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J Biol Chem, Vol. 275, Issue 4, 2661-2668, January 28, 2000

Characterization of the Monomeric and Dimeric Forms of Latent and Active Matrix Metalloproteinase-9
DIFFERENTIAL RATES FOR ACTIVATION BY STROMELYSIN 1^*

Matthew W. Olson^§, M. Margarida Bernardo, Martin Pietila, David C. Gervasi, Marta Toth, Lakshmi P. Kotra^¶, Irina Massova^¶, Shahriar Mobashery^¶, and Rafael Fridman

From the  Department of Pathology and Karmanos Cancer Institute and the ^¶ Department of Chemistry, Wayne State University, Detroit, Michigan 48201

Matrix metalloproteinase-9 (MMP-9) is a member of the MMP family that has been associated with degradation of the extracellular matrix in normal and pathological conditions. A unique characteristic of MMP-9 is its ability to exist in a monomeric and a disulfide-bonded dimeric form. However, there exists a paucity of information on the properties of the latent (pro-MMP-9) and active MMP-9 dimer. Here we report the purification to homogeneity of the monomer and dimer forms of pro-MMP-9 and the characterization of their biochemical properties and interactions with tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. Gel filtration and surface plasmon resonance analyses demonstrated that the pro-MMP-9 monomeric and dimeric forms bind TIMP-1 with similar affinities. In contrast, TIMP-2 binds only to the active forms. After activation, the two enzyme forms exhibited equal catalytic competence in the turnover of a synthetic peptide substrate with comparable kinetic parameters for the onset of inhibition with TIMPs and for dissociation of the inhibited complexes. Kinetic analyses of the activation of monomeric and dimeric pro-MMP-9 by stromelysin 1 revealed K_m values in the nanomolar range and relative low k_cat values (1.9 × 10³ and 4.1 × 10⁴ s¹, for the monomer and dimer, respectively) consistent with a faster rate (1 order of magnitude) of activation of the monomeric form by stromelysin 1. This suggests that the rate-limiting event in the activation of pro-MMP-9 may be a requisite slow unfolding of pro-MMP-9 near the site of the hydrolytic cleavage by stromelysin 1.

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