Peptidase M12A, meprin alpha subunit <p>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:</p><ul> <li>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.</li><li>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. </li></ul><p>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. </p><p>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 [<cite idref="PUB00003579"/>]. 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 [<cite idref="PUB00003579"/>].</p><p>This family contains the alpha subunit of meprin. Meprins are metazoan zinc metallopeptidases belonging to MEROPS peptidase family M12 (clan MA(M)), subfamily M12A (astacin family). They are complex and structurally unique homo- or heterotetrameric glycoproteins composed of evolutionarily related alpha and/or beta subunits that contain disulphide-bridged dimers. The two subunits are differentially expressed and processed to yield latent and active proteases as well as membrane-associated and secreted forms. They are excellent models of homo- and hetero-oligomeric enzymes that are regulated at the transcriptional and post translational levels [<cite idref="PUB00005405"/>]. Each chain contains an astacin domain, MAM, MATH, and AM (after MATH) domains [<cite idref="PUB00006426"/>], and an EGF-like domain.</p> <p>The astacin domain is a Zn-metalloprotease domain characterised by a unique 18-amino acid signature sequence, HEXXHXXGFXHEXXRXDR [<cite idref="PUB00005025"/>], which begins with the zinc binding motif HEXXH. The MAM domain is necessary for correct folding and transport through the secretory pathway. The MATH domain is required for folding of an activatable zymogen, and the AM domain is important for activity against proteins and efficient secretion of the protein. </p>