SII-SWORD/CoKE huggingface dataset:
Peptidase M4, C-terminal (Peptidase_M4_C_domain)
Type: Domain

This entry represents a domain found in the C-terminal of the peptidase M4 family members.

This group of metallopeptidases that belong to the MEROPS peptidase family M4 (thermolysin family, clan MA(E)). The protein fold of the peptidase domain of thermolysin (MEROPS identifier M04.001), is the type example for members of the clan MA. The thermolysin family is composed only of secreted eubacterial endopeptidases. The zinc-binding residues of thermolysin are H-142, H-146 and E-166, with E-143 acting as the catalytic residue. Thermolysin also contains four calcium-binding sites, which contribute to its unusual thermostability. The family also includes enzymes from a number of pathogens, including Legionella and Listeria, and the protein pseudolysin (MEROPS identifier M04.005), all with a substrate specificity for an aromatic residue in the P1' position. Three-dimensional structure analysis has shown that the enzymes undergo a hinge-bend motion during catalysis. Pseudolysin has a broader specificity, acting on large molecules such as elastin and collagen, possibly due to its wider active site cleft .
A kinase-anchoring protein AKAP5 and AKAP12, calmodulin (CaM)-binding motif (AKAP_WSK)
Type: Domain

The AKAP CaM-binding motif (also known as the WSK motif) is short motif, named after three conserved residues found in the WXSXK motif, found in protein kinase A anchoring proteins.

The A kinase-anchoring proteins AKAP-5 and AKAP-12 (Gravin) bind calmodulin (CaM), a Ca(2+)-sensing protein that is expressed in all eukaryotic cells and mediates many essential processes driven by Ca(2+), including long-term changes in synaptic connections in the brain, apoptosis, and immune responses. The AKAP CaM-binding motif contains hydrophobic amino acids in a 1-4-7-8 pattern within an helix .
Ribosome-inactivating protein (Ribosome_inactivat_prot)
Type: Family

A number of bacterial and plant toxins act by inhibiting protein synthesis in eukaryotic cells. The toxins of the shiga and ricin family inactivate 60S ribosomal subunits by an N-glycosidic cleavage which releases a specific adenine base from the sugar-phosphate backbone of 28S rRNA . Members of the family include shiga and shiga-like toxins, and type I (e.g. trichosanthin and luffin) and type II (e.g. ricin, agglutinin and abrin) ribosome inactivating proteins (RIPs). All these toxins are structurally related. RIPs have been of considerable interest because of their potential use, conjugated with monoclonal antibodies, as immunotoxins to treat cancers. Further, trichosanthin has been shown to have potent activity against HIV-1-infected T cells and macrophages . Elucidation of the structure-function relationships of RIPs has therefore become a major research effort. It is now known that RIPs are structurally related. A conserved glutamic residue has been implicated in the catalytic mechanism ; this lies near a conserved arginine, which also plays a role in catalysis .
Phosphoglycerate kinase (Phosphoglycerate_kinase)
Type: Family

Phosphoglycerate kinase (

) (PGK) is an enzyme that catalyses the formation of ATP to ADP and vice versa. In the second step of the second phase in glycolysis, 1,3-diphosphoglycerate is converted to 3-phosphoglycerate, forming one molecule of ATP. If the reverse were to occur, one molecule of ADP would be formed. This reaction is essential in most cells for the generation of ATP in aerobes, for fermentation in anaerobes and for carbon fixation in plants.

PGK is found in all living organisms and its sequence has been highly conserved throughout evolution. The enzyme exists as a monomer containing two nearly equal-sized domains that correspond to the N-and C-termini of the protein (the last 15 C-terminal residues loop back into the N-terminal domain). 3-phosphoglycerate (3-PG) binds to the N-terminal, while the nucleotide substrates, MgATP or MgADP, bind to the C-terminal domain of the enzyme. This extended two-domain structure is associated with large-scale 'hinge-bending' conformational changes, similar to those found in hexokinase . At the core of each domain is a 6-stranded parallel β-sheet surrounded by α helices. Domain 1 has a parallel β-sheet of six strands with an order of 342156, while domain 2 has a parallel β-sheet of six strands with an order of 321456. Analysis of the reversible unfolding of yeast phosphoglycerate kinase leads to the conclusion that the two lobes are capable of folding independently, consistent with the presence of intermediates on the folding pathway with a single domain folded .
Peptidase M8, leishmanolysin (Peptidase_M8)
Type: Family

This group of metallopeptidases belong to the MEROPS peptidase family M8 (leishmanolysin family, clan MA(M)). The protein fold of the peptidase domain for members of this family resembles that of thermolysin, the type example for clan MA.

