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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.

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


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.


MMPs; protease; specificity-determining positions

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