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Proc Natl Acad Sci U S A. 2014 Oct 7;111(40):E4148-55. doi: 10.1073/pnas.1406134111. Epub 2014 Sep 22.

Basis for substrate recognition and distinction by matrix metalloproteinases.

Author information

1
The Cancer Center and.
2
Research and Training Center on Bioinformatics, Institute for Information Transmission Problems, Russian Academy of Sciences, Moscow 127994, Russia.
3
The Cancer Center and The Inflammatory and Infectious Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037; and.
4
The Cancer Center and jsmith@sanfordburnham.org.

Abstract

Genomic sequencing and structural genomics produced a vast amount of sequence and structural data, creating an opportunity for structure-function analysis in silico [Radivojac P, et al. (2013) Nat Methods 10(3):221-227]. Unfortunately, only a few large experimental datasets exist to serve as benchmarks for function-related predictions. Furthermore, currently there are no reliable means to predict the extent of functional similarity among proteins. Here, we quantify structure-function relationships among three phylogenetic branches of the matrix metalloproteinase (MMP) family by comparing their cleavage efficiencies toward an extended set of phage peptide substrates that were selected from ∼ 64 million peptide sequences (i.e., a large unbiased representation of substrate space). The observed second-order rate constants [k(obs)] across the substrate space provide a distance measure of functional similarity among the MMPs. These functional distances directly correlate with MMP phylogenetic distance. There is also a remarkable and near-perfect correlation between the MMP substrate preference and sequence identity of 50-57 discontinuous residues surrounding the catalytic groove. We conclude that these residues represent the specificity-determining positions (SDPs) that allowed for the expansion of MMP proteolytic function during evolution. A transmutation of only a few selected SDPs proximal to the bound substrate peptide, and contributing the most to selectivity among the MMPs, is sufficient to enact a global change in the substrate preference of one MMP to that of another, indicating the potential for the rational and focused redesign of cleavage specificity in MMPs.

KEYWORDS:

MMPs; protease; specificity-determining positions

PMID:
25246591
PMCID:
PMC4210027
DOI:
10.1073/pnas.1406134111
[Indexed for MEDLINE]
Free PMC Article

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