Leishmanolysin (

) is an enzyme found in eukaryotes including Leishmania and related parasitic protozoa . The endopeptidase is the most abundant protein on the cell surface during the promastigote stage of the parasite, and is attached to the membrane by a glycosylphosphatidylinositol anchor . In the amastigote form, the parasite lives in lysosomes of host macrophages, producing a form of the protease that has an acidic pH optimum . This differs from most other metalloproteases and may be an adaptation to the environment in which the organism survives .

Tris entry also includes proteins from humans and other chordates, including Leishmanolysin-like peptidase or invadolysin and Ciliated left-right organizer metallopeptidase, CIROP). CIROP plays a role in left-right patterning process .
Glycosyl hydrolase family 18, active site (Glyco_hydro_18_chit_AS)
Type: Active_site

The glycosyl hydrolase family 18 (GH18) is widely distributed in all domains of life. The GH18 family contains hydrolytic enzymes with chitinase or endo-N-acetyl-beta-D-glucosaminidase (ENGase) activity as well as chitinase like lectins (chi-lectins/proteins (CLPs). Chitinases (EC 3.2.1.14) are hydrolytic enzymes that cleave the beta-1,4-bond releasing oligomeric, dimeric (chitobiose) or monomeric (N-actetylglucosamine, GlcNAc) products. ENGases (EC

) hydrolyse the beta-1,4 linkage in the chitobiose core of N-linked glycans from glycoproteins leaving one GlcNAc residue on the substrate. CLPs do not display chitinase activity but some of them have been reported to have specific functions and carbohydrate binding property. The catalytic domain of GH18s may be connected to one or several substrate binding modules (CBMs), which enhance binding of enzymes to insoluble substrates. Certain GH18s also contain peptide signals for localization such as an N-terminal secretion peptide, a C-terminal glycosyl-phosphatidylinositol (GPI) anchor signal for attachment to the plasma-membrane, or N-or O-linked glycosylation sites for oligosaccharide modifications .

The catalytic domain of GH18s has a common (β/α)8 triosephosphate isomerase (TIM)-barrel structure, which consists of a barrel-like framework made from eight internal parallel β-strands that are alternately connected by eight exterior α-helices. The active site motif
DxxDxDxE is essential for the activity of the GH18 catalytic domain. The Glu (E) in this motif acts as the catalytic proton donor, and the last Asp (D(3))
is supposed to contribute to the stabilization of the essential distortion of the substrate .

This entry represents the active site of GH18 members predominantly found in bacteria and eukaryotes.
Leukemia inhibitory factor /oncostatin (Leukemia_IF/oncostatin)
Type: Family

On the basis of functional and structural similarities, the small cytokines leukemia inhibitory factor (LIF) and oncostatin (OSM) can be classified into a single family .

It has been said that LIF and OSM can be included in the IL-6 family of cytokines, but while all these cytokines seem to be structurally related, the sequence similarity is not high enough to allow the use of a single consensus pattern.
Integrase, catalytic core (Integrase_cat-core)
Type: Domain

The retroviral integrase is the enzyme responsible for the insertion of a DNA copy of the viral genome into host DNA, an essential step in the replication cycle of viruses . Integrases comprise three functional and structural domains: the central core domain, which contains the catalytic residues, an N-terminal zinc finger and a C-terminal DNA binding domain .

The integrase catalytic domain catalyses a series of reactions to integrate the viral genome into a host chromosome. In the first step, it removes two 3' end nucleotides from each strand of the linear viral DNA, leaving overhanging CA-OH ends. In the second step, the processed 3' ends are covalently joined to the 5' ends of the target DNA. In the third step, which probably involves additional cellular enzymes, unpaired nucleotides at the viral 5' ends are removed and the ends are joined to the target site 3' ends, generating an integrated provirus flanked by five base-pair direct repeats of the target site DNA .

