The role of exon 5 in fibroblast collagenase (MMP-1) substrate specificity and inhibitor selectivity

Knauper, Vera ORCID: https://orcid.org/0000-0002-3965-9924, Patterson, Margaret L., Gomis-Ruth, Franz X., Smith, Bryan, Lyons, Alan, Docherty, Andrew J.P. and Murphy, Gillian 2001. The role of exon 5 in fibroblast collagenase (MMP-1) substrate specificity and inhibitor selectivity. European Journal of Biochemistry 268 (6) , pp. 1888-1896. 10.1046/j.1432-1327.2001.02062.x

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Abstract

Interstitial collagen is degraded by members of the matrix metalloproteinase (MMP) family, including MMP-1. Previous work has shown that the region of MMP-1 coded for by exon 5 is implicated both in substrate specificity and inhibitor selectivity. We have constructed a chimeric enzyme, the exon 5 chimera, consisting primarily of MMP-1, with the region coded for by exon 5 replaced with the equivalent region of MMP-3, a noncollagenolytic MMP. Unlike MMP-3, the exon 5 chimera is capable of cleaving type I collagen, but the activity is only 2.2% of trypsin-activated MMP-1. ‘Superactivation’ of the chimera has no discernible effect, suggesting that the salt bridge formed in ‘superactive’ MMP-1 is not present. The kinetics for exon 5 chimera cleavage of two synthetic substrates display an MMP-3 phenotype, however, cleavage of gelatin is slightly impaired as compared to the parent enzymes. The Kiapp values for the exon 5 chimera complexed with synthetic inhibitors and N-terminal TIMP-2 also show a more MMP-3-like behaviour. However, the kon values for N-terminal TIMP-1 and N-terminal TIMP-2 are more comparable to those for MMP-1. These data show that the region of MMP-1 coded for by exon 5 is involved in both substrate specificity and inhibitor selectivity and the structural basis for our findings is discussed.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Dentistry
Subjects:	R Medicine > R Medicine (General)
Uncontrolled Keywords:	MMP-1 ; MMP-3 ; Collagenolysis ; Inhibitor ; TIMP
ISSN:	1432-1327
Last Modified:	17 Oct 2022 08:40
URI:	https://orca.cardiff.ac.uk/id/eprint/720

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