SII-SWORD/CoKE huggingface dataset:
Deoxyribonuclease I, conservied site (DNASE_I_2)
Type: Conserved_site

This entry represents the DNase I conserved site that is involved in disulphide bond formation. It has the consensus pattern G-D-F-N-A-x-C-[SAK].

Deoxyribonuclease I (DNase I) (

) is a vertebrate enzyme which catalyzes the endonucleolytic cleavage of double-stranded DNA to 5'- phosphodinucleotide and 5'-phosphooligonucleotide end-products. DNase I is an enzyme involved in DNA degradation; it is normally secreted outside of the cell but seems to be able to gain access to the nucleus where it is involved in cell death by apoptosis .

As shown in the following schematic representation, DNase I is a glycoprotein of about 260 residues with two conserved disulphide bonds.

+-+ +--------+
| | | |
xxxxxxxxxxxxxxxxx#xxxxxxCxCxxxxx#xxxxxxxxxCxxxxxxxxCxxxxxxxxxxxxx

'C': conserved cysteine involved in a disulphide bond.
'#': active site residue.

DNase I has a pH-optimum around 7.5 and requires calcium and magnesium for full activity. It causes single strand nicks in duplex DNA. A proton acceptor-donor chain composed of a histidine and a glutamic acid produce a nucleophilic hydroxyl ion from water, which cleaves the 3'-P-O bond . DNase I forms a 1:1 complex with G-actin, resulting in the inhibition of DNase activity and loss of the ability of G-actin to polymerise into fibres . DNase I has been used in the treatment of lung problems in patients with cystic fibrosis: here it acts by degrading DNA found in purulent lung secretions, reducing their viscosity and making it easier for the patient to breathe .

The sequence of DNase I is evolutionary related to that of human muscle-specific DNase-like protein and human proteins DHP1 and DHP2. However, the first disulphide bond of DNase I is not conserved in these proteins.
Glycosyl hydrolases family 9, Asp/Glu active sites (Glyco_hydro_9_Asp/Glu_AS)
Type: Active_site

The microbial degradation of cellulose and xylans requires several types of enzymes such as endoglucanases, cellobiohydrolases (exoglucanases), or xylanases . Fungi and bacteria produces a spectrum of cellulolytic enzymes (cellulases) and xylanases which, on the basis of sequence similarities, can be classified into families. One of these families is known as the cellulase family E or as the glycosyl hydrolases family 9 .

Two of the most conserved regions in these enzymes are centred on conserved residues which have been shown , in the endoglucanase D from Cellulomonas thermocellum, to be important for the catalytic activity. The first region contains an active site histidine and the second region contains two catalytically important residues: an aspartate and a glutamate. This entry represents the second region.
Ubiquitin-activating enzyme E1, Cys active site (UBQ-activ_enz_E1_Cys_AS)
Type: Active_site

Ubiquitin-activating enzyme (E1 enzyme) activates ubiquitin by first adenylating with ATP its C-terminal glycine residue and thereafter linking this residue to the side chain of a cysteine residue in E1, yielding an ubiquitin-E1 thiolester and free AMP. Later the ubiquitin moiety is transferred to a cysteine residue on one of the many forms of ubiquitin- conjugating enzymes (E2).

E1 is a large monomeric protein of about 110 to 115 Kd (about 1000 residues). In yeast there are two forms (UBA1 and UBA2) , while in plants and mammals multiple forms exist including a form which is Y-linked in mouse and some other mammals and which may be involved in spermatogenesis.

It has been shown that the last of the five cysteines that are conserved in the sequence of E1 from various species is the one that binds ubiquitin . This entry represents a conserved region containing the active site cysteine.
Adenylosuccinate synthase, active site (Adenylosuccin_syn_Lys_AS)
Type: Active_site

Adenylosuccinate synthetase (

) plays an important role in purine biosynthesis by catalysing the GTP-dependent conversion of IMP and aspartic acid to AMP. Adenylosuccinate synthetase has been characterised from various sources ranging from Escherichia coli (gene purA) to vertebrate tissues. In vertebrates, two isozymes are present, one involved in purine biosynthesis and the other in the purine nucleotide cycle.

