Catalytic domain architecture of metzincin metalloproteases

Abstract

Metalloproteases cleave proteins and peptides, and deregulation of their function leads to pathology. An understanding of their structure and mechanisms of action is necessary to the development of strategies for their regulation. Among metallopeptidases are the metzincins, which are mostly multidomain proteins with approximately 130-260-residue globular catalytic domains showing a common core architecture characterized by a long zinc-binding consensus motif, HEXXHXXGXX(H/D), and a methionine-containing Met-turn. Metzincins participate in unspecific protein degradation such as digestion of intake proteins and tissue development, maintenance, and remodeling, but they are also involved in highly specific cleavage events to activate or inactivate themselves or other (pro)enzymes and bioactive peptides. Metzincins are subdivided into families, and seven such families have been analyzed at the structural level: the astacins, ADAMs/adamalysins/reprolysins, serralysins, matrix metalloproteinases, snapalysins, leishmanolysins, and pappalysins. These families are reviewed from a structural point of view.

FIGURE 1.

Overlay of structural segments common to the seven prototypes as C^α plots. A, the active-site helix αB (including the side chains of the zinc-liganding histidines and aspartate and the general base/acid) and the Met-turn (with the methionine side chain). Blue, astacin; cyan, adamalysin II; red, leishmanolysin; green, MMP-8; white, aeruginolysin; yellow, snapalysin; orange, ulilysin. The magenta curved arrows indicate where an extra domain is inserted in leishmanolysin. B, the upper domain β-sheet (strands βI–βV, in cyan, blue, green, orange, and yellow, respectively), the posterior helix αA (red), and the C-terminal helix αC (purple) as found in the seven leads. Leishmanolysin lacks strand βII.