SII-SWORD/CoKE huggingface dataset:
HPr(Ser) kinase/phosphorylase, N-terminal (Hpr_kin/Pase_Hpr_N)
Type: Domain

Two-component signal transduction systems enable bacteria to sense, respond, and adapt to a wide range of environments, stressors, and growth conditions . Some bacteria can contain up to as many as 200 two-component systems that need tight regulation to prevent unwanted cross-talk . These pathways have been adapted to response to a wide variety of stimuli, including nutrients, cellular redox state, changes in osmolarity, quorum signals, antibiotics, and more . Two-component systems are comprised of a sensor histidine kinase (HK) and its cognate response regulator (RR) . The HK catalyses its own auto-phosphorylation followed by the transfer of the phosphoryl group to the receiver domain on RR; phosphorylation of the RR usually activates an attached output domain, which can then effect changes in cellular physiology, often by regulating gene expression. Some HK are bifunctional, catalysing both the phosphorylation and dephosphorylation of their cognate RR. The input stimuli can regulate either the kinase or phosphatase activity of the bifunctional HK.

A variant of the two-component system is the phospho-relay system. Here a hybrid HK auto-phosphorylates and then transfers the phosphoryl group to an internal receiver domain, rather than to a separate RR protein. The phosphoryl group is then shuttled to histidine phosphotransferase (HPT) and subsequently to a terminal RR, which can evoke the desired response .

This entry represents the N-terminal region of Hpr Serine/threonine kinase PtsK. This kinase is the sensor in a multicomponent phosphorelay system in control of carbon catabolic repression in bacteria . This kinase is unusual in that it recognises the tertiary structure of its target and is a member of a novel family unrelated to any previously described protein phosphorylating enzymes . X-ray analysis of the full-length crystalline enzyme from Staphylococcus xylosus at a resolution of 1.95 A shows the enzyme to consist of two clearly separated domains that are assembled in a hexameric structure resembling a three-bladed propeller. The blades are formed by two N-terminal domains each, and the compact central hub assembles the C-terminal kinase domains .
D-alanine--D-alanine ligase, N-terminal domain (Dala_Dala_lig_N)
Type: Domain

This entry represents the N-terminal region of the D-alanine--D-alanine ligase enzyme (

) which is thought to be involved in substrate binding . D-Alanine is one of the central molecules of the cross-linking step of peptidoglycan assembly. There are three enzymes involved in the D-alanine branch of peptidoglycan biosynthesis: the pyridoxal phosphate-dependent D-alanine racemase (Alr), the ATP-dependent D-alanine:D-alanine ligase (Ddl), and the ATP-dependent D-alanine:D-alanine-adding enzyme (MurF) .
Glycerol-3-phosphate dehydrogenase, NAD-dependent, N-terminal (G3P_DH_NAD-dep_N)
Type: Domain

NAD-dependent glycerol-3-phosphate dehydrogenase (GPDH) catalyses the interconversion of dihydroxyacetone phosphate and L-glycerol-3-phosphate. This family represents the N-terminal NAD-binding domain .
Cold-shock domain (CSD)
Type: Domain

A conserved domain of about 70 amino acids has been found in prokaryotic and eukaryotic single-strand nucleic-acid binding proteins . This domain, which is known as the 'cold-shock domain' (CSD) is present in the proteins listed below.

Escherichia coli protein CS7.4 (gene cspA) which is induced in response to low temperature (cold-shock protein) and which binds to and stimulates the transcription of the CCAAT-containing promoters of the HN-S protein and of gyrA.

Transcription termination factor Rho, a prokaryotic protein which facilitates transcription termination.

Mammalian Y box binding protein 1 (YB1). A protein that binds to the CCAAT-containing Y box of mammalian HLA class II genes.

Xenopus Y box binding proteins -1 and -2 (Y1 and Y2). Proteins that bind to the CCAAT-containing Y box of Xenopus hsp70 genes.

Xenopus B box binding protein (YB3). YB3 binds the B box promoter element of genes transcribed by RNA polymerase III.

Enhancer factor I subunit A (EFI-A) (dbpB). A protein that also bind to CCAAT-motif in various gene promoters.

DbpA, a human DNA-binding protein of unknown specificity.

Bacillus subtilis cold-shock proteins cspB and cspC.

Streptomyces clavuligerus protein SC 7.0.