This entry represents a conserved region containing a lysine residue known to be essential for the enzyme's activity .
Phosphoenolpyruvate carboxylase, His active site (PEPCASE_His_AS)
Type: Active_site

Phosphoenolpyruvate carboxylase (

) (PEPcase) catalyses the irreversible β-carboxylation of phosphoenolpyruvate by bicarbonate to yield oxaloacetate and phosphate. The enzyme is found in all plants and in a variety of microorganisms. A histidine and a lysine have been implicated in the catalytic mechanism of this enzyme; the regions around these active site residues are highly conserved in PEPcase from various plants, bacteria and cyanobacteria.
Ribonuclease T2, His active site 2 (RNase_T2_His_AS_2)
Type: Active_site

The fungal ribonucleases T2 from Aspergillus oryzae, M from Aspergillus saitoi and Rh from Rhizopeus niveus are structurally and functionally related 30 Kd glycoproteins that cleave the 3'-5' internucleotide linkage of RNA via a nucleotide 2',3'-cyclic phosphate intermediates (

).

A number of other RNAses have been found to be evolutionary related to these fungal enzymes:

Self-incompatibility in flowering plants is often controlled by a single gene (S-gene) that has several alleles. This gene prevents fertilization by self-pollen or by pollen bearing either of the two S- alleles expressed in the style. The self-incompatibility glycoprotein from several higher plants of the solanaceae family has been shown to be a ribonuclease.

Phosphate-starvation induced RNAses LE and LX from tomato . These two enzymes are probably involved in a phosphate-starvation rescue system.

Escherichia coli periplasmic RNAse I (EC 3.1.27.6) (gene rna) .

Aeromonas hydrophila periplasmic RNAse.

Haemophilus influenzae hypothetical protein HI0526.

Two histidines residues have been shown to be involved in the catalytic mechanism of RNase T2 and Rh. These residues and the region around them are highly conserved.
Pectinesterase, Asp active site (Pectinesterase_Asp_AS)
Type: Active_site

Pectinesterase (

) (pectin methylesterase) catalyses the hydrolysis of pectin into pectate and methanol. In plants, it plays an important role in cell wall metabolism during fruit ripening, cell wall extension and during pollen germination. In plant bacterial pathogens such as Erwinia carotovora and in fungal pathogens such as Aspergillus niger, pectinesterase is involved in maceration and soft-rotting of plant tissue. Plant pectinesterases are regulated by pectinesterase inhibitors, which are ineffective against microbial enzymes .
Glycosyl hydrolases family 1, N-terminal conserved site (GH_1_N_CS)
Type: Conserved_site

This entry represents a conserved site at the N-terminal in Glycosyl hydrolases family 1 proteins.

Glycoside hydrolase family 1 (

) comprises enzymes with a number of known activities; beta-glucosidase (

); beta-galactosidase (

); 6-phospho-beta-galactosidase (

); 6-phospho-beta-glucosidase (

); lactase-phlorizin hydrolase (

)/(

); beta-mannosidase (

); myrosinase (

).
Pumilio homology domain (PUM-HD)
Type: Domain

Members of the Pumilio family of proteins (Puf) regulate translation and mRNA stability in a wide variety of eukaryotic organisms including mammals, flies, worms, slime mold, and yeast . Pumilio family members are characterised by the presence of eight tandem copies of an imperfectly repeated 36 amino acids sequence motif, the Pumilio repeat, surrounded by a short N- and C-terminal conserved region. The eight repeats and the N- and C-terminal regions form the Pumilio homology domain (PUM-HD). The PUM-HD domain is a sequence-specific RNA binding domain. Several Puf members have been shown to bind specific RNA sequences mainly found in the 3' UTR of mRNA and repress their translation . Frequently, Puf proteins function asymmetrically to create protein gradients, thus causing asymmetric cell division and regulating cell fate specification .

Crystal structure of Pumilio repeats has been solved . The PUM repeat with the N- and C-terminal regions pack together to form a right-handed superhelix that approximates a half doughnut structurally similar to the Armadillo (ARM) repeat proteins, beta-catenin and karyopherin alpha. The RNA binds the concave surface of the molecule, where each of the protein's eight repeats makes contacts with a different RNA base via three amino acid side chains at conserved positions .

This entry represents the PUM-HD domain.
Asp/Glu racemase, active site 2 (Asp/Glu_racemase_AS_2)
Type: Active_site

Aspartate racemase (

) and glutamate racemase (

) are two evolutionary related bacterial enzymes that do not seem to require a cofactor for their activity . Glutamate racemase, which interconverts L-glutamate into D-glutamate, is required for the biosynthesis of peptidoglycan and some peptide-based antibiotics such as gramicidin S. In addition to characterised aspartate and glutamate racemases, this entry also includes a hypothetical protein from Erwinia carotovora and one from Escherichia coli (ygeA).

