SII-SWORD/CoKE huggingface dataset:
PIK3R1, inter-SH2 domain (ISH2_PIK3R1)
Type: Domain

Phosphoinositide 3-kinases (PI3Ks) are essential for cell growth, migration, and survival. Class IA PI3Ks are heterodimers of a p110 catalytic (C) subunit and a p85-related regulatory (R) subunit . p110 is composed of an adaptor-binding domain, a Ras-binding domain, a C2 domain, a helical domain, and a kinase domain. p85 is composed of an SH3 domain, a RhoGap domain, a N-terminal SH2 (nSH2) domain, a inter SH2 (iSH2) domain, and C-terminal (cSH2) domain. There are two inhibitory interactions between p110alpha and p85 of P13K: 1) p85 nSH2 domain with the C2, helical, and kinase domains of p110alpha and 2) p85 iSH2 domain with C2 domain of p110alpha. There are three inhibitory interactions between p110beta and p85 of P13K: 1) p85 nSH2 domain with the C2, helical, and kinase domains of p110beta, 2) p85 iSH2 domain with C2 domain of p110beta, and 3) p85 cSH2 domain with the kinase domain of p110beta .

Among all the class IA PI3K combinations, p85alpha/p110alpha heterodimer has been the most intensely investigated. p110alpha has been shown to be stabilized and inhibited by dimerization with p85alpha . Moreover, p85alpha (also called PIK3R1) has functions independent of its PI3K regulatory role. It can independently stimulate signalling pathways involved in cytoskeletal rearrangements . PIK3R1 has been shown to play an important role in insulin signalling .

This entry represents the iSH2 domain found in PIK3R1.
DNA Ligase 4, adenylation domain (Adenylation_DNA_ligase_IV)
Type: Domain

DNA ligase (polydeoxyribonucleotide synthase) is the enzyme that joins two DNA fragments by catalysing the formation of an internucleotide ester bond between phosphate and deoxyribose. It is active during DNA replication, DNA repair and DNA recombination. There are two forms of DNA ligase, one requires ATP (

), the other NAD (

), the latter being restricted to eubacteria. Eukaryotic, archaebacterial, viral and some eubacterial DNA ligases are ATP-dependent. The first step in the ligation reaction is the formation of a covalent enzyme-AMP complex. The co-factor ATP is cleaved to pyrophosphate and AMP, with the AMP being covalently joined to a highly conserved lysine residue in the active site of the ligase. The activated AMP residue is then transferred to the 5'phosphate of the nick, before the nick is sealed by phosphodiester-bond formation and AMP elimination .

There are three classes of ATP-dependent DNA ligase in eukaryotic cells (I, III and IV). DNA ligase IV is required for DNA non-homologous end joining pathways, including recombination of the V(D)J immunoglobulin gene segments in cells of the mammalian immune system. DNA ligases have a highly modular architecture consisting of a unique arrangement of two or more discrete domains. The adenylation and C-terminal oligonucleotide/oligosaccharide binding (OB)-fold domains comprise a catalytic core unit that is common to all members of the ATP-dependent DNA ligase family. The adenylation domain binds ATP and contains many of the active-site residues .

DNA ligase 4 is involved in DNA double-strand break repair . In higher eukaryotes it forms a complex with XRCC4, which is responsible for the ligation step during the DNA-PK-dependent non-homologous end joining (D-NHEJ) . The Ku component of the DNA-PK (DNA-dependent protein kinase) complex contributes to the recruitment of the LIG4-XRCC4 complex at the DNA break site .

This entry represents the adenylation domain found in DNA ligase 4.
IF2a, S1-like domain (S1_IF2_alpha)
Type: Domain

Eukaryotic and archaeal Initiation Factor 2 (e- and aIF2, respectively) are heterotrimeric proteins with three subunits (alpha, beta, and gamma). The IF2a subunit is a major site of control of the translation initiation process, via phosphorylation of a specific serine residue . This alpha subunit is well conserved in eukaryotes and archaea but is not present in bacteria.

