Heparan sulfate proteoglycans as extracellular docking molecules for matrilysin (matrix metalloproteinase 7)

Many matrix metalloproteinases (MMPs) are tightly bound to tissues; matrily sin (MMP-7), although the smallest of the MMPs, is one of the most tightly bound. The most likely docking molecules for MMP-7 are heparan sulfate prot eoglycans on or around epithelial cells and in the underlying basement memb rane. This is established by extraction experiments and confocal microscopy , The enzyme is extracted from homogenates of postpartum rat uterus by hepa rin/heparan sulfate and by heparinase III treatment. The enzyme is colocali zed with heparan sulfate in the apical region of uterine glandular epitheli al cells and can be released by heparinase digestion. Heparan sulfate and M MP-7 are expressed at similar stages of the rat estrous cycle. The strength of heparin binding by recombinant rat proMMP-7 was examined by affinity ch romatography, affinity coelectrophoresis, and homogeneous enzyme-based bind ing assay; the K-D, is 5-10 nM. Zymographic measurement of MMP-7 activity i s greatly enhanced by heparin, Two putative heparin-binding peptides have b een identified near the C- and N-terminal regions of proMMP-7; however, mol ecular modeling suggests a more extensive binding track or cradle crossing multiple peptide strands. Evidence is also found for the binding of MMP-2, -9, and -13. Binding of MMP-7 and other MMPs to heparan sulfate in the extr acellular space could prevent loss of secreted enzyme, provide a reservoir of latent enzyme, and facilitate cellular sensing and regulation of enzyme levels. Binding to the cell surface could position the enzyme for directed proteolytic attack, for activation of or by other MMPs and for regulation o f other cell surface proteins. Dislodging MMPs by treatment with compounds such as heparin might be beneficial in attenuating excessive tissue breakdo wn such as occurs in cancer metastasis, arthritis, and angiogenesis.