E. coli proteins cspB, cspC, cspD, cspE and cspF.

Unr, a mammalian gene encoded upstream of the N-ras gene. Unr contains nine repeats that are similar to the CSD domain. The function of Unr is not yet known but it could be a multivalent DNA-binding protein.

PPPin, a mammalian brain-specific protein that binds to histone mRNA and which is thought to play a role in the regulation of brain development.
SecA, preprotein cross-linking domain (SecA_preprotein_X-link_dom)
Type: Domain

The SecA ATPase is involved in the insertion and retraction of preproteins through the plasma membrane. This domain has been found to cross-link to preproteins, thought to indicate a role in preprotein binding. The pre-protein cross-linking domain is comprised of two sub domains that are inserted within the ATPase domain .
Allophycocyanin linker protein (Allophyco_linker)
Type: Family

Members of this family are linker polypeptides that are associated with phycobilisomes. Phycobiliproteins (biliproteins) are accessory pigments that serve as receptors of light energy for photosystem II. Phycobilisomes are highly organised complex structures of biliproteins and linker polypeptides. The linker polypeptides are involved in the attachment of phycobilisomes to the thylakoid membrane and in the assembly of biliproteins into phycobilisomes.

The three dimensional structure of an electrophoretically purified allophycocyanin-linker complex has been determined . The asymmetric unit contains two side-to-side associated trimeric (alphabeta)
3
allophycocyanin complexes comprising the linker polypeptide in a defined orientation inside the trimer. The linker representing a protein fold related to the prosegment of procarboxypeptidase A is in contact with only two of the three beta-subunits and directly interacts with the corresponding chromophores of these proteins.

For additional information please see .
Succinate dehydrogenase cytochrome b558 subunit (Cytochrome_b-558)
Type: Family

This family contains succinate dehydrogenase (also known as succinate:quinone oxidoreductase, SQR) subunit C of Bacillus subtilis, designated cytochrome b-558, and related sequences that include a fumarate reductase subunit C. This family is only weakly similar to the main group of succinate dehydrogenase cytochrome b subunits described by

, so that some members score above the gathering threshold and some do not .

SQR catalyzes the oxidation of succinate to fumarate coupled to the reduction of quinone to quinol. Bacillus subtilis SQR reduces low potential quinones such as menaquinone . SQR is part of the citric acid cycle and the aerobic respiratory chain. SQR is composed of a flavoprotein catalytic subunit, an iron-sulfur protein and one or two hydrophobic transmembrane subunits. Members of this entry are classified as Type B as they contain one transmembrane subunit and two heme groups . The heme and quinone binding sites reside on the cytochrome b558 subunit . The structural arrangement allows efficient electron transfer between the catalytic subunit, through iron-sulfur centres, and the transmembrane subunit containing the electron acceptor (quinone). The reversible reduction of quinone is an essential feature of respiration, allowing transfer of electrons between respiratory complexes .
Autonomous glycyl radical cofactor GrcA (Glycyl_radical_cofactor_GrcA)
Type: Family

This group represents a glycyl radical cofactor protein, YfiD-type. YfiD of Escherichia coli, and the homologous Y06I of Bacteriophage T4, show striking sequence similarity with the C-terminal region of pyruvate formate-lyase (PFL). Expression of YfiD is known to be controlled by transcription regulator FNR, and in response to pH-stress conditions . YfiD homologues generally occur in facultative anaerobic eubacteria that have a PFL enzyme. It is thought that YfiD may act as an independent glycyl radical carrier replacing the C-terminal glycyl radical domain in PFL, perhaps in cases where PFL has undergone oxygen-induced fragmentation .

This small protein, previously designated YfiD in E. coli, is closely homologous to pyruvate formate_lyase (PFL) in a region surrounding the stable glycyl radical that is prepared by the action of pyruvate formate-lyase activase, a radical SAM enzyme. When damage at the site of this radical breaks the main chain of PFL, this protein acts as a spare part that reintroduces the needed stable glycyl radical .
Polyketide synthase, type III (Polyketide_synthase_type-III)
Type: Family

Type III polyketide synthases include plant naringenin-chalcone synthases (CHSs) and stilbene synthases (STSs) (resveratrol synthases) . This group also includes CHS-related enzymes such as bibenzyl synthase (BBS) and acridone synthase (ACS) that share a common chemical mechanism but differ from CHS in their substrate specificity and/or in the stereochemistry of the polyketide cyclisation reaction. It also includes prokaryotic type III polyketide synthases (PKSs).