This entry represents the S1-like domain found in alpha subunit of both eukaryotic and archaeal translation initiator factor 2. The S1 domain is a RNA binding domain identified in Escherichia coli polynucleotide phosphorylase .
Initiation factor eIF2 gamma, domain 2 (eIF2g_dom_2)
Type: Domain

In eukaryotes and archaea, the e/aIF2 factor is involved in the initiation of protein biosynthesis. In its GTP bound form, e/aIF2 delivers methionylated initiator tRNA to the small subunit of the ribosome. After the pairing between the AUG initiation codon on mRNA and the CAU anticodon of the initiator tRNA, GTP is hydrolysed and e/aIF2:GDP is released from the ribosome. In eukaryotes, eIF2B acts as the guanine nucleotide exchange factor for eIF2. Archaea have no equivalent of eIF2B, and the exchange between GDP and GTP is thought to be spontaneous . eIF2 is composed of three subunits, alpha, beta and gamma. The gamma subunit forms the core of the heterotrimer and confers both tRNA binding and GTP/GDP binding .

This entry represents the domain 2 of eIF2gamma (EIF2g) from eukaryota and archaea. It adopts a β-barrel structure, and is involved in binding to both charged tRNA .
Initiation factor eIF2 gamma, GTP-binding domain (eIF2g_GTP-bd)
Type: Domain

In eukaryotes and archaea, the e/aIF2 factor is involved in the initiation of protein biosynthesis. In its GTP bound form, e/aIF2 delivers methionylated initiator tRNA to the small subunit of the ribosome. After the pairing between the AUG initiation codon on mRNA and the CAU anticodon of the initiator tRNA, GTP is hydrolysed and e/aIF2:GDP is released from the ribosome. In eukaryotes, eIF2B acts as the guanine nucleotide exchange factor for eIF2. Archaea have no equivalent of eIF2B, and the exchange between GDP and GTP is thought to be spontaneous . eIF2 is composed of three subunits, alpha, beta and gamma. The gamma subunit forms the core of the heterotrimer and confers both tRNA binding and GTP/GDP binding .

This entry represents the GTP-binding domain of eIF2gamma (EIF2g) from eukaryotes and archaea .
Rho guanine nucleotide exchange factor 3, PH domain (PH_RhoGEF3_XPLN)
Type: Domain

PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner . They share little sequence conservation, but all have a common fold, which is electrostatically polarised. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity . PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane . A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signalling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes .

ARHGEF3 (also known as XPLN) is a guanine nucleotide exchange factor (GEF) for RhoA and RhoB GTPases . It contains a tandem Dbl homology and a PH domain. This entry represents the PH domain.
Iron transport multicopper oxidase Fet3-like, the second Cupredoxin domain (CuRO_2_Fet3-like)
Type: Domain

Fet3 is a multicopper-containing glycoprotein localised to the yeast plasma membrane that catalyses the oxidation of Fe(II) to Fe(III). The periplasmic produced Fe(III) is transferred to the permease Ftr1 for import into the cytosol. The four copper ions are inserted post-translationally and are essential for catalytic activity, thus linking copper and iron homeostasis .

Like other related multicopper oxidases (MCOs), Fet3 is composed of three cupredoxin domains that include one mononuclear and one trinuclear copper centre. The copper ions are bound in several sites: Type 1, Type 2, and/or Type 3. The ensemble of types 2 and 3 copper is called a trinuclear cluster. MCOs oxidize their substrate by accepting electrons at a mononuclear copper centre and transferring them to the active site trinuclear copper centre. The cupredoxin domain 2 of 3-domain MCOs has lost the ability to bind copper .

This entry represents the the second Cupredoxin domain of Fet3. This domain can also be found in Fet5, Gmc1 from budding yeasts and Fio1 from fission yeasts .
Dual specificity tyrosine-phosphorylation-regulated kinase 1A/1B, catalytic domain (PKc_DYR1A/1B)
Type: Domain

Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) (

) phosphorylates serine, threonine and tyrosine residues in proteins such as CRY2, FOXO1 and SIRT1 . It can be activated by tyrosine autophosphorylation . DYRK1A play a role in a signaling pathway regulating nuclear functions of cell proliferation. DYRK1A is a neurogenesis regulator and plays an important role in altered brain development in Down syndrome .