The crystal structure of the catalytic domain shows a dimeric structure, with each monomer containing a five-stranded β-sheet and six α-helices . This fold is characteristic of the polynucleotidyltransferase superfamily whose members include RNase H, the bacteriophage Mu transposase, and the E. coli Holliday junction resolving enzyme, RuvC . The catalytic domain of integrase contains the DD35E triad motif. As in other DNA-binding proteins containing this motif, these acidic residues coordinate a divalent Mg2+ in the resting enzyme. Substituting any one of these residues abolishes both processing and integration activities of integrase.

The integrase catalytic domain is also found in various transposase proteins.
Transaldolase/Fructose-6-phosphate aldolase (TAL/FSA)
Type: Family

Transaldolase (TAL) is an enzyme of the pentose phosphate pathway (PPP) found almost ubiquitously in the three domains of life (Archaea, Bacteria, and Eukarya). TAL shares a high degree of structural similarity and sequence identity with fructose-6-phosphate aldolase (FSA) . They both belong to the class I aldolase family . Their protein structures have been revealed .

Transaldolase (

) catalyses the reversible transfer of a three-carbon ketol unit from sedoheptulose 7-phosphate to glyceraldehyde 3-phosphate to form erythrose 4-phosphate and fructose 6-phosphate. This enzyme, together with transketolase, provides a link between the glycolytic and pentose-phosphate pathways. Transaldolase is an enzyme of about 34kDa whose sequence has been well conserved throughout evolution. A lysine has been implicated in the catalytic mechanism of the enzyme; it acts as a nucleophilic group that attacks the carbonyl group of fructose-6-phosphate.

Fructose-6-phosphate aldolase was originally thought to be transaldolases or transaldolase-related proteins. However, they perform a novel reaction, the cleavage or formation of fructose 6-phosphate .
Beta-lactamase, class-C active site (Beta-lactam_class-C_AS)
Type: Active_site

This active site signature detects all class C Beta-lactamases. The class C beta-lactamases are serine hydrolases belonging to MEROPS peptidase family S12 (D-Ala-D-Ala carboxypeptidase B family, clan SE). They are classed as non-peptidase homologues.

Beta-lactamases (

) are enzymes which catalyse the hydrolysis of an amide bond in the beta-lactam ring of antibiotics belonging to the penicillin/cephalosporin family. Four kinds of beta-lactamase have been identified . Class-B enzymes are zinc containing proteins whilst class -A, C and D enzymes are serine hydrolases. The three classes of serine beta-lactamases are evolutionary related and belong to a superfamily that also includes DD-peptidases and a variety of other penicillin-binding proteins (PBP's). All these proteins contain a Ser-x-x-Lys motif, where the serine is the active site residue. Although clearly homologous, the sequences of the three classes of serine beta-lactamases exhibit a large degree of variability and only a small number of residues are conserved in addition to the catalytic serine.
Ribonuclease J, conserved site (RNase_J_CS)
Type: Conserved_site

This conserved region is found in proteins characterised as RNase J. They are about 50 to 77kDa. The central region is well conserved and contains three conserved histidines. Most of these proteins are related at the N-terminal region to the beta-lactamase family.

RNase J cleaves the 5'-leader sequence of certain mRNAs and may play a role in the maturation and stability of specific mRNAs. It is also required for the maturation of the 16S rRNA acting preferentially on 16S rRNA precursors after association of the 30S and 50S ribosomal subunits.
Casein, alpha/beta (Casein)
Type: Family

Caseins are the major protein constituent of milk. In milk, caseins interact with calcium phosphate, forming large stable colloidal particles termed micelles. These micelles make it possible to maintain a supersaturated calcium phosphate concentration in milk, providing the newborn with sufficient calcium phosphate for the mineralisation of calcified tissues . Caseins can be classified into two families; the first consists of the kappa-caseins, and the second groups the alpha-s1, alpha-s2, and beta-caseins. The alpha/beta caseins are a rapidly diverging family of proteins . However two regions are conserved: a cluster of phosphorylated serine residues and the signal sequence.

Alpha-s2 casein is known as epsilon-casein in mouse, gamma-casein in rat and casein-A in guinea pig. Alpha-s1 casein is known as alpha-casein in rat and rabbit and as casein-B in guinea pig.
Actinin-type actin-binding domain, conserved site (Actinin_actin-bd_CS)
Type: Conserved_site

Alpha-actinin is a F-actin cross-linking protein which is thought to anchor actin to a variety of intracellular structures . The actin-binding domain of alpha-actinin seems to reside in the first 250 residues of the protein. A similar actin-binding domain has been found in the N-terminal region of many different actin-binding proteins , like the beta chain of spectrin (or fodrin), dystrophin, the slime mold gelation factor (or ABP-120), filamin and fimbrin.

