SII-SWORD/CoKE huggingface dataset:
DNA ligase, ATP-dependent, N-terminal (DNA_ligase_ATP-dep_N)
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 .

Vertebrate cells encode three well-characterised DNA ligases (DNA ligases I, III and IV), all of which are related in structure and sequence. With the exception of the atypically small PBCV-1 viral enzyme, two regions of primary sequence are common to all members of the family. The catalytic region comprises six conserved sequence motifs (I, III, IIIa, IV, V-VI), motif I includes the lysine residue that is adenylated in the first step of the ligation reaction. The function of the second, less well-conserved region is unknown. When folded, each protein comprises of two distinct sub-domains: a large amino-terminal sub-domain ('domain 1') and a smaller carboxy-terminal sub-domain ('domain 2'). The ATP-binding site of the enzyme lies in the cleft between the two sub-domains. Domain 1 consists of two antiparallelβ-sheets flanked by α-helices, whereas domain 2 consists of a five-stranded β-barrel and a single α-helix, which form the oligonucleotide-binding fold .

This domain is found in many but not all ATP-dependent DNA ligase enzymes (

). It is thought to be involved in DNA binding and in catalysis. In human DNA ligase I (

), and in Saccharomyces cerevisiae (Baker's yeast) (

), this region was necessary for catalysis, and separated from the amino terminus by targeting elements. In Vaccinia virus (

) this region was not essential for catalysis, but deletion decreases the affinity for nicked DNA and decreased the rate of strand joining at a step subsequent to enzyme-adenylate formation .
DNA ligase, ATP-dependent, C-terminal (DNA_ligase_ATP-dep_C)
Type: Domain

This region is found in many but not all ATP-dependent DNA ligase enzymes (

). It is thought to constitute part of the catalytic core of ATP dependent DNA ligase .

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 .

Vertebrate cells encode three well-characterised DNA ligases (DNA ligases I, III and IV), all of which are related in structure and sequence. With the exception of the atypically small PBCV-1 viral enzyme, two regions of primary sequence are common to all members of the family. The catalytic region comprises six conserved sequence motifs (I, III, IIIa, IV, V-VI), motif I includes the lysine residue that is adenylated in the first step of the ligation reaction. The function of the second, less well-conserved region is unknown. When folded, each protein comprises of two distinct sub-domains: a large amino-terminal sub-domain ('domain 1') and a smaller carboxy-terminal sub-domain ('domain 2'). The ATP-binding site of the enzyme lies in the cleft between the two sub-domains. Domain 1 consists of two antiparallelβ-sheets flanked by α-helices, whereas domain 2 consists of a five-stranded β-barrel and a single α-helix, which form the oligonucleotide-binding fold .
DNA ligase, ATP-dependent, central (DNA_ligase_ATP-dep_cent)
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 .

This domain belongs to a more diverse superfamily, including catalytic domain of the mRNA capping enzyme (

) and NAD-dependent DNA ligase (

) .

Vertebrate cells encode three well-characterised DNA ligases (DNA ligases I, III and IV), all of which are related in structure and sequence. With the exception of the atypically small PBCV-1 viral enzyme, two regions of primary sequence are common to all members of the family. The catalytic region comprises six conserved sequence motifs (I, III, IIIa, IV, V-VI), motif I includes the lysine residue that is adenylated in the first step of the ligation reaction. The function of the second, less well-conserved region is unknown. When folded, each protein comprises of two distinct sub-domains: a large amino-terminal sub-domain ('domain 1') and a smaller carboxy-terminal sub-domain ('domain 2'). The ATP-binding site of the enzyme lies in the cleft between the two sub-domains. Domain 1 consists of two antiparallelβ-sheets flanked by α-helices, whereas domain 2 consists of a five-stranded β-barrel and a single α-helix, which form the oligonucleotide-binding fold .
Hemerythrin-like (Hemerythrin-like)
Type: Domain

This entry represents a hemerythrin cation-binding domain that occurs in hemerythrins, myohemerythrin and related proteins. This domain binds iron in hemerythrin, but can bind other metals in related proteins, such as cadmium in a Nereis diversicolor protein (

) . This domain is also found in Repair of iron centres or Ric proteins .
Zinc finger, FCS-type (Znf_FCS)
Type: Domain

Zinc finger (Znf) domains are relatively small protein motifs which contain multiple finger-like protrusions that make tandem contacts with their target molecule. Some of these domains bind zinc, but many do not; instead binding other metals such as iron, or no metal at all. For example, some family members form salt bridges to stabilise the finger-like folds. They were first identified as a DNA-binding motif in transcription factor TFIIIA from Xenopus laevis (African clawed frog), however they are now recognised to bind DNA, RNA, protein and/or lipid substrates . Their binding properties depend on the amino acid sequence of the finger domains and of the linker between fingers, as well as on the higher-order structures and the number of fingers. Znf domains are often found in clusters, where fingers can have different binding specificities. There are many superfamilies of Znf motifs, varying in both sequence and structure. They display considerable versatility in binding modes, even between members of the same class (e.g. some bind DNA, others protein), suggesting that Znf motifs are stable scaffolds that have evolved specialised functions. For example, Znf-containing proteins function in gene transcription, translation, mRNA trafficking, cytoskeleton organisation, epithelial development, cell adhesion, protein folding, chromatin remodelling and zinc sensing, to name but a few . Zinc-binding motifs are stable structures, and they rarely undergo conformational changes upon binding their target.