This entry represents the catalytic domain found in DYRK1A and DYRK1B.
Glutamine-binding periplasmic protein GlnH, type 2 periplasmic binding protein fold (PBP2_GlnH)
Type: Domain

GlnH belongs to the type 2 periplasmic-binding fold protein (PBP2) superfamily, whose members are involved in chemotaxis and uptake of nutrients and other small molecules from the extracellular space as a primary receptor . PBP2 typically comprises of two globular subdomains connected by a flexible hinge and bind their ligand in the cleft between these domains in a manner resembling a Venus flytrap. After binding their specific ligand with high affinity, they can interact with a cognate membrane transport complex comprised of two integral membrane domains and two receptor cytoplasmically-located ATPase domains. This interaction triggers the ligand translocation across the cytoplasmic membrane energized by ATP hydrolysis .
KMT2A, PHD domain 3 (KMT2A_PHD3)
Type: Domain

Histone-lysine N-methyltransferase 2A (KMT2A;

) is the catalytic subunit of the MLL1/MLL complex, mediating methylation of 'Lys-4' of histone H3 (H3K4me), a specific tag for epigenetic transcriptional activation . KMT2A is processed by the threonine endopeptidase taspase, releasing products N320 and C180 . KMT2A contains a CxxC (x for any residue) zinc finger domain, three plant homeodomain (PHD) fingers, a Bromodomain domain, an extended PHD (ePHD) finger, Cys2HisCys5HisCys2His, two FY (phenylalanine tyrosine)-rich domains, and a SET (Suppressor of variegation, Enhancer of zeste, Trithorax) domain.

This entry represents the third PHD domain of KMT2A.
Synaptotagmin-like protein 4 , FYVE-related domain (FYVE_Slp4)
Type: Domain

Synaptotagmin-like protein 4 (SYTL4, Slp4), also known as granuphilin or exophilin-2, belongs to the synaptotagmin-like protein family (Slp), which is a group of putative membrane trafficking proteins . The characteristic feature of the Slp family is the N-terminal Slp homology domain (SHD), which functions as a Rab27-binding domain and C-terminal tandem C2 domains (known as the C2A domain and C2B domain), putative Ca2+-binding motifs . SHD consists of two conserved regions, designated SHD1 and SHD2, which may function as protein interaction sites. The SHD1 and SHD2 of Slp4 are separated by a putative FYVE zinc finger, which resembles a FYVE-related domain that is structurally similar to the canonical FYVE domains but lacks the three signature sequences: an N-terminal WxxD motif (x for any residue), the central basic R(R/K)HHCRxCG patch, and a C-terminal RVC motif.

There are several alternatively spliced isoform of Slp4. Slp4-a (granuphilin-a) has two C2 domains, whereas Slp4-b (granuphilin-b) contains only the first C2 domain. Expression of Slp4-a inhibits regulated secretion in endocrine cells. Slp4-a binds to both the GTP- and GDP-bound forms of Rab27A and inhibits a specific GTP/GDP exchange cycle required for dense-core vesicle exocytosis . Slp4 has been detected in the pancreatic islet, in particular in insulin-positive beta cells, and in pituitary .

This entry represents the FYVE-related domain of synaptotagmin-like protein 4.
Methionyl-tRNA formyltransferase, C-terminal domain (Met-tRNA-FMT_C)
Type: Domain

Met-tRNA-FMT transfers a formyl group from N-10 formyltetrahydrofolate to the amino terminal end of a methionyl-aminoacyl-tRNA acyl moiety, yielding formyl-Met-tRNA. Formyl-Met-tRNA plays an essential role in protein translation initiation by forming a complex with IF2. The formyl group plays a dual role in the initiator identity of N-formylmethionyl-tRNA by promoting its recognition by IF2 and by impairing its binding to EFTU-GTP. The N-terminal domain contains a Rossmann fold and it is the catalytic domain of the enzyme .

