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J. Biol. Chem., Vol. 280, Issue 28, 26160-26168, July 15, 2005

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Mutational and Structural Analyses of the Hinge Region of Membrane Type 1-Matrix Metalloproteinase and Enzyme Processing^*

Pamela Osenkowski, Samy O. Meroueh¶, Dumitru Pavel¶, Shahriar Mobashery¶, and Rafael Fridman||

From the Department of Pathology, School of Medicine, Wayne State University, Detroit, Michigan 48201 and the ^¶Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556

Membrane type 1 (MT1)-matrix metalloproteinase (MMP) is a major mediator of collagen degradation in the pericellular space in both physiological and pathological conditions. Previous evidence has shown that on the cell surface, active MT1-MMP undergoes autocatalytic processing to a major membrane-tethered 44-kDa product lacking the catalytic domain and displaying Gly²⁸⁵ at its N terminus, which is at the beginning of the hinge domain. However, the importance of this site and the hinge region in MT1-MMP processing is unknown. In the current study, we generated mutations and deletions in the hinge of MT1-MMP and followed their effect on processing. These studies established Gly²⁸⁴–Gly²⁸⁵ as the main cleavage site involved in the formation of the 44-kDa species. However, alterations at this site did not prevent processing. Instead, they forced downstream cleavages within the stretch of residues flanked by Gln²⁹⁶ and Ser³⁰⁴ in the hinge region, as determined by the processing profile of various hinge deletion mutants. Also, replacement of the hinge of MT1-MMP with the longer MT3-MMP hinge did not prevent processing of MT1-MMP. Molecular dynamic studies using a computational model of MT1-MMP revealed that the hinge region is a highly motile element that undergoes significant motion in the highly exposed loop formed by Pro²⁹⁵–Arg³⁰² consistent with being a prime target for proteolysis, in agreement with the mutational data. These studies suggest that the hinge of MT1-MMP evolved to facilitate processing, a promiscuous but compulsory event in the destiny of MT1-MMP, which may play a key role in the control of pericellular proteolysis.

Received for publication, December 21, 2004 , and in revised form, May 4, 2005.

^* This work was supported in part by National Institutes of Health Grant NCI-CA61986 (to R. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by Cancer Biology Training Grant T32-CA09531 from the NCI, National Institutes of Health.

^|| To whom correspondence should be addressed: Dept. of Pathology, Wayne State University School of Medicine, 540 E. Canfield Ave., Detroit, MI 48201. Tel.: 313-577-1218; Fax: 313-577-8180; E-mail: rfridman{at}med.wayne.edu.

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