The FCS-type zinc finger, named after the signature FCS residues associated with the third cysteine, is present in several polycomb group proteins. The FCS zinc finger is expected to adopt a Zn-ribbon like fold. Molecular data suggest that this domain can bind RNA in a non-sequence-specific manner .

Proteins known to contain an FCS-type zinc finger include:

Drosphila polyhomeotic (ph) protein and vertebrate homologues. They are members of the Polycomb repressive complex 1 (PRC1), an inhibitory complex that acts by preventing chromatin remodeling and transcription.

Drosophila Sex comb on midleg (Scm) and vertebrate homologues. They are also members of the PRC1.

Drosphila Lethal(3) malignant brain tumor (l(3)mbt) protein and vertebrate homologues.
Peptidase M12B, GON-ADAMTSs (Pept_M12B_GON-ADAMTSs)
Type: Domain

Over 70 metallopeptidase families have been identified to date. In these enzymes a divalent cation, which is usually zinc but may be cobalt, manganese or copper, activates the water molecule. The metal ion is held in place by amino acid ligands, usually three in number. In some families of co-catalytic metallopeptidases, two metal ions are observed in crystal structures ligated by five amino acids, with one amino acid ligating both metal ions. The known metal ligands are His, Glu, Asp or Lys. At least one other residue is required for catalysis, which may play an electrophilic role.

Many metalloproteases contain an HEXXH motif, which has been shown in crystallographic studies to form part of the metal-binding site . The HEXXH motif is relatively common but can be more stringently defined for metalloproteases as 'abXHEbbHbc', where 'a' is most often valine or threonine and forms part of the S1' subsite in thermolysin and neprilysin, 'b' is an uncharged residue, and 'c' a hydrophobic residue. Proline is never found in this site, possibly because it would break the helical structure adopted by this motif in metalloproteases .

The ADAMTSs (a disintegrin and metalloproteinase domain with thrombospondin type-1 modules) are a family of zinc dependent metalloproteinases that play important roles in a variety of normal and pathological conditions. These enzymes show a complex domain organisation including signal sequence, propeptide, metalloproteinase domain (see

), disintegrin-like domain (see

), central TS-1 motif (see

), cysteine-rich region, and a variable number of TS-like repeats at the C-terminal region. The GON domain is an approximately 200-residue module, whose presence is the hallmark of a subfamily of structurally and evolutionarily related ADAMTSs, called GON- ADAMTSs. The GON domain is characterised by the presence of several conserved cysteine residues and is likely to be globular , .

Some proteins known to contain a GON domain are listed below:

Mammalian ADAMTS-9

Mammalian ADAMTS-20

Caenorhabditis elegans gon-1, a protease required for gonadal morphogenesis

Proteins containing the GON domain belong to MEROPS peptidase subfamily M12B (adamalysin, clan MA).
KASH domain (KASH)
Type: Domain

The KASH (Klarsicht/ANC-1/Syne-1 homology), or KLS domain is a highly hydrophobic nuclear envelope localization domain of approximately 60 amino acids comprising a 20-amino-acid transmembrane region and a 30-35-residue C-terminal region that lies between the inner and the outer nuclear membranes. The KASH domain is found in association with other domains, such as spectrin repeats and CH, at the C terminus of proteins tethered to the nuclear membrane in diverse cell types .

Some proteins known to contain a KASH domain are listed below:

Caenorhabditis elegans nuclear anchorage protein 1 (ANC-1).

Drosophila Klarsicht (Klar), a protein associated with nuclei and required for a subset of nuclear migrations.

Drosophila MSP-300.