Two conserved cysteines are present in the sequence of these enzymes. They are expected to play a role in catalytic activity by acting as bases in proton abstraction from the substrate. This entry represents a conserved region containing the second cysteine.
ClpP, histidine active site (ClpP_His_AS)
Type: Active_site

The endopeptidase Clp (

) from Escherichia coli cleaves peptides in various proteins in a process that requires ATP hydrolysis . Clp is a dimeric protein which consists of a proteolytic subunit (gene clpP) and either of two related ATP-binding regulatory subunits (genes clpA and clpX). ClpP is a serine protease which has a chymotrypsin-like activity. Its catalytic activity seems to be provided by a charge relay system similar to that of the trypsin family of serine proteases, but which evolved by independent convergent evolution.

Proteases highly similar to ClpP have been found to be encoded in the genome of the chloroplast of plants and seem to be also present in other eukaryotes.

This entry represents a conserved region containing a histidine that is involved in the catalytic triad.
NAD-dependent DNA ligase, conserved site (DNA_ligase_CS)
Type: Conserved_site

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 (

).

Bacterial DNA ligases are NAD-dependent. They are proteins of about 75 to 85 Kd whose sequence is well conserved . They also show similarity to yicF, an Escherichia coli hypothetical protein of 63 Kd.

This entry represents a conserved region found in DNA ligases.
Neuromodulin, phosphorylation site (Neuromodulin_P_site)
Type: PTM

This entry represents a conserved region in Neuromodulin containing a serine residue which can be phosphorylated by protein kinase C and which is adjacent to the calmodulin-binding domain.

Neuromodulin (also known as growth-associated protein 43 or GAP-43) is a component of the motile growth cones. It is membrane protein whose expression is widely correlated with successful axon elongation . It is a crucial component of an effective regeneration response in the nervous system . Although its function is uncertain, the N-terminal region is well conserved and contains both a calmodulin binding domain, and sites for acylation, membrane attachment and protein kinase C phosphorylation. Structure predictions suggest that the C-terminal region may exist as an extended, negatively-charged rod with some similarity to the side arms of neurofilaments, indicating that the biological role of neuromodulin may depend on its ability to form a dynamic membrane-cytoplasm-calmodulin complex .
Multicopper oxidases, conserved site (Cu_oxidase_CS)
Type: Conserved_site

Multicopper oxidases are enzymes that possess three spectroscopically different copper centres. These centres are called: type 1 (or blue), type 2 (or normal) and type 3 (or coupled binuclear). The enzymes that belong to this family include:

Laccase (EC 1.10.3.2) (urishiol oxidase), an enzyme found in fungi and plants, which oxidizes many different types of phenols and diamines.

L-ascorbate oxidase (EC 1.10.3.3), a higher plant enzyme.

Ceruloplasmin (EC 1.16.3.1) (ferroxidase), a protein found in the serum of mammals and birds, which oxidizes a great variety of inorganic and organic substances. Structurally ceruloplasmin exhibits internal sequence homology, and seem to have evolved from the triplication of a copper-binding domain similar to that found in laccase and ascorbate oxidase.

In addition to the above enzymes there are a number of proteins which, on the basis of sequence similarities, can be said to belong to this family. These proteins are:

Copper resistance protein A (copA) from a plasmid in Pseudomonas syringae. This protein seems to be involved in the resistance of the microbial host to copper.

Blood coagulation factor V (Fa V).

Blood coagulation factor VIII (Fa VIII).

Yeast FET3 , which is required for ferrous iron uptake.

Yeast hypothetical protein YFL041w and SpAC1F7.08, the fission yeast homologue.

Factors V and VIII act as cofactors in blood coagulation and are structurally similar . Their sequence consists of a triplicated A domain, a B domain and a duplicated C domain; in the following order: A-A-B-A-C-C. The A-type domain is related to the multicopper oxidases.

This entry is drawn from a conserved region, which in ascorbate oxidase, laccase, in the third domain of ceruloplasmin, and in copA, contains five residues that are known to be involved in the binding of copper centres. However, it does not make any assumption on the presence of copper-binding residues and thus can detect domains that have lost the ability to bind copper (such as those in Fa V and Fa VIII).
Peptidase family C14A, cysteine active site (Caspase_cys_AS)
Type: Active_site

Interleukin-1 beta converting enzyme (

) (ICE) is responsible for the cleavage of the IL-1 beta precursor at an Asp-Ala bond to generate the mature biologically active cytokine. ICE a thiol protease composed of two subunits of 10 (p10) and 20 Kd (p20), both derived by the autocleavage of a 45 Kd precursor (p45). Two residues are implicated in the catalytic mechanism: a cysteine and an histidine. They are located in the P20 subunit after cleavage of the precursor. ICE belongs to a family of peptidases which is implicated in programmed cell death (apoptosis) and which has been termed 'caspase' for cysteine aspase. ICE is known as Caspase-1 and the other members of this family include:

Caspase-2 (ICH-1, NEDD-2).

