Figure 3. MMP domain structure.

(A) MT1-MMP (MMP-14) is a transmembrane protease comprised of a pro-peptide (processed intracellularly by furin in the secretory pathway; not shown) and a catalytic domain containing the Zn²⁺-binding consensus sequence HExxHxxGxxH. A flexible hinge region connects the catalytic domain to the hemopexin-like domain. The hemopexin-like domain may contain a dimerization interface and is important in substrate recognition. Following this region, a short stalk connects the transmembrane domain to the short cytoplasmic tail. In addition to degrading protein substrates such as interstitial (type I) collagen, MT1-MMP also catalyzes activation of pro-MMP-2. This reaction proceeds via an unusual mechanism requiring a trimeric complex among MT1-MMP, TIMP-2 and pro-MMP-2. Anchoring of pro-MMP-2 via trimeric complex formation enables cleavage of the pro-peptide domain of pro-MMP-2 by a second molecule of MT1-MMP, releasing soluble active MMP-2. (B) MMP-9 is initially secreted in zymogen form. Proteolytic processing of the pro-peptide region, catalyzed by numerous proteinases in the extracellular mileu, exposes the active Zn²⁺-binding catalytic domain. The active site of MMP-9 is also connected via a flexible hinge to a hemopexin-domain that imparts substrate specificity.

MMP: Matrix metalloproteinase; MT1: Membrane type 1; TIMP-2: Tissue inhibitor of metalloproteinase-2.