Vertebrate nesprin-1, -2, -3 and -4 (also known as Syne1-4). They are components of the linker of the nucleoskeleton and cytoskeleton (LINC) complex, which plays critical roles in nuclear positioning, cell polarisation and cellular stiffness .
ITAM motif, hantavirus type (ITAM_motif_hantavir-typ)
Type: Domain

Signal transduction by T and B cell antigen receptors and certain receptors for Ig Fc regions involves a conserved sequence motif, termed an immunoreceptor tyrosine-based activation motif (ITAM). It is also found in the cytoplasmic domain of the apoptosis receptor. Phosphorylation of the two ITAM tyrosines is a critical event in signal transduction. All (p)2ITAMs, but not their nonphosphorylated counterparts, induced extensive protein tyrosine phosphorylation in permeabilised cells. After binding of the ligand via an SH2 domain, phosphorylation of the two conserved tyrosines of ITAM creates binding sites for downstream signalling molecules and thus enables the initiation of signalling events. This phosphorylation was found to reflect activation of the src family kinases Lyn and Syk. Different ITAMs may preferentially activate distinct signalling pathways as a consequence of distinct SH2 effector binding preference . Furthermore, in viruses, ITAMs may play key roles in viral pathogenesis by regulating viral clearance, immune cell activation, immune cell recruitment through binding of cellular kinases and thereby down regulate their function .

This motif can be found in one to three copies and in association with the Ig-like domain. Proteins currently known to contain an ITAM motif are:

Mammalian alpha and beta immunoglobulin proteins, TCR gamma receptors, FCR gamma receptors subunits, CD3 chains receptors and NFAT activation molecule.

Hantavirus cytoplasmic elements.
Poly(ADP-ribose) polymerase, catalytic domain (Poly(ADP-ribose)pol_cat_dom)
Type: Domain

Poly(ADP-ribose) polymerases (PARP) are a family of enzymes present in eukaryotes, which catalyse the poly(ADP-ribosyl)ation of a limited number of proteins involved in chromatin architecture, DNA repair, or in DNA metabolism, including PARP itself. PARP, also known as poly(ADP-ribose) synthetase and poly(ADP-ribose) transferase, transfers the ADP-ribose moiety from its substrate, nicotinamide adenine dinucleotide (NAD), to carboxylate groups of aspartic and glutamic residues. Whereas some PARPs might function in genome protection, others appear to play different roles in the cell, including telomere replication and cellular transport. PARP-1 is a multifunctional enzyme. The polypeptide has a highly conserved modular organisation consisting of an N-terminal DNA-binding domain, a central regulating segment, and a C-terminal or F region accommodating the catalytic centre. The F region is composed of two parts: a purely α-helical N- terminal domain (alpha-hd), and the mixed α/β C-terminal catalytic domain bearing the putative NAD binding site. Although proteins of the PARP family are related through their PARP catalytic domain, they do not resemble each other outside of that region, but rather, they contain unique domains that distinguish them from each other and hint at their discrete functions. Domains with which the PARP catalytic domain is found associated include zinc fingers, SAP, ankyrin, BRCT, Macro, SAM, WWE and UIM domains .

The alpha-hd domain is about 130 amino acids in length and consists of an up-up-down-up-down-down motif of helices. It is thought to relay the activation signal issued on binding to damaged DNA . The PARP catalytic domain is about 230 residues in length. Its core consists of a five-stranded antiparallel β-sheet and four-stranded mixed β-sheet. The two sheets are consecutive and are connected via a single pair of hydrogen bonds between two strands that run at an angle of 90 degrees. These central β-sheets are surrounded by five α-helices, three 3(10)-helices, and by a three- and a two-stranded β-sheet in a 37-residue excursion between two central β-strands . The active site, known as the 'PARP signature' is formed by a block of 50 amino acids that is strictly conserved among the vertebrates and highly conserved among all species. The 'PARP signature' is characteristic of all PARP protein family members. It is formed by a segment of conserved amino acid residues formed by a β-sheet, an α-helix, a 3(10)-helix, a β-sheet, and an α-helix .
Crp-type HTH domain (HTH_CRP)
Type: Domain

The Crp-type HTH domain is a DNA-binding, winged helix-turn-helix (wHTH) domain of about 70-75 amino acids present in transcription regulators of the crp-fnr family, involved in the control of virulence factors, enzymes of aromatic ring degradation, nitrogen fixation, photosynthesis, and various types of respiration. The Crp-Fnr family is named after the first members identified in Escherichia coli: the well characterised cyclic AMP receptor protein CRP or CAP (catabolite activator protein) and the fumarate and nitrate reductase regulator Fnr. Crp-type HTH domain proteins occur in most bacteria and in chloroplasts of red algae. The DNA-binding HTH domain is located in the C-terminal part; the N-terminal part of the proteins of the Crp-Fnr family contains a nucleotide-binding domain and a dimerization/linker helix occurs in between. The Crp-Fnr regulators predominantly act as transcription activators, but can also be important repressors, and respond to diverse intracellular and exogenous signals, such as cAMP, anoxia, redox state, oxidative and nitrosative stress, carbon monoxide, nitric oxide or temperature .
Formamidopyrimidine-DNA glycosylase, catalytic domain (FPG_cat)
Type: Domain

This entry represents the catalytic domain of DNA glycosylase/AP lyase enzymes including formamidopyrimidine-DNA glycosylases (Fpg; MutM) and endonuclease VIII (Nei).