Caspase-3 (also known as apopain, CPP32, Yama), a protease which, at the onset of apoptosis, proteolytically cleaves poly(ADP-ribose) polymerase at an Asp-Gly bond.

Caspase-4 (ICH-2, TX, ICErel-II).

Caspase-5 (ICH-3, TY, ICErel-III).

Caspase-6 (MCH-2).

Caspase-7 (MCH-3, ICE-LAP3, CMH-1, SCA-2, LICE2).

Caspase-8 (MCH-5, MACH, FLICE).

Caspase-9 (MCH-6, ICE-LAP6).

Caspase-10 (MCH-4, FLICE2).

Caspase-11.

Caspase-12.

Caspase-13 (ERICE).

Caspase-14.

Caenorhabditis elegans ced-3 involved in the initiation of apoptosis.

Drosophila Ice.

This entry represents a conserved region containing the cysteine active site.
Lipase, GDXG, putative serine active site (Lipase_GDXG_put_SER_AS)
Type: Active_site

The following lipolytic enzymes are evolutionarily related:

Mammalian hormone sensitive lipase (HSL). In adipose tissue and heart, HSL primarily hydrolyzes stored triglycerides to free fatty acids, while in steroidogenic tissues, it principally converts cholesteryl esters to free cholesterol for steroid hormone production.

Mammalian arylacetamide deacetylase (DAC).

Moraxella strain TA144 lipase 2 (gene lip2), an enzyme active at a low temperature.

Acinetobacter calcoaceticus esterase which seems to be active on simple triglycerides such as triacetin.

Streptomyces hygroscopicus acetyl-hydrolase (gene bah), which removes the N-acetyl group from the antibiotic bialaphos.

Escherichia coli acetyl esterase.

These enzymes contain a Ser-centred consensus sequence and a conserved His-Gly dipeptide found in most lipase N-terminal domains. These sequences are involved in the lipase active site conformation since substitution of the conserved Ser or His residues by Ala and Gln, respectively, results in the loss of both lipase and esterase activities .

This entry represents a conserved region containing the putative Ser active site.
Cathepsin D (Cathepsin_D)
Type: Family

Cathepsin D (

and MEROPS identifier A01.009) is an aspartic endopeptidase located in the lysosome of animal cells. It is synthesized as an inactive precursor and activated in the lysosome, either autolytically or by other lysosomal peptidases . Its optimum pH is ~3.5 . Quantitative N-terminal proteomics has been used to study the specificity of the enzyme . Although primarily thought to be involved in lysosomal catabolism of proteins, knockout of the mouse CATD gene is neonatally fatal and associated with numerous defects . Cathepsin D has been shown to induce apoptosis . Procathepsin D is also secreted in some cancers, where it can be activated at the acidic pH of the tumour microenvironment and promote the growth of cancer tissue or metastasis by degradation of extracellular matrix , or act as a mitogen .
Cathepsin Z (CTSZ)
Type: Family

Cathepsin Z (also known as Cathepsin X ,

and MEROPS identifier C01.013) is predominantly a cysteine-type carboxypeptidase with limited endopeptidase or dipeptidyl-peptidase activity, mainly against synthetic substrates . The substrate specificity has been examined by peptide scanning and shows that proline is not tolerated in the P1 or P1' positions and poorly accepted in P2, and Tyr, Met and Cys are marginally prefered in P2, P1 and P1' .

Cathepsin X is synthesized as an inactive zymogen, but the propeptide lacks the ERFNIN motif characteristic of lysosomal cysteine peptidases. A disulfide bridge can be formed between the proregion and the enzyme which leads to inactivation of the zymogen by the formation of a reversible covalent bond with the active site residue . From the crystal structure of the mature enzyme, a short, five-residue 'mini-loop' which includes the motif His-Xaa-Xaa-Xaa-Tyr restricts access to the S2' binding pocket, and it is the histidine that confers carboxypeptidase activity . Rotation of the histidine ring permits dipeptidyl-peptidase substrates to bind. The presence of an exposed RGD motif allows binding to beta3-integrin and the enzyme may have a role in cell signalling. Cathepsin X deficiency leads to accelerated cell senescence . Cathepsin X also regulates the immune response to Helicobacter pylori infection .
Tubulin-folding cofactor D (TBCD)
Type: Family

This entry represents TBCD and its homologues in eukaryotes.

