SII-SWORD/CoKE huggingface dataset:
Protein-tyrosine phosphatase, non-receptor type-1/2 (Ptpn1/Ptpn2)
Type: Family

Protein tyrosine (pTyr) phosphorylation is a common post-translational modification which can create novel recognition motifs for protein interactions and cellular localisation, affect protein stability, and regulate enzyme activity. Consequently, maintaining an appropriate level of protein tyrosine phosphorylation is essential for many cellular functions. Tyrosine-specific protein phosphatases (PTPase;

) catalyse the removal of a phosphate group attached to a tyrosine residue, using a cysteinyl-phosphate enzyme intermediate. These enzymes are key regulatory components in signal transduction pathways (such as the MAP kinase pathway) and cell cycle control, and are important in the control of cell growth, proliferation, differentiation and transformation . The PTP superfamily can be divided into four subfamilies :

(1) pTyr-specific phosphatases

(2) dual specificity phosphatases (dTyr and dSer/dThr)

(3) Cdc25 phosphatases (dTyr and/or dThr)

(4) LMW (low molecular weight) phosphatases

Based on their cellular localisation, PTPases are also classified as:

Receptor-like, which are transmembrane receptors that contain PTPase domains

Non-receptor (intracellular) PTPases

All PTPases carry the highly conserved active site motif C(X)5R (PTP signature motif), employ a common catalytic mechanism, and share a similar core structure made of a central parallel β-sheet with flanking α-helices containing a β-loop-α-loop that encompasses the PTP signature motif . Functional diversity between PTPases is endowed by regulatory domains and subunits.

This entry represents non-receptor PTPase types 1 and 2 (also known as T-cell PTPase). These types appear to have different biological functions: in knock-out mice, type1 knock-outs showed increased insulin sensitivity but a normal lifespan, while type 2 knock-outs died when only a few weeks old . Substrate-trapping experiments suggest that these types recognise different cellular targets, though it is not known if this is due to sequence differences or to other regulatory mechanisms. Regulation of function and activity can occur at the transcriptional, alternative splicing, proteolytic processing and covalent modification levels. For example, T-cell PTPase has two different isoforms generated by alternative splicing, one of which recognises nuclear substrates, while the other recognises cytoplasmic substrates. These proteins adopt an α-β-α fold where the active site is located in a deep cleft located on the surface of the protein .
Tyrosine-protein phosphatase non-receptor type 12 (PTN12)
Type: Family

This entry represents Tyrosine-protein phosphatase non-receptor type 12 (PTN12).

Protein tyrosine (pTyr) phosphorylation is a common post-translational modification which can create novel recognition motifs for protein interactions and cellular localisation, affect protein stability, and regulate enzyme activity. Consequently, maintaining an appropriate level of protein tyrosine phosphorylation is essential for many cellular functions. Tyrosine-specific protein phosphatases (PTPase;

) catalyse the removal of a phosphate group attached to a tyrosine residue, using a cysteinyl-phosphate enzyme intermediate. These enzymes are key regulatory components in signal transduction pathways (such as the MAP kinase pathway) and cell cycle control, and are important in the control of cell growth, proliferation, differentiation and transformation . The PTP superfamily can be divided into four subfamilies :

(1) pTyr-specific phosphatases

(2) dual specificity phosphatases (dTyr and dSer/dThr)

(3) Cdc25 phosphatases (dTyr and/or dThr)

(4) LMW (low molecular weight) phosphatases

Based on their cellular localisation, PTPases are also classified as:

Receptor-like, which are transmembrane receptors that contain PTPase domains

Non-receptor (intracellular) PTPases

All PTPases carry the highly conserved active site motif C(X)5R (PTP signature motif), employ a common catalytic mechanism, and share a similar core structure made of a central parallel β-sheet with flanking α-helices containing a β-loop-α-loop that encompasses the PTP signature motif . Functional diversity between PTPases is endowed by regulatory domains and subunits.
Peptidase S1A, acrosin (Pept_S1A_acrosin)
Type: Family

