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J Biol Chem. 2010 Oct 29;285(44):34181-90. doi: 10.1074/jbc.M110.128355. Epub 2010 Aug 2.

Local conformation and dynamics of isoleucine in the collagenase cleavage site provide a recognition signal for matrix metalloproteinases.

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  • 1Department of Chemistry and Chemical Biology, BIOMAPS Institute, Rutgers, the State University of New Jersey, Piscataway, New Jersey 08854, USA.

Abstract

The mechanism by which enzymes recognize the "uniform" collagen triple helix is not well understood. Matrix metalloproteinases (MMPs) cleave collagen after the Gly residue of the triplet sequence Gly∼[Ile/Leu]-[Ala/Leu] at a single, unique, position along the peptide chain. Sequence analysis of types I-III collagen has revealed a 5-triplet sequence pattern in which the natural cleavage triplets are always flanked by a specific distribution of imino acids. NMR and MMP kinetic studies of a series of homotrimer peptides that model type III collagen have been performed to correlate conformation and dynamics at, and near, the cleavage site to collagenolytic activity. A peptide that models the natural cleavage site is significantly more active than a peptide that models a potential but non-cleavable site just 2-triplets away and NMR studies show clearly that the Ile in the leading chain of the cleavage peptide is more exposed to solvent and less locally stable than the Ile in the middle and lagging chains. We propose that the unique local instability of Ile at the cleavage site in part arises from the placement of the conserved Pro at the P(3) subsite. NMR studies of peptides with Pro substitutions indicate that the local dynamics of the three chains are directly modulated by their proximity to Pro. Correlation of peptide activity to NMR data shows that a single locally unstable chain at the cleavage site, rather than two or three labile chains, is more favorable for cleavage by MMP-1 and may be the determining factor for collagen recognition.

PMID:
20679339
PMCID:
PMC2962516
DOI:
10.1074/jbc.M110.128355
[PubMed - indexed for MEDLINE]
Free PMC Article
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