Tubulin-folding cofactor D (TBCD) can interact with beta tubulin, which is regulated via its interaction with ARL2 (ADP ribosylation factor-like protein 2), a small monomeric G protein. ARL2 inhibits the beta-tubulin GTPase activating protein (GAP) activity of TBCD, and its interaction with native tubulin dimers . TBCD does not co-polymerise with microtubules either in vivo or in vitro, but instead modulates microtubule dynamics by sequestering beta-tubulin from GTP-bound alpha/beta-heterodimers in microtubules .

The tubulin heterodimer consists of one alpha- and one beta-tubulin polypeptide. In humans, five tubulin-specific chaperones termed TBCA/B/C/D/E are essential for bring the alpha- and beta-tubulin subunits together into a tightly associated heterodimer. Following the generation of quasi-native beta- and alpha-tubulin polypeptides (via multiple rounds of ATP-dependent interaction with the cytosolic chaperonin), TBCA and TBCB bind to and stabilise newly synthesised beta- and alpha-tubulin, respectively. The exchange of beta-tubulin between TBCA and TBCD, and of alpha-tubulin between TBCB and TBCE, resulting in the formation of TBCD/beta and TBCE/alpha. These two complexes then interact with each other and form a supercomplex (TBCE/alpha/TBCD/beta). Interaction of the supercomplex with TBCC causes the disassembly of the supercomplex and the release of E-site GDP-bound alpha/beta tubulin heterodimer, which becomes polymerization competent following spontaneous exchange with GTP .
Archaeal Nre (Nre)
Type: Family

This entry represents archaeal Nre proteins. While most archaeal organisms encode only a single Nre protein, some encode two, NreA and NreB.

NreA is an archaeal PCNA interacting protein that works together with the UvrABC proteins in repairing DNA damage resulting from exposure to DNA damaging agent MMC. NreA contains a putative PIP motif at its C terminus that is important for its function .
Caspase-8, death effector domain 1 (Caspase-8_DED1)
Type: Domain

This entry represents the first repeat of the Death effector domain (DED1) found at the N-terminal end of CASP8. This domain plays a unique structural role.

Caspase-8 (MEROPS identifier C14.009) is a cytoplasmic cysteine endopeptidase with a preference for aspartyl bonds, acting at neutral pH . It is active as a homodimer or as a heterodimer in association with the long isoform of FLICE, and proteolytic processing of the caspase-8 precursor is required for stabilisation of the dimer . It is one of the activator caspases. Caspase-8 has a strict requirement for Asp in P1, a preference for Glu in P3 and small residues in P1' . The caspase-8 proenzyme has two N-terminal death effector domains, which are removed upon activation along with a linker region between the large and small subunits of the C-terminal catalytic domain. The death-inducing signalling complex, composed of a transmembrane death receptor and the adapter protein FADD, assembles at the cell membrane following binding of a death ligand. Procaspase-8 is recruited to this complex and becomes active by dimerisation. Active caspase-8 can then activate the executioner caspases -3 and -7 .

Caspase-8 cleaves RIPK1, which is crucial to inhibit RIPK1 kinase activity, limiting TNF-induced apoptosis, necroptosis and inflammatory response. In humans, non-cleavable RIPK1 leads to autoinflammatory disease characterised by hypersensitivity to apoptosis and necroptosis and increased inflammatory response .
Phosphatidylserine decarboxylase, prokaryotes (PSD-A)
Type: Family

This entry represents Phosphatidylserine decarboxylase proenzyme and similar sequences mainly found in prokaryotes. Phosphatidylserine decarboxylase (PSD,

) is synthesised as a single chain precursor. Generation of the pyruvoyl active site from a Ser is coupled to cleavage of a Gly-Ser bond between the larger (beta) and smaller (alpha chains). This enzyme catalyses the formation of phosphatidylethanolamine (PtdEtn) from phosphatidylserine (PtdSer). It is an integral membrane protein.

Phosphatidylserine decarboxylases (PSDs) have been classified in two types. Type I PSDs include enzymes of eukaryotic mitochondria and bacterial origin which contain the amino acid sequence LGST as a characteristic motif. Type II PSDs are found in the endomembrane system of eukaryotes and contain a typical GGST motif. These characteristic motifs are considered as autocatalytic cleavage sites where proenzymes are split into alpha and beta subunits .