This group of proteins are serine peptidases belonging to MEROPS peptidase family S1, subfamily S1A (chymotrypsin, clan PA(S)). Members of this family are found specifically within the acrosomal vesicle of all mammalian spermatozoa. Acrosin is thought to be involved in the recognition and binding of the sperm to the zona pellucida of the ovum and the sperm penetration through the zona pellucida. Mouse knock-out mutants suggest that Acr- sperm have a selective disadvantage when they are in competition with Acr+ sper .
CCR4-NOT complex, subunit 3/ 5 (CCR4-NOT_su3/5)
Type: Family

The Ccr4-Not complex is a global regulator of gene expression that is conserved from yeast to human. It affects genes positively and negatively and is thought to regulate transcription factor IID function. In Saccharomyces cerevisiae, it exists in two prominent forms and consists of at least nine core subunits: the five Not proteins (Not1 to Not5), Caf1, Caf40, Caf130 and Ccr4 . The Ccr4-Not complex regulates many different cellular functions, including RNA degradation and transcription initiation. It may be a regulatory platform that senses nutrient levels and stress . Caf1 and Ccr4, are directly involved in mRNA deadenylation, and Caf1p is associated with Dhh1, a putative RNA helicase thought to be a component of the decapping complex . Pop2, a component of the Ccr4-Not complex, functions as a deadenylase .

This group represents CCR4-NOT complex, subunits 3 and 5.
Semialdehyde dehydrogenase, dimerisation domain (Semialdhyde_DH_dimer_dom)
Type: Domain

This domain contains N-acetyl-glutamine semialdehyde dehydrogenase (AgrC), which is involved in arginine biosynthesis, and aspartate-semialdehyde dehydrogenase , an enzyme involved in the biosynthesis of various amino acids from aspartate. It also contains the yeast and fungal Arg5,6 protein, which is cleaved into the enzymes N-acety-gamma-glutamyl-phosphate reductase and acetylglutamate kinase. These are also involved in arginine biosynthesis. All proteins in this entry contain a dimerisation domain of semialdehyde dehydrogenase.
Phospholipid biosynthesis protein, PlsX-like (Phospholipid_synth_PlsX-like)
Type: Family

The proteins in this group are phospholipid biosynthesis proteins of unknown function. Escherichia coli PlsX protein has been shown to be required for phospholipid biosynthesis, but its exact function is not yet known . It has been suggested to be an enzyme.
Tetrahaem cytochrome domain (Tetrahaem_cytochrome)
Type: Domain

Flavocytochrome C3 (Fcc3) enzymes from a number of Shewanella species, including Shewanella frigidimarina (strain NCIMB 400), have respiratory fumarate reductase activity, which enables the bacteria to respire anaerobically with fumarate as a terminal electron acceptor. Flavocytochrome C3 in S. frigidimarina is a soluble, single chain tetrahaem enzyme found in the periplasm, making it distinct from other bacterial fumarate reductases (

), which are membrane-bound, multi-subunit enzymes, even though their function is analogous.

Shewanella Fcc3 is composed of three domains: an N-terminal tetrahaem cytochrome domain, a flavin domain and a clamp domain. The cytochrome domain can also occur on its own in some tetrahaem cytochromes implicated in iron oxidation. This entry represents the cytochrome domain, which has a different arrangement of the polypeptide chain in comparison to classical tetra-haem cytochrome C3 .
Lytic transglycosylase, superhelical linker (Lytic_TGlycosylase_superhlx_L)
Type: Domain

Bacterial lytic transglycosylases degrade murein via cleavage of the beta-1,4-glycosidic bond between N-acetylmuramic acid and N-acetylglucosamine, with the concomitant formation of a 1,6-anhydrobond in the muramic acid residue. There are both soluble (Slt enzymes) and membrane-bound (Mlt enzymes) lytic transglycosylases that differ in size, sequence, activity, specificity and location. The multi-domain structure of the 70 Kd soluble lytic transglycosylase Slt70 is known . Slt70 has 3 distinct domains, each rich in α helices: an N-terminal superhelical U-shaped domain, a superhelical linker domain (L-domain,

), and a C-terminal catalytic domain (

). Both the U-and L-domain share a similar superhelical structure. These two domains are connected, and together form a closed ring with a large central hole; the catalytic domain is packed on top of, and interacts with, this ring. The catalytic domain has a lysosome-like fold.

