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Originally published In Press as doi:10.1074/jbc.M407186200 on August 2, 2004

J. Biol. Chem., Vol. 279, Issue 41, 43336-43344, October 8, 2004
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Characterization of the Distinct Collagen Binding, Helicase and Cleavage Mechanisms of Matrix Metalloproteinase 2 and 14 (Gelatinase A and MT1-MMP)

THE DIFFERENTIAL ROLES OF THE MMP HEMOPEXIN C DOMAINS AND THE MMP-2 FIBRONECTIN TYPE II MODULES IN COLLAGEN TRIPLE HELICASE ACTIVITIES*

Eric M. Tam{ddagger}§, Todd R. Moore¶, Georgina S. Butler¶, and Christopher M. Overall{ddagger}¶||

From the Departments of {ddagger}Biochemistry and Molecular Biology and Oral Biological and Medical Sciences, UBC Centre for Blood Research and the Canadian Institutes for Health Research Group in Matrix Dynamics, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada

Matrix metalloproteinase-2 (MMP-2, gelatinase A) and membrane type (MT)1-MMP (MMP-14) are cooperative dynamic components of a cell surface proteolytic axis involved in regulating the cellular signaling environment and pericellular collagen homeostasis. Although MT1-MMP exhibits type I collagenolytic but poor gelatinolytic activities, MMP-2 is a potent gelatinase with weak type I collagenolytic behavior. Recombinant linker/hemopexin C domain (LCD) of MT1-MMP binds native type I collagen, blocks MT1-MMP collagenolytic activity in trans, and by circular dichroism spectroscopy, induces localized structural perturbation in the collagen. These changes were reflected by enhanced cleavage of the MT1-LCD-bound collagen by the collagenases MMP-1 and MMP-8 but not by trypsin or MMP-7. Thus, the MT1-LCD alone can initiate triple helicase activity. In contrast, the native and denatured collagen binding properties of MMP-2 reside in the fibronectin type II modules, accordingly termed the collagen binding domain (CBD). Recombinant CBD (but not the MMP-2 LCD) also changed the circular dichroism spectra leading to increased MMP-1 and -8 cleavage of native collagen. However, recombinant CBD reduced gelatin and collagen cleavage by MMP-2 in trans as did CBD23, which comprises the second and third fibronectin type II modules, but not the CBD23 mutant W316A/W374A, which neither binds gelatin nor collagen. This indicates that MMP-2 and MT1-MMP bind collagen at a different site than MMP-1 and MMP-8. Thus, MMP-2 utilizes the CBD in cis for collagen binding and triple helicase activity, which compensates for the lack of collagen binding by the MMP-2 LCD. Hence, the MMP family has evolved two distinct mechanisms for collagen triple helicase activity using two structurally distinct domains, with triple helicase activity occurring independent of {alpha}-chain hydrolysis.

Received for publication, June 28, 2004 , and in revised form, July 26, 2004.

* This work was supported by grants from the Canadian Arthritis Network of Centres of Excellence (CAN) and the Canadian Institutes for Health Research (CIHR). 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 a CIHR Strategic Training Fellowship in Cell Signals (CIHR Grant STP-53877) and a Canadian Arthritis Network Trainee Award.

|| Supported by a Canada Research Chair in Metalloproteinase Biology. To whom correspondence should be addressed: University of British Columbia, 2199 Wesbrook Mall, J. B. Macdonald Building, Vancouver, B. C. V6T 1Z3, Canada. Tel.: 604-822-2958; Fax: 604-822-3562; E-mail: chris.overall{at}ubc.ca; Web: www.clip.ubc.ca.


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