate dehydrogenase), are important for the allosteric regulation of many enzymes, including a wide range of metabolic enzymes.

The archetypical ACT domain is the C-terminal regulatory domain of 3-phosphoglycerate dehydrogenase (3PGDH), which folds with a ferredoxin-like topology. A pair of ACT domains form an eight-stranded antiparallel sheet with two molecules of allosteric inhibitor serine bound in the interface. Biochemical exploration of a few other proteins containing ACT domains supports the suggestions that these domains contain the archetypical ACT structure .

This entry represents the ACT-like domain found in diverse proteins from bacteria, eukaryotes and archaea.
Protein FAM210A/B-like (FAM210A/B-like)
Type: Family

This protein family includes Protein FAM210A (and its homologues) and FAM210B, which contain a transmembrane peptide .

FAM210A, a protein essential in maintaining skeletal muscle structure and strength , interacts with mitochondrial translation elongation factor EF-Tu and promotes mitochondrial protein expression. FAM210B plays a role in erythroid differentiation and is involved in cell proliferation and tumor cell growth suppression .