This entry represents two conserved sites for the actin-binding domain.
Peptidase M12B, ADAM/reprolysin (Peptidase_M12B)
Type: Domain

This group of metallopeptidases belong to the MEROPS peptidase family M12, subfamily M12B (adamalysin family, clan (MA(M)). The protein fold of the peptidase domain for members of this family resembles that of thermolysin, the type example for clan MA and the predicted active site residues for members of this family and thermolysin occur in the motif HEXXH .

The M12B proteinases are also referred to as adamalysins or reprolysins . The adamalysins are zinc dependent endopeptidases found in snake venom. There are some mammalian proteins such as

, and fertilin

. Fertilin and closely related proteins appear to not have some active site residues and may not be active enzymes.

CD156 (also called ADAM8 (

) or MS2 human) has been implicated in extravasation of leukocytes.

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 .
Influenza RNA-dependent RNA polymerase subunit PB2 (INV_PB2)
Type: Family

Orthomyxoviridae RNA polymerase with the subunit composition of PB1-PB2-PA is a unique multifunctional enzyme with the activities of both synthesis and cleavage of RNA, and is involved in both transcription and replication of the RNA genome. Transcription is initiated by using capped RNA fragments, which are generated after cleavage of host cell mRNA by the RNA polymerase-associated capped RNA endonuclease . The PB2 subunit has cap-binding and cap-dependent endonuclease activities . It appears that two separate sequences, one N-(242-282) and the other C-terminal (538-577) proximal segments of PB2 subunit, constitute the RNA cap-binding site of the Influenza virus RNA polymerase .
Potyvirus coat protein (Poty_coat)
Type: Family

This protease is found in genome polyproteins of potyviruses. The genome polyprotein contains: N-terminal protein (P1), helper component protease
(

, HC-PRO), protein P3, 6KD protein (6K1), cytoplasmic inclusion protein (CI), 6KD protein 2 (6K2), genome-linked protein (VPG), nuclear inclusion protein A (

), nuclear inclusion protein B (

) and coat protein (CP).
The coat protein is at the C terminus of the polyprotein.
Small ribosomal subunit protein eS1 (Ribosomal_eS1)
Type: Family

A number of eukaryotic and archaebacterial ribosomal proteins can be grouped on the basis of sequence similarities. This family represents the small ribosomal subunit protein eS1, previously known as S1 in yeast and S3A in archaea and mammals , which consists of proteins that have from 220 to 250 amino acids.

Ribosomes are the particles that catalyse mRNA-directed protein synthesis in all organisms. The codons of the mRNA are exposed on the ribosome to allow tRNA binding. This leads to the incorporation of amino acids into the growing polypeptide chain in accordance with the genetic information. Incoming amino acid monomers enter the ribosomal A site in the form of aminoacyl-tRNAs complexed with elongation factor Tu (EF-Tu) and GTP. The growing polypeptide chain, situated in the P site as peptidyl-tRNA, is then transferred to aminoacyl-tRNA and the new peptidyl-tRNA, extended by one residue, is translocated to the P site with the aid the elongation factor G (EF-G) and GTP as the deacylated tRNA is released from the ribosome through one or more exit sites . About 2/3 of the mass of the ribosome consists of RNA and 1/3 of protein. The proteins are named in accordance with the subunit of the ribosome which they belong to the small (S1 to S31) and the large (L1 to L44). Usually they decorate the rRNA cores of the subunits.

Many ribosomal proteins, particularly those of the large subunit, are composed of a globular, surfaced-exposed domain with long finger-like projections that extend into the rRNA core to stabilise its structure. Most of the proteins interact with multiple RNA elements, often from different domains. In the large subunit, about 1/3 of the 23S rRNA nucleotides are at least in van der Waal's contact with protein, and L22 interacts with all six domains of the 23S rRNA. Proteins S4 and S7, which initiate assembly of the 16S rRNA, are located at junctions of five and four RNA helices, respectively. In this way proteins serve to organise and stabilise the rRNA tertiary structure. While the crucial activities of decoding and peptide transfer are RNA based, proteins play an active role in functions that may have evolved to streamline the process of protein synthesis. In addition to their function in the ribosome, many ribosomal proteins have some function 'outside' the ribosome .
Palmitoyltransferase, DHHC domain (Palmitoyltrfase_DHHC)
Type: Domain

This entry refers to the DHHC domain, found in DHHC proteins which are palmitoyltransferases .