Type III polyketide synthases catalyse the formation of structurally diverse polyketides. They are homodimeric iterative PKSs and contain two independent active sites, each of which catalyses single or multiple condensation reactions to generate polyketides of different lengths . CHS and STS are plant-specific polyketide synthases. With a starter CoA-ester, they perform three sequential condensation steps with acetate units from malonyl-CoA to form a tetraketide intermediate that is folded to the ring systems specific to the different products. Each monomer subunit is capable of performing all three condensation steps, and malonyl-CoA is the direct donor of the acetate units. The structure of the Medicago sativa (Alfalfa) CHS2 has the active site architecture that defines the sequence and chemistry of multiple decarboxylation and condensation reactions .

CHSs (

) are key enzymes in flavonoid assembly. They synthesize naringenin chalcone, the precursor for a large number of flavonoids. CHS is essential for the formation of 4,2',4',6'-tetrahydroxychalcone, a plant secondary metabolite that sits at a critical metabolic branch point leading to the biosynthesis of anthocyanin pigments, anti-microbial phytoalexins, and flavonoid inducers of Rhizobium nodulation genes. STSs (

) occur in a limited number of unrelated plants and synthesize the backbone of the stilbene phytoalexins that have antifungal properties and contribute to pathogen defence.
Spider toxin CSTX, Knottin scaffold conserved site (Spider_toxin_CSTX_Knottin_CS)
Type: Conserved_site

Spider toxins of the CSTX family are ion channel toxins containing an inhibitor cystine knot structural motif or Knottin scaffold (https://www.dsimb.inserm.fr/KNOTTIN/). The four disulphide bonds present in the CSTX spider toxin family are arranged in the following pattern: 1-4, 2-5, 3-8 and 6-7.

This family includes:

Cupiennius salei (Wandering spider) toxin CSTX-1 and its proteolytic products CSTX-2a and CSTX-2b .

C. salei (Wandering spider) CSTX-9 .

C. salei (Wandering spider) CSTX-13, a neurotoxic enhancer. In contrast to CSTX-1 and CSTX-9, CSTX-13 is a two-chain peptide with two interchain and two intrachain disulphide bridges .
Ganglioside GM2 synthase (GM2_synthase)
Type: Family

Ganglioside GM2 synthase (N-acetylgalactosaminyltransferase, GalNAcT) is one of the key enzymes in gangliosides biosynthesis, which involves a series of ER- or Golgi-based glycosyltransferases. GalNAcT is a type II integral membrane protein of the Golgi apparatus that catalyses the synthesis of the glycosphingolipids GM2, GD2, and GA2. GalNAcT and galactosyltransferase II form a Golgi-localised enzyme complex that is stabilised by non-covalent association. This enzyme association has been suggested to facilitate the biosynthesis sequence from GM3/GD3 to GM1/GD1b via GM2/GD2 as intermediates . Complex gangliosides are required for the maintenance of axons and myelin .

Beta-1,4 N-acetylgalactosaminyltransferase (CT-GalNAcT) shares 51% sequence identity with GalNAcT, showing the strongest conservation in the catalytic domains. CT-GalNAcT is a type II Golgi transmembrane protein characteristic of other mammalian glycosyltransferases. It functions in the synthesis of murine T-lymphocyte CT antigen .
Scavenger mRNA decapping enzyme, N-terminal (Scavenger_mRNA_decap_enz_N)
Type: Homologous_superfamily

This superfamily represents the N-terminal domain of scavenger mRNA decapping enzymes, such as Dcp2 and DcpS. DcpS is a scavenger pyrophosphatase that hydrolyses the residual cap structure following 3' to 5' mRNA degradation. DcpS uses cap dinucleotides or capped oligonucleotides as substrate to release m(7)GMP (N7-methyl GMP), while Dcp2 uses capped mRNA as substrate in order to hydrolyse the cap to release m(7)GDP (N7-methyl GDP) . The association of DcpS with 3' to 5' exonuclease exosome components suggests that these two activities are linked and there is a coupled exonucleolytic decay-dependent decapping pathway.
HIT-like domain (HIT-like)
Type: Domain