This entry represents the superhelical linker domain (also called the L domain), which contains two small and four large α helices, the latter forming a four-α-helical bundle with a double-layer, superhelical topology that is similar to that found in the U-shaped domain.
Fibrinogen, alpha/beta/gamma chain, coiled coil domain (Fibrinogen_a/b/g_coil_dom)
Type: Domain

Fibrinogen plays key roles in both blood clotting and platelet aggregation. During blood clot formation, the conversion of soluble fibrinogen to insoluble fibrin is triggered by thrombin, resulting in the polymerisation of fibrin, which forms a soft clot; this is then converted to a hard clot by factor XIIIA, which cross-links fibrin molecules. Platelet aggregation involves the binding of the platelet protein receptor integrin α(IIb)-β(3) to the C-terminal D domain of fibrinogen . In addition to platelet aggregation, platelet-fibrinogen interaction mediates both adhesion and fibrin clot retraction.

This entry represents the coiled-coil domain and part of the N-terminal E domain found in all three fibrinogen polypeptides, namely the alpha, beta and gamma chains.
CBM2, carbohydrate-binding domain superfamily (CBM2_carb-bd_dom_sf)
Type: Homologous_superfamily

The microbial degradation of cellulose and xylans requires several types of enzyme such as endoglucanases (EC 3.2.1.4), cellobiohydrolases (EC 3.2.1.91) (exoglucanases), or xylanases (EC 3.2.1.8) . Structurally, cellulases and xylanases generally consist of a catalytic domain and a conserved region of ~100 amino acid residues, the carbohydrate-binding module 2 (CBM2) . It is found either at the N-terminal or at the C-terminal extremity of these enzymes.

CBM2 can be classified in 2 subfamilies according to substrate specificities: CBM2a which binds cellulose and CBM2b which interacts specifically with xylan. Like other CBM domains CBM2 is a β-sheet domain containing a planar face which interacts with its ligand via a hydrophobic strip of aromatic residues . In family 2a this hydrophobic surface consists of three tryptophan residues, which are all required for binding soluble and insoluble forms of cellulose . In family 2b only 2 surface-exposed tryptophans are conserved and the first one is oriented differently. It is therefore not well oriented to interact with cellulose but is ideal for binding xylan .

This entry recognises both CBM2 subfamilies.
Globin/Protoglobin (Globin/Proto)
Type: Homologous_superfamily

Globins are haem-containing proteins involved in binding and/or transporting oxygen. They belong to a very large and well studied family that is widely distributed in many organisms . Globins have evolved from a common ancestor and can be divided into three groups: single-domain globins, and two types of chimeric globins, flavohaemoglobins and globin-coupled sensors. Bacteria have all three types of globins, while archaea lack flavohaemoglobins, and eukaryotes lack globin-coupled sensors . Several functionally different haemoglobins can coexist in the same species. The major types of globins include:

Haemoglobin (Hb): tetramer of two alpha and two beta chains, although embryonic and foetal forms can substitute the alpha or beta chain for ones with higher oxygen affinity, such as gamma, delta, epsilon or zeta chains. Hb transports oxygen from lungs to other tissues in vertebrates . Hb proteins are also present in unicellular organisms where they act as enzymes or sensors .

Myoglobin (Mb): monomeric protein responsible for oxygen storage in vertebrate muscle .

Neuroglobin: a myoglobin-like haemprotein expressed in vertebrate brain and retina, where it is involved in neuroprotection from damage due to hypoxia or ischemia . Neuroglobin belongs to a branch of the globin family that diverged early in evolution.

Cytoglobin: an oxygen sensor expressed in multiple tissues. Related to neuroglobin .

Erythrocruorin: highly cooperative extracellular respiratory proteins found in annelids and arthropods that are assembled from as many as 180 subunit into hexagonal bilayers .

