Matrix Metalloproteinases

Abstract

The matrix metalloproteinases (MMPs) constitute a family of (in man) 23 different extracellular soluble/cell surface–anchored multidomain zinc endopeptidases, all of which exhibit a common catalytic domain of a metzincin‐like topology, that is, possess a Met‐containing tight turn and carry an extended His‐Glu‐Xaa‐Xaa‐His‐Xaa‐Xaa‐Gly‐Xaa‐Xaa‐His zinc‐binding consensus segment enwrapping the catalytic zinc, with the three histidine imidazole side chains and a nucleophilic water ligating the catalytic zinc, and the glutamine side chain presumably acting as a proton shuttle. The MMPs are involved not only in extracellular matrix degradation but also in a number of other biological processes such as shedding of membrane‐bound growth factor and cytokine precursors, pro‐proteinase activation, or inhibitor inactivation. Normally, their proteolytic activity is precisely regulated by endogenous protein inhibitors, in particular, by the tissue inhibitors of metalloproteinases (TIMPs). Disruption of this balance results in serious diseases such as arthritis, tumor growth, and metastasis, thus rendering the MMPs attractive targets for inhibition therapy. Individual vertebrate MMPs have been named according to their presumed substrates or classified by sequential (chronological) numbers, which run from MMPs 1 to 28. These MMPs are synthesized with an N‐terminal signal sequence, a pro‐domain, and a catalytic domain containing the catalytic zinc, a structural zinc, and up to three calcium ions. Additionally, most MMPs possess a C‐terminal ion containing hemopexin‐like domain, which, in the membrane‐bound MMPs, is followed by a transmembrane helix and a cytoplasmic domain, or a glycosil phosphatidyl inositol (GPI) anchor. This overview presents common and special structural features of the MMPs, in particular of their catalytic domain.