The histidine triad motif (HIT) consists of the conserved sequence HXHXHXX (where X is a hydrophobic amino acid) at the enzymatic catalytic centre, in which the second histidine is strictly conserved and participates in catalysis with the third histidine . Proteins containing HIT domains form a superfamily of nucleotide hydrolases and transferases that act on the alpha-phosphate of ribonucleotides . They are highly conserved from archaea to humans and are involved in galactose metabolism, DNA repair, and tumor suppression . HIT-containing proteins can be divided in five families based on catalytic specificities, sequence compositions, and structural similarities of its members:

Hint family of protein kinase-interacting proteins, the most ancient class in this superfamily. These include adenosine 5'-monophosphoramide hydrolases (e.g. HIT-nucleotide-binding protein, or HINT) . They also have a conserved zinc-binding motif C-X-X-C (where C is a cysteine residue and X is a hydrophobic residue), and a zinc ion is coordinated by these cysteine residues, together with the first histidine residue .

Fragile HIT protein, or FINT, whose name is due to its high rate of mutation at its locus on chromosome 3 in many cancers has been characterised as a tumor suppressor and plays a role in the hydrolysis of dinucleotide polyphosphates . HINT and FINT HIT domains have a topology similar to that found in the N-terminal of protein kinases .

GalT family. These include specific nucleoside monophosphate transferases (e.g. galactose-1-phosphate uridylyltransferase, diadenosine tetraphosphate phosphorylase, and adenylyl sulphate:phosphate adenylytransferase). These HIT domains are a duplication consisting of 2 HIT-like motifs. This family binds zinc and iron .

Aprataxin, which hydrolyses both dinucleotide polyphosphates and phophoramidates, and is involved in DNA repair systems .

mRNA decapping enzyme family. These include enzymes such as DcpS and Dcp2. The HIT-domain is usually C-terminal in these proteins .
Bifunctional aspartokinase/homoserine dehydrogenase, homoserine dehydrogenase domain (Bifunc_Aspkin/hSer_DH)
Type: Domain

This entry represents the homoserine dehydrogenase domain from the bifunctional enzyme aspartokinase/homoserine dehydrogenase (AK-HSDH) found in bacteria and plant chloroplasts, which catalyses the first and third steps of the aspartate pathway. Homoserine dehydrogenase (

) catalyses the conversion of L-homoserine to L-aspartate-4-semialdehyde using NAD(P), while aspartate kinase (

) catalyses the phosphorylation of L-aspartate to 4-phospho-L-aspartate. There are two genes encoding different isoforms of this bifunctional enzymes; one isoform is threonine-sensitive, while the other is methionine-sensitive .

Bifunctional enzymes that catalyse consecutive reactions offer the advantages of efficient channelling and protection of potentially reactive intermediates. AK-HSDH is unusual in its ability to catalyse two non-consecutive reactions. The enzyme that catalyses the intermediary step, aspartate semialdehyde dehydrogenase, is thought to provide a bridge to channel the intermediates between the non-consecutive reactions of AK-HSDH .

This entry also includes homoserine dehydrogenase from fungi, which catalyses the third step in the aspartate pathway and it is found in a monofunctional form in yeast. Structural analysis of this monofunctional form (

) indicates that the enzyme is a dimer composed of an N-terminal nucleotide-binding domain that forms a modified Rossman fold, a short central dimerisation region, and a C-terminal catalytic domain which forms a novel α-β mixed sheet .

Bacteria, plants and fungi metabolise aspartic acid to produce four amino acids -lysine, threonine, methionine and isoleucine -in a series of reactions known as the aspartate pathway. Additionally, several important metabolic intermediates are produced by these reactions, such as diaminopimelic acid, an essential component of bacterial cell wall biosynthesis, and dipicolinic acid, which is involved in sporulation in Gram-positive bacteria. Members of the animal kingdom do not posses this pathway and must therefore acquire these essential amino acids through their diet. Research into improving the metabolic flux through this pathway has the potential to increase the yield of the essential amino acids in important crops, thus improving their nutritional value. Additionally, since the enzymes are not present in animals, inhibitors of them are promising targets for the development of novel antibiotics and herbicides. For more information see .
DNA polymerase II small subunit, archaeal (Pol2_small_arc)
Type: Family

