Catalytic Domain Architecture of Metzincin Metalloproteases

F. Xavier Gomis-Rüth

doi:10.1074/jbc.r800069200

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.

Highlights

Cleavage of peptide bonds is essential for life, and the factors responsible for peptide cleavage are ubiquitous
Among them are MPs,2 which are mostly zinc-dependent peptide-bond hydrolases. They participate in metabolism through both extensive and unspecific protein degradation and controlled hydrolysis of specific peptide bonds [1]
Metzincins split into families, seven of which have been characterized at the structural level for at least one of their members: astacins, ADAMs/adamalysins/reprolysins, serralysins, matrix metalloproteinases, snapalysins, leishmanolysins, and pappalysins

Summary

The Metzincin Fold

Ͼ200 structures of metzincins, comprising at least the catalytic domain, have been deposited with the Protein Data Bank (supplemental Table 1). The loop segment connecting strands ␤III and ␤IV (referred to as L␤III␤IV) leads to the appearance of bulge-like elements, which mainly affect subsites S1Ј and S2Ј (see Ref. 17 for subsite nomenclature in proteases) This gives rise to extensive variations in enzyme-substrate interactions on the primed side of the active-site clefts. The CSD starts after this glycine, and the chain leads to the third zinc ligand, a histidine or an aspartate, which approaches the metal from below (supplemental Fig. 1) This subdomain contains few repetitive secondary structure elements, mainly a C-terminal helix ␣C at the end of the polypeptide chain. Some metzincins display an additional protein ligand at a slightly greater distance from the catalytic cation in the form of a tyrosine O␩ atom, as seen in unbound astacin and serralysins and as hypothesized in ulilysin [21] This tyrosine residue lies two positions ahead of the Met-turn methionine. Such a role is performed by other, non-conserved residues in tyrosine-lacking metzincins

Structural Relatedness among Families

Distinguishing Features of Each Family

Conclusions