Leghaemoglobin (legHb or symbiotic Hb): occurs in the root nodules of leguminous plants, where it facilitates the diffusion of oxygen to symbiotic bacteriods in order to promote nitrogen fixation.

Non-symbiotic haemoglobin (NsHb): occurs in non-leguminous plants, and can be over-expressed in stressed plants .

Flavohaemoglobins (FHb): chimeric, with an N-terminal globin domain and a C-terminal ferredoxin reductase-like NAD/FAD-binding domain. FHb provides protection against nitric oxide via its C-terminal domain, which transfers electrons to haem in the globin .

Globin-coupled sensors: chimeric, with an N-terminal myoglobin-like domain and a C-terminal domain that resembles the cytoplasmic signalling domain of bacterial chemoreceptors. They bind oxygen, and act to initiate an aerotactic response or regulate gene expression .

Protoglobin: a single domain globin found in archaea that is related to the N-terminal domain of globin-coupled sensors .

Truncated 2/2 globin: lack the first helix, giving them a 2-over-2 instead of the canonical 3-over-3 α-helical sandwich fold. Can be divided into three main groups (I, II and II) based on structural features .

Anaerobic nitrite reductase: phytoglobin that reduces nitrite to nitric oxide (NO) under anoxic conditions .

This domain superfamily is found in the entire globin family of proteins, including the microbial globins .
TBP domain superfamily (TBP_dom_sf)
Type: Homologous_superfamily

The TATA-box binding protein (TBP) is required for the initiation of transcription by RNA polymerases I, II and III, from promoters with or without a TATA box . The core of TBP (~180 residues) is highly conserved and contains two 77-amino acid repeats that produce a saddle-shaped structure that straddles the DNA; this region binds to the TATA box, and interacts with transcription factors and regulatory proteins .
Nuclease, putative, TT1808 (Nuclease_put_TT1808)
Type: Homologous_superfamily

This superfamily represents a structural motif found in the putative nuclease, hypothetical protein TT1808 (or TTHA1514), an AT-rich DNA-binding protein from Thermus thermophilus. This domain has a 3-layer α/β/α topology similar to that found in restriction endonucleases . The nuclease domain is ubiquitously found in enzymes involved in metabolism of nucleic acids, mostly in nucleases with diverse biological functions .
Restriction endonuclease EcoO109IR, catalytic domain superfamily (EcoO109IR_cat_dom_sf)
Type: Homologous_superfamily

There are four classes of restriction endonucleases: types I, II,III and IV. All types of enzymes recognise specific short DNA sequences and carry out the endonucleolytic cleavage of DNA to give specific double-stranded fragments with terminal 5'-phosphates. They differ in their recognition sequence, subunit composition, cleavage position, and cofactor requirements , as summarised below:

Type I enzymes (

) cleave at sites remote from recognition site; require both ATP and S-adenosyl-L-methionine to function; multifunctional protein with both restriction and methylase (

) activities.

Type II enzymes (

) cleave within or at short specific distances from recognition site; most require magnesium; single function (restriction) enzymes independent of methylase.

Type III enzymes (

) cleave at sites a short distance from recognition site; require ATP (but doesn't hydrolyse it); S-adenosyl-L-methionine stimulates reaction but is not required; exists as part of a complex with a modification methylase methylase (

).

Type IV enzymes target methylated DNA.

Type II restriction endonucleases (

) are components of prokaryotic DNA restriction-modification mechanisms that protect the organism against invading foreign DNA. These site-specific deoxyribonucleases catalyse the endonucleolytic cleavage of DNA to give specific double-stranded fragments with terminal 5'-phosphates. Of the 3000 restriction endonucleases that have been characterised, most are homodimeric or tetrameric enzymes that cleave target DNA at sequence-specific sites close to the recognition site. For homodimeric enzymes, the recognition site is usually a palindromic sequence 4-8 bp in length. Most enzymes require magnesium ions as a cofactor for catalysis. Although they can vary in their mode of recognition, many restriction endonucleases share a similar structural core comprising four β-strands and one α-helix, as well as a similar mechanism of cleavage, suggesting a common ancestral origin . However, there is still considerable diversity amongst restriction endonucleases . The target site recognition process triggers large conformational changes of the enzyme and the target DNA, leading to the activation of the catalytic centres. Like other DNA binding proteins, restriction enzymes are capable of non-specific DNA binding as well, which is the prerequisite for efficient target site location by facilitated diffusion. Non-specific binding usually does not involve interactions with the bases but only with the DNA backbone .