Palmitoylation or, more specifically S-acylation, plays important roles in the regulation of protein localization, stability, and activity. It is a post-translational protein modification that involves the attachment of palmitic acid to Cys residues through a thioester linkage. Protein acyltransferases (PATs), also known as palmitoyltransferases, catalyse this reaction by transferring the palmitoyl group from palmitoyl-CoA to the thiol group of Cys residues. They are characterised by the presence of 50-residue-long domain called the DHHC domain, which in most but not all cases is also cysteine-rich and gets its name from a highly conserved DHHC signature tetrapeptide (Asp-His-His-Cys). The Cys residue within the DHHC domain forms a stable acyl intermediate and transfers the acyl chain to the Cys residues of a target protein .

Some of the proteins containing a DHHC domain are listed below:

Drosophila DNZ1 protein

Mouse Abl-philin 2 (Aph2) protein. Interacts with c-Abl. May play a role in apoptosis

Mammalian ZDHHC9, an integral membrane protein

Yeast ankyrin repeat-containing protein AKR1

Yeast Erf2 protein. This protein localizes to the endoplasmic reticulum and seems to be important for Ras function

Arabidopsis thaliana tip growth defective 1
Mycoplasma-specific lipoprotein, type 3 (Lipoprotein_3)
Type: Family

This family of lipoproteins is Mycoplasma specific, and includes a variety of hypothetical proteins . They all have a prokaryotic membrane lipoprotein lipid attachment site which is probable acts as a membrane anchor.
Aromatic amino acid beta-eliminating lyase/threonine aldolase (ArAA_b-elim_lyase/Thr_aldolase)
Type: Domain

This domain is found in many tryptophanases (tryptophan indole-lyase, TNase), tyrosine phenol-lyases (TPL) and threonine aldolases. It is involved in the degradation of amino acids. The glycine cleavage system is composed of four proteins: P, T, L and H. In Bacillus subtilis, the P 'protein' is an heterodimer of two subunits. The glycine cleavage system catalyses the degradation of glycine. The P protein binds the alpha-amino group of glycine through its pyridoxal phosphate cofactor; CO(2) is released and the remaining methylamine moiety is then transferred to the lipoamide cofactor of the H protei
Transposase, IS30, conserved site (Transposase_IS30_CS)
Type: Conserved_site

Autonomous mobile genetic elements such as transposon or insertion sequences (IS) encode an enzyme, called transposase, required for excising and inserting the mobile element. On the basis of sequence similarities, transposases can be grouped into various families. One of these families has been shown to consist of proteins of 340 to 380 amino acids.
Alpha-2-macroglobulin (Macroglobln_a2)
Type: Domain

This entry contains serum complement C3 and C4 precursors and alpha-macrogrobulins.

The alpha-macroglobulin (aM) family of proteins includes protease inhibitors , typified by the human tetrameric a2-macroglobulin (a2M); they belong to the MEROPS proteinase inhibitor family I39, clan IL. These protease inhibitors share several defining properties, which include (i) the ability to inhibit proteases from all catalytic classes, (ii) the presence of a 'bait region' and a thioester, (iii) a similar protease inhibitory mechanism and (iv) the inactivation of the inhibitory capacity by reaction of the thiol ester with small primary amines. aM protease inhibitors inhibit by steric hindrance . The mechanism involves protease cleavage of the bait region, a segment of the aM that is particularly susceptible to proteolytic cleavage, which initiates a conformational change such that the aM collapses about the protease. In the resulting aM-protease complex, the active site of the protease is sterically shielded, thus substantially decreasing access to protein substrates. Two additional events occur as a consequence of bait region cleavage, namely (i) the h-cysteinyl-g-glutamyl thiol ester becomes highly reactive and (ii) a major conformational change exposes a conserved COOH-terminal receptor binding domain (RBD). RBD exposure allows the aM protease complex to bind to clearance receptors and be removed from circulation . Tetrameric, dimeric, and, more recently, monomeric aM protease inhibitors have been identified .