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Matrix metalloproteinase (MMP)-7 binds to cell surface cholesterol sulfate (CS) and acts as a membrane-associated protease. We have previously found that CS modulates the substrate preference of MMP-7, thereby regulating its pericellular proteolytic action. MMP-7 potentially associates with the cell surface via sulfatide (SM4) and cardiolipin (CL) when they are overexpressed on the cell surface. Here, we investigated the molecular interaction between these acidic lipids and MMP-7 or its substrates, and their effects on the activity of MMP-7. Studies using MMP-7 variants with low CS-binding ability suggested that these lipids interact with a similar site on MMP-7. The hydroxamate-based MMP inhibitor TAPI-1 markedly reduced the affinity of MMP-7 for CS and CL, whereas that for SM4 was not affected by TAPI-1. These three acidic lipids also had different effects on the hydrolytic activity of MMP-7 towards a small peptide substrate: SM4, CL and CS reduced the activity to 80%, 92%, and 20%, respectively. Nevertheless, SM4 and CS similarly accelerated the MMP-7-catalyzed degradation of fibronectin and laminin-332, whereas CL did not. The increased proteolysis of substrate was observed only when both substrate and enzyme had affinity for the lipid, suggesting that the lipids probably bring the reactants into closer proximity. Furthermore, MMP-7 bound to cell surface SM4 or CS cleaved specific cell surface proteins and released similar fragments, whereas the cleavage was not stimulated by cell surface CL-bound MMP-7. This study provides a novel mechanism by which acidic lipids differentially regulate pericellular proteolysis by MMP-7 through allosteric alteration of the substrate-binding site and their inherent affinities for MMP-7 substrates.

Original publication

DOI

10.1111/febs.12865

Type

Journal article

Journal

FEBS J

Publication Date

08/2014

Volume

281

Pages

3346 - 3356

Keywords

acidic lipid, extracellular matrix, metalloproteinase, pericellular proteolysis, substrate preference, Binding, Competitive, Cardiolipins, Cell Adhesion Molecules, Cell Line, Tumor, Cell Membrane, Cholesterol Esters, Dipeptides, Fibronectins, Humans, Hydroxamic Acids, Kinetics, Matrix Metalloproteinase 7, Matrix Metalloproteinase Inhibitors, Protein Binding, Proteolysis, Sulfoglycosphingolipids