This superfamily represents the catalytic domain of the restriction endonuclease EcoO109IR, which recognises the DNA sequence RGGNCCY. The catalytic domain of this endonuclease moves drastically to capture the DNA. EcoO109IR requires a metal ion, which acts as a Lewis acid to stabilise the pentavalent phosphorus atom in the transition state. EcoO109I is similar to EcoRI family enzymes in terms of its DNA cleavage pattern and folding topology of the common motif in the catalytic domain, but it differs in the manner of DNA recognition .
Peptidase M6, InhA (Pept_M6_InhA)
Type: Family

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 .

This group of metallopeptidases belong to MEROPS peptidase family M6 (immune inhibitor A family, clan MA(M)). The predicted active site residues for members of this family and thermolysin, the type example for clan MA, occur in the motif HEXXH.
Malic enzyme, N-terminal domain (Malic_N_dom)
Type: Domain

This entry represents the N-terminal domain of the NAD(P)-dependent malic enzyme and related proteins from bacteria, eukaryotes and archaea.

Malic enzymes (malate oxidoreductases) catalyse the oxidative decarboxylation of malate to form pyruvate, a reaction important in a number of metabolic pathways - e.g. carbon dioxide released from the reaction may be used in sugar production during the Calvin cycle of photosynthesis . There are 3 forms of the enzyme : an NAD-dependent form that decarboxylates oxaloacetate; an NAD-dependent form that does not decarboxylate oxalo-acetate; and an NADPH-dependent form . Other proteins known to be similar to malic enzymes are the Escherichia coli scfA protein; an enzyme from Zea mays (Maize), formerly thought to be cinnamyl-alcohol dehydrogenase ; and the hypothetical Saccharomyces cerevisiae protein YKL029c.

Studies on the duck liver malic enzyme reveals that it can be alkylated by bromopyruvate, resulting in the loss of oxidative decarboxylation and the subsequent enhancement of pyruvate reductase activity . The alkylated form is able to bind NADPH but not L-malate, indicating impaired substrate or divalent metal ion-binding in the active site . Sequence analysis has highlighted a cysteine residue as the point of alkylation, suggesting that it may play an important role in the activity of the enzyme , although it is absent in the sequences from some species.

Malic enzyme is a tetramer comprised of subunits with four domains each .
Malic enzyme, NAD-binding (Malic_NAD-bd)
Type: Domain

This entry represents the NAD-binding domain of malic enzymes.

Malic enzymes (malate oxidoreductases) catalyse the oxidative decarboxylation of malate to form pyruvate, a reaction important in a number of metabolic pathways - e.g. carbon dioxide released from the reaction may be used in sugar production during the Calvin cycle of photosynthesis . There are 3 forms of the enzyme : an NAD-dependent form that decarboxylates oxaloacetate; an NAD-dependent form that does not decarboxylate oxalo-acetate; and an NADPH-dependent form . Other proteins known to be similar to malic enzymes are the Escherichia coli scfA protein; an enzyme from Zea mays (Maize), formerly thought to be cinnamyl-alcohol dehydrogenase ; and the hypothetical Saccharomyces cerevisiae protein YKL029c.

Studies on the duck liver malic enzyme reveals that it can be alkylated by bromopyruvate, resulting in the loss of oxidative decarboxylation and the subsequent enhancement of pyruvate reductase activity . The alkylated form is able to bind NADPH but not L-malate, indicating impaired substrate or divalent metal ion-binding in the active site . Sequence analysis has highlighted a cysteine residue as the point of alkylation, suggesting that it may play an important role in the activity of the enzyme , although it is absent in the sequences from some species.

Malic enzyme is a tetramer comprised of subunits with four domains each .