Pathways & interactions
Peptidase M10A, cysteine switch, zinc binding site (IPR021158)
Short name: Pept_M10A_Zn_BS
In the MEROPS database peptidases and peptidase homologues are grouped into clans and families. Clans are groups of families for which there is evidence of common ancestry based on a common structural fold:
- Each clan is identified with two letters, the first representing the catalytic type of the families included in the clan (with the letter 'P' being used for a clan containing families of more than one of the catalytic types serine, threonine and cysteine). Some families cannot yet be assigned to clans, and when a formal assignment is required, such a family is described as belonging to clan A-, C-, M-, N-, S-, T- or U-, according to the catalytic type. Some clans are divided into subclans because there is evidence of a very ancient divergence within the clan, for example MA(E), the gluzincins, and MA(M), the metzincins.
- Peptidase families are grouped by their catalytic type, the first character representing the catalytic type: A, aspartic; C, cysteine; G, glutamic acid; M, metallo; N, asparagine; S, serine; T, threonine; and U, unknown. The serine, threonine and cysteine peptidases utilise the amino acid as a nucleophile and form an acyl intermediate - these peptidases can also readily act as transferases. In the case of aspartic, glutamic and metallopeptidases, the nucleophile is an activated water molecule. In the case of the asparagine endopeptidases, the nucleophile is asparagine and all are self-processing endopeptidases.
In many instances the structural protein fold that characterises the clan or family may have lost its catalytic activity, yet retain its function in protein recognition and binding.
Metalloproteases are the most diverse of the four main types of protease, with more than 50 families identified to date. In these enzymes, a divalent cation, usually zinc, activates the water molecule. The metal ion is held in place by amino acid ligands, usually three in number. The known metal ligands are His, Glu, Asp or Lys and at least one other residue is required for catalysis, which may play an electrophillic role. Of the known metalloproteases, around half contain an HEXXH motif, which has been shown in crystallographic studies to form part of the metal-binding site [PMID: 7674922]. 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 [PMID: 7674922].
This group of metallopeptidases belong to the MEROPS peptidase family M10 (clan MA(M)), subfamily M10A.
The protein fold of the peptidase domain for members of this family resembles that of thermolysin, the type example for clan MA.
Sequences having this domain are extracellular metalloproteases, such as collagenase and stromelysin, which degrade the extracellular matrix, are known as matrixins. They are zinc-dependent, calcium-activated proteases synthesised as inactive precursors (zymogens), which are proteolytically cleaved to yield the active enzyme [PMID: 2551898, PMID: 2167841]. All matrixins and related proteins possess 2 domains: an N-terminal domain, and a zinc-binding active site domain. The N-terminal domain peptide, cleaved during the activation step, includes a conserved PRCGVPDV octapeptide, known as the cysteine switch, whose Cys residue chelates the active site zinc atom, rendering the enzyme inactive [PMID: 2841336, PMID: 1988438]. The active enzyme degrades components of the extracellular matrix, playing a role in the initial steps of tissue remodelling during morphogenesis, wound healing, angiogenesis and tumour invasion [PMID: 2551898, PMID: 2167841].
- PS00546 (CYSTEINE_SWITCH)