Research Article
Conformational selection and collagenolysis in Type III collagen
Ramon Salsas-Escat,
Collin M. Stultz,
Ramon Salsas-Escat
Computational and Systems Biology Initiative, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Search for more papers by this authorCorresponding Author
Collin M. Stultz
Computational and Systems Biology Initiative, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Harvard-MIT Division of Health Sciences and Technology, Cambridge, Massachusetts 02139
77 Massachusetts Avenue, Bldg 36-796, Cambridge, MA 02139===Search for more papers by this authorRamon Salsas-Escat,
Collin M. Stultz,
Ramon Salsas-Escat
Computational and Systems Biology Initiative, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Search for more papers by this authorCorresponding Author
Collin M. Stultz
Computational and Systems Biology Initiative, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Harvard-MIT Division of Health Sciences and Technology, Cambridge, Massachusetts 02139
77 Massachusetts Avenue, Bldg 36-796, Cambridge, MA 02139===Search for more papers by this authorAbstract
Matrix metalloproteases (MMPs) cleave native collagen at a single site despite the fact that collagen contains more than one scissile bond that can, in principle, be cleaved. For peptide bond hydrolysis to occur at one specific site, MMPs must (1) localize to a region near the unique scissile bond, (2) bind residues at the catalytic site that form the scissile bond, and (3) hydrolyze the corresponding peptide bond. Prior studies suggest that for some types of collagen, binding of noncatalytic MMP domains to amino acid sequences in the vicinity of the true cleavage site facilitates the localization of collagenases. In the present study, our goal was to determine whether binding to the catalytic site also plays a role in determining MMP specificity. To investigate this, we computed the conformational free energy landscape of Type III collagen at each potential cleavage site. The free energy profiles suggest that although all potential cleavage sites sample unfolded states at relatively low temperatures, the true cleavage site samples structures that are complementary to the catalytic site. By contrast, potential cleavage sites that are not cleaved sample states that are relatively incompatible with the MMP active site. Furthermore, our findings point to a specific role for arginine residues in modulating the structural stability of collagen near the collagenase cleavage site. These data imply that locally unfolded potential cleavage sites in Type III collagen sample distinct unfolded ensembles, and that the region about the true collagenase cleavage site samples states that are most complementary to the MMP active site. Proteins 2010. © 2009 Wiley-Liss, Inc.
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