This entry represents the C-terminal domain of methionyl-tRNA formyltransferase (Met-tRNA-FMT). This domain has been shown to be involved in the tRNA binding .
Aconitase A, swivel domain (AcnA_IRP_Swivel)
Type: Domain

Aconitase (aconitate hydratase;

) is an iron-sulphur protein that contains a [4Fe-4S]-cluster and catalyses the interconversion of isocitrate and citrate via a cis-aconitate intermediate. Aconitase functions in both the TCA and glyoxylate cycles, however unlike the majority of iron-sulphur proteins that function as electron carriers, the [4Fe-4S]-cluster of aconitase reacts directly with an enzyme substrate. In eukaryotes there is a cytosolic form (cAcn) and a mitochondrial form (mAcn) of the enzyme. In bacteria there are also 2 forms, aconitase A (AcnA) and B (AcnB). Several aconitases are known to be multi-functional enzymes with a second non-catalytic, but essential function that arises when the cellular environment changes, such as when iron levels drop . Eukaryotic cAcn and mAcn, and bacterial AcnA have the same domain organisation, consisting of three N-terminal α/β/α domains, a linker region, followed by a C-terminal 'swivel' domain with a β/β/α structure (1-2-3-linker-4), although mAcn is smaller than cAcn. However, bacterial AcnB has a different organisation: it contains an N-terminal HEAT-like domain, followed by the 'swivel' domain, then the three α/β/α domains (HEAT-4-1-2-3) .

This entry represents the swivel domain found in Aconitase A and related proteins. This domain is believed to undergo swivelling conformational change in the enzyme mechanism .
Sulfate adenylyltransferase subunit CysN, Domain II (CysN_II)
Type: Domain

CysN, together with protein CysD, form the ATP sulfurylase (ATPS) complex in some bacteria and lower eukaryotes. ATPS catalyzes the production of ATP sulfurylase (APS) and pyrophosphate (PPi) from ATP and sulfate. CysD, which catalyzes ATP hydrolysis, is a member of the ATP pyrophosphatase (ATP PPase) family. CysN hydrolysis of GTP is required for CysD hydrolysis of ATP; however, CysN hydrolysis of GTP is not dependent on CysD hydrolysis of ATP. CysN is an example of lateral gene transfer followed by acquisition of new function. In many organisms, an ATPS exists which is not GTP-dependent and shares no sequence or structural similarity to CysN .

This entryvrepresents the central domain (domain II) of CysN.
Sulfate adenylyltransferase subunit CysN, Domain III (CysN_NoDQ_III)
Type: Domain

CysN, together with protein CysD, form the ATP sulfurylase (ATPS) complex in some bacteria and lower eukaryotes. ATPS catalyzes the production of ATP sulfurylase (APS) and pyrophosphate (PPi) from ATP and sulfate. CysD, which catalyzes ATP hydrolysis, is a member of the ATP pyrophosphatase (ATP PPase) family. CysN hydrolysis of GTP is required for CysD hydrolysis of ATP; however, CysN hydrolysis of GTP is not dependent on CysD hydrolysis of ATP. CysN is an example of lateral gene transfer followed by acquisition of new function. In many organisms, an ATPS exists which is not GTP-dependent and shares no sequence or structural similarity to CysN .

This entry represents the C-terminal domain (domain III) of CysN.
Proline--tRNA ligase, anticodon binding domain (ProRS_anticodon_short)
Type: Domain

This entry represents the short version of anticodon binding domain found predominantly in bacteria. This domain can be found in proline--tRNA ligase ProRS, which belongs to class II aminoacyl-tRNA synthetase. This domain is responsible for specificity in tRNA-binding, so that the activated amino acid is transferred to a ribose 3' OH group of the appropriate tRNA only .

Prolyl-tRNA synthetase belongs to class IIa. Prolyl-tRNA synthetase (

) exists in two forms, which are loosely related. The first form is present in the majority of eubacteria species. The second one, present in some eubacteria, is essentially present in archaea and eukaryota. This entry contains the first form of prolyl-tRNA synthetase.

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 anti-parallel 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 .
AhpF, N-terminal domain, C-terminal TRX-fold subdomain (AhpF_NTD_C)
Type: Domain

This entry represents the C-terminal TRX subdomain that contains the catalytic CXXC motif .

