The α subunit of meprin A: Molecular cloning and sequencing, differential expression in inbred mouse strains, and evidence for divergent evolution of the α and β subunits

Meprin A, a membrane-bound oligomeric metalloendopeptidase, contains two different subunits, α and β. We report here the cloning and sequencing of the α subunit cDNA. The translated polypeptide consists of 760 amino acids, including a preprosequence (77 amino acids) that precedes the NH₂ terminus of the purified enzyme. The next 198 amino acids constitute the "astacin family" protease domain, which includes the astacin family signature sequence, HE(L,I)XHXXGFXHE(Q,H)XRXDRDX(Y,H)(V,I)X(I,V). An immunoglobulin/major histocompatibility complex protein signature was found at the end of the protease domain. At the COOH terminus of the α subunit, there is an epidermal growth factor-like domain, followed by a transmembrane domain, and six additional amino acids. Ten potential glycosylation sites have been identified, and at least three of those sites are glycosylated. Northern blot analyses of kidney tissue from C57BL/6 and C3H/He mice indicate that variations in meprin A activity in these strains reflect differences in the levels of the α subunit mRNA. Several internal peptide sequences obtained from the β subunit indicate that it is approximately 50% identical to the α subunit. Furthermore, NH₂-terminal sequence analyses (39 residues) indicate that rat and mouse a are 79% identical, rat and mouse β are 74% identical, and that α and β subunits for both species are 47% identical. These data indicate that α and β are closely related products of divergent evolution.