Biology Reference
In-Depth Information
meprin B and heteromeric meprin A also tend to be found at high concentrations in
the brush border membranes of the kidney and the intestine.
4.2.3 Evolution and Relation of Meprins to Other Proteases
Meprins are members of the “astacin family of metalloproteinases” (Clan MA(M)-
M12A) and the “metzincin” superfamily. Extensive information about these
families can be found at the MEROPS database (
http://merops.sanger.ac.uk
). The
astacin evolutionary family was named after the crayfish enzyme; it is the smallest
member of the family, contains only a prosequence and the protease domain, and it
is the only member of the family for which there is a crystal structure to date. There
are hundreds of members of the astacin family that have been identified in hydra to
mammals. Bone morphogenetic protein-1 (BMP-1) is one of the family members
and one of the proteinases important to the processing of collagen. Meprins are
unique in the family in terms of the COOH-terminal domains, disulfide bridging of
the subunits to form dimers, higher order oligomerization, and enzymatic activities
(Bertenshaw et al.
2003
; Sterchi et al.
2008
).
The metzincin superfamily contains several evolutionary families in addition to
the astacins. The other families include the matrixins, the ADAMs, serralysins
(bacterial proteases), pappalysins (pregnancy-associated plasma proteins), and
leishmanolysins (protozoan proteases). The different families have very little pri-
mary sequence identity, but their protease domains contain strikingly similar three-
dimensional structures, and they have a conserved zinc-binding sequence and a
methionine-turn (Met-turn) underlying the active site. These features gave rise to
the name “Metzincins” for the superfamily.
4.3 Meprin Substrates and Inhibitors
4.3.1 Peptide Bond Specificity of the Subunits
Meprin
subunit
has a preference for cleaving peptide bonds flanked by negatively charged amino
acids (Asp, Glu), whereas the
and
have different peptide bond specificities (Fig.
4.3
). The
a
b
b
subunit prefers neutral, aliphatic, and aromatic
amino acids (e.g., serine, leucine, tyrosine, phenylalanine). The
a
subunit also has a
preference for proline residues one amino acid removed from the cleavage site. This
latter preference may be important for the ability of meprin A to hydrolyze
extracellular proteins such as collagens and gelatins. Because of these very different
peptide bond specificities, the homomeric isoforms of meprin A and B tend to have
distinct peptide substrates. For example, gastrin-17 that has a cluster of Glu residues is
a good substrate for mouse meprin B, but is not hydrolyzed by homomeric meprin A.
Whereas the nine-amino acid bradykinin peptide is cleaved by homomeric meprin
A at a Phe-Ser bond, but the peptide is not cleaved by meprin B.
a