Alkyl hydroperoxide reductase subunit F (AhpF) is a homodimeric flavoenzyme which catalyzes the NADH-dependent reduction of the peroxiredoxin AhpC, which then reduces hydrogen peroxide and organic hydroperoxides. AhpF contains an NTD containing two contiguous TRX-fold subdomains similar to Pyrococcus furiosus protein disulfide oxidoreductase (PfPDO). It also contains a catalytic core similar to TRX reductase containing FAD and NADH binding domains with an active site disulfide . The NAD(P)H binding domain of AhpF may act to resolve the disulphide which forms after oxidation of the active site cysteine in AphC . This protein contains two paired conserved cysteine motifs, CxxC and CxHCDGP.
AhpF, N-terminal domain, N-terminal TRX-fold subdomain (AhpF_NTD_N)
Type: Domain

Alkyl hydroperoxide reductase subunit F (AhpF) is a homodimeric flavoenzyme which catalyzes the NADH-dependent reduction of the peroxiredoxin AhpC, which then reduces hydrogen peroxide and organic hydroperoxides. AhpF contains an NTD containing two contiguous TRX-fold subdomains similar to Pyrococcus furiosus protein disulfide oxidoreductase (PfPDO). It also contains a catalytic core similar to TRX reductase containing FAD and NADH binding domains with an active site disulfide . The NAD(P)H binding domain of AhpF may act to resolve the disulphide which forms after oxidation of the active site cysteine in AphC . This protein contains two paired conserved cysteine motifs, CxxC and CxHCDGP.

This entry represents the N-terminal TRX-fold subdomain. It is redox inactive, but is proposed to contain an important residue that aids in the catalytic function of the redox-active CXXC motif contained in the C-terminal TRX-fold subdomain .
Glycogen branching enzyme GlgB, N-terminal Early set domain (GlgB_N_E_set_prok)
Type: Domain

This entry represents the N-terminal Early set domain found in GlgB. GlgB is a glycogen branching enzyme responsible for the transfer of chains of approximately seven alpha-(1,4)-linked glucosyl residues to other similar chains (in new alpha-(1,6) linkages) in the biosynthesis of glycogen . The branching enzyme is responsible for the degree of alpha(1,6) branch linkages found in polysaccharides .

This E or "early" set domains are associated with the catalytic domain of glycogen branching enzymes at the N-terminal end. The N-terminal domain of the 1,4 alpha glucan branching enzyme may be related to the immunoglobulin and/or fibronectin type III superfamilies. These domains are associated with different types of catalytic domains at either the N-terminal or C-terminal end and may be involved in homodimeric/tetrameric/dodecameric interactions .
UxaA/GarD, SAF domain (SAF_UxaA/GarD)
Type: Domain

This entry represents the SAF domain found in altronate dehydratase UxaA and related proteins. UxaA converts D-altronate into 2-dehydro-3-deoxy-D-gluconate and is part of a bacterial pathway for the degradation of D-galacturonate. D-galactarate dehydratase eliminates water from D-galactarate to yield 5-dehydro-4-deoxy-D-glucarate, initializing the degradation of D-galactarate. The function of the SAF domain in these enzymes is not clear. It may participate in dimerization .

This domain can also be found in galactarate dehydratase GarD, which catalyses the dehydration of galactarate to form 5-dehydro-4-deoxy-D-glucarate (5-KDG). The N-terminal SAF domain of GarD has been shown to form a β-clip fold .
Translation initiation factor IF-2, domain II (IF2_II)
Type: Domain

Initiation factor 2 (IF-2) (gene infB) is one of the three factors required for the initiation of protein biosynthesis in bacteria. IF-2 promotes the GTP-dependent binding of the initiator tRNA to the small subunit of the ribosome. IF-2 is a protein of about 70 to 95 Kd which contains a central GTP-binding domain flanked by a highly variable N-terminal domain and a more conserved C-terminal domain. Bacterial IF-2 is structurally and functionally related to eukaryotic mitochondrial IF-2 (IF-2(mt)) as well as to algal and plants chloroplast IF-2 (IF-2(chl)). Both IF-2(mt) and IF-2(chl) are encoded by nuclear genes and are produced as precursor proteins with a transit peptide. An exception are red algae where IF-2(chl) is encoded by the plastid genome .

This entry represents the domain II of bacterial Initiation Factor 2 (IF2) and its eukaryotic mitochondrial homologue mtIF2.
Tex, S1 domain (S1_Tex)
Type: Domain

Tex is a putative transcription accessory factor essential in Bordetella pertussis and is named for its role in toxin expression. Tex has two functional domains, an N-terminal domain homologous to the Escherichia coli maltose repression protein, which is a poorly defined transcriptional factor, and a C-terminal S1 RNA-binding domain. Tex is found in prokaryotes, eukaryotes, and archaea .

This entry represents the S1 domain found in Tex and related proteins.