Formamidopyrimidine-DNA glycosylases (Fpg, MutM) are trifunctional DNA base excision repair enzymes that remove a wide range of oxidation-damaged bases (N-glycosylase activity;

) and cleave both the 3'- and 5'-phosphodiester bonds of the resulting apurinic/apyrimidinic site (AP lyase activity;

). Fpg has a preference for oxidised purines, excising oxidised purine bases such as 7,8-dihydro-8-oxoguanine (8-oxoG). Its AP (apurinic/apyrimidinic) lyase activity introduces nicks in the DNA strand, cleaving the DNA backbone by beta-delta elimination to generate a single-strand break at the site of the removed base with both 3'- and 5'-phosphates. Fpg is a monomer composed of 2 domains connected by a flexible hinge . The two DNA-binding motifs (a zinc finger and the helix-two-turns-helix motifs) suggest that the oxidised base is flipped out from double-stranded DNA in the binding mode and excised by a catalytic mechanism similar to that of bifunctional base excision repair enzymes . Fpg binds one ion of zinc at the C-terminal, which contains four conserved and essential cysteines .

Endonuclease VIII (Nei) has the same enzyme activities as Fpg (

,

), but with a preference for oxidised pyrimidines, such as thymine glycol, 5,6-dihydrouracil and 5,6-dihydrothymine . These proteins contain three structural domains: an N-terminal catalytic core domain, a central helix-two turn-helix (H2TH) module and a C-terminal zinc finger . The N-terminal catalytic domain and the C-terminal zinc finger straddle the DNA with the long axis of the protein oriented roughly orthogonal to the helical axis of the DNA. Residues that contact DNA are located in the catalytic domain and in a β-hairpin loop formed by the zinc finger .
Stonin homology (SHD_dom)
Type: Domain

Human stonins, like their Drosophila homologue stoned B, are supposed to be endocytotic proteins involved in clathrin-mediated endocytosis at synapses. The two human stonins, as well as their Drosophila melanogaster (Fruit fly) and Caenorhabditis elegans homologues, exhibit a modular structure consisting of an N-terminal proline- and serine-rich domain, a central stonin homology domain (SHD), and a C-terminal domain homologous to the signal-binding domain of the mu subunits of adaptor protein (AP) complexes (mu-homology domain). The ~140 amino-acid SHD domain has not been described in other proteins and may thus be unique to members of the stonin family. Its function is not yet known .
Conotoxin, omega-type, conserved site (Conotoxin_omega-typ_CS)
Type: Conserved_site

Cone snail toxins, conotoxins, are small neurotoxic peptides with disulphide connectivity that target ion-channels or G-protein coupled receptors. Based on the number and pattern of disulphide bonds and biological activities, conotoxins can be classified into several families . Omega, delta and kappa families of conotoxins have a knottin or inhibitor cysteine knot scaffold. The knottin scaffold is a very special disulphide-through-disulphide knot, in which the III-VI disulphide bond crosses the macrocycle formed by two other disulphide bonds (I-IV and II-V) and the interconnecting backbone segments, where I-VI indicates the six cysteine residues starting from the N terminus.

Conotoxins represent a unique arsenal of neuropharmacologically active peptides that have been evolutionarily tailored to afford unprecedented and exquisite selectivity for a wide variety of ion-channel subtypes. The toxins derived from cone snails are currently being investigated for the treatment of chronic pain, epilepsy, cardiovascular diseases, psychiatric and movement disorders, spasticity, cancer, and stroke, as well as an anesthetic agent. Several potential analgesic and anti-inflammatory peptides from conotoxin family have been identified and patented :

Conus magus (Magus cone) (Magician's cone snail) omega-conotoxin MVIIa (Ziconotide) is used for the treatment of chronic pain.

Conus catus (Cat cone) omega-conotoxin CVID is tested for treating severe morphine-resistant pain stress.

Conus geographus (Geography cone) (Nubecula geographus) omega-conotoxin GVIA may exert antagonistic effects against beta-endorphin induced anti-nociception.

The cysteine arrangements [C-C-CC-C-C] are the same for the omega and delta families, even though omega conotoxins are calcium channel blockers, whereas delta conotoxins delay the inactivation of sodium channels. The disulphide bonding network as well as specific amino acids in inter-cysteine loops provide the specificity of conotoxins . Two signature patterns were developed for the omega and delta conotoxin families. The patterns each include six conserved cysteines thought to be important for the maintenance of the tertiary structure of the conotoxins. This entry represents the omega-conotoxins.