Archaeal DNA polymerase II (Pol II, or Pol D) is heterodimeric, containing a DP1 small subunit, and a DP2 large subunit, the latter acting as the catalytic subunit. This entry represents the DP1 small subunit, which shows sequence similarity with the small subunit of eukaryotic DNA polymerase delta; a homologue of this protein has not been found in bacteria. Archaeal Pol II possesses an excellent primer extension ability, but may require accessory proteins to perform all its functions .
Cutinase, monofunctional (Cutinase_monf)
Type: Family

Aerial plant organs are protected by a cuticle composed of an insoluble polymeric structural compound, cutin, which is a polyester composed of hydroxy and hydroxyepoxy fatty acids. Plant pathogenic fungi produce extracellular degradative enzymes that play an important role in pathogenesis. They include cutinase, which hydrolyses cutin, facilitating fungus penetration through the cuticle. Inhibition of the enzyme can prevent fungal infection through intact cuticles. Cutin monomers released from the cuticle by small amounts of cutinase on fungal spore surfaces can greatly increase the amount of cutinase secreted by the spore, the mechanism for which process is as yet unknown .

Cutinase is a serine esterase containing the classical Ser, His, Asp triad of serine hydrolases. The protein belongs to the α-β class, with a central β-sheet of 5 parallel strands covered by 5 helices on either side of the sheet. The active site cleft is partly covered by 2 thin bridges formed by amino acid side chains, by contrast with the hydrophobic lid possessed by other lipases . The protein also contains 2 disulphide bridges, which are essential for activity, their cleavage resulting in complete loss of enzymatic activity.
Phosphoesterase MJ0912 (Pesterase_MJ0912)
Type: Family

This group of conserved proteins from bacteria and archaea contain one copy of the calcineurin-like phosphoesterase domain. Many members possess motifs characteristic of a variety of enzymatically active phosphoesterases , including acid and alkaline phosphatases, phosphoprotein phosphatases, 5'-nucleotidase, bis(5'-nucleosyl)-tetraphosphatase (symmetrical), sphingomyelin phosphodiesterase, 2',3'-cylic-nucleotide 2'-phosphodiesterase, and the 3',5'-nucleotide phosphodiesterase CpdA. In others, the calcineurin-like phosphoesterase domain is poorly conserved and residues thought to be essential are not preserved.
Phosphoprotein phosphatase PPZ/Ppq1 (PPPtase_PPZ/Ppq1)
Type: Family

This group represents the yeast phosphoprotein phosphatase, Ppz-type. Ppz proteins function in the regulation of K+ transport. Ppz proteins and the Hal3p inhibitory subunit of Ppz1 are important determinants of salt tolerance, cell wall integrity and cell cycle progression, each of which is dependent upon the Trk K+ transporters . The decreased Ppz activity found in Ppz mutants results in the activation of Trk and the subsequent plasma membrane depolarisation (reducing uptake of toxic cations), increased intracellular K+ and turgor (compromising cell integrity), and increased intracellular pH (augmenting the expression of pH-regulated genes and facilitating alpha-factor recovery). Ppz1 orthologues are found only in fungi .

Ppq1 yeast phosphatase consists of two distinct domains: the C-terminal phosphatase domain is approximately 60% identical to either PP1 or the carboxy-terminal domains of PPZ1 and PPZ2, while the N-terminal region is rich in serine and asparagine. Ppq1 seems to be involved in the regulation of protein synthesis and functions as a negative regulator of the mating MAPK pathway .
Sphingomyelin phosphodiesterase (Sphingomy_PDE)
Type: Family

Sphingomyelin phosphodiesterase, or sphingomyelinase (SMase), enzymes catalyse the hydrolysis of sphingomyelin into ceramide (N-acylsphingosine) and phosphorylcholine. There are six types of SMases: acid SMase, secretory SMase, neutral magnesium-dependent SMase, neutral magnesium-independent SMase, alkaline SMase, and bacterial SMase . This entry covers the acid SMases.

Sphingomyelin is a ubiquitous lipid found in plasma membranes, as well in lipoproteins; in mammalian cells, it is the most abundant sphingolipid. Sphingoid molecules generated from the breakdown of sphingolipids can act as intracellular bio-modulators. In particular, ceramide can act as a second messenger in diverse signalling pathways leading to different cellular responses, such as apoptosis . Hence, SMase activation can be an early event in the apoptosis-signalling cascade. SMase is regulated by several mechanisms, including tumour necrosis factor (TNF) receptor-associated protein FAN (Factor Associated with N-sphingomyelinase activation) and oxidative stress.