title: Basis for substrate recognition and distinction by matrix metalloproteinases.
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.
authors.affiliation: The Cancer Center and.
authors.forename: Boris I
authors.initials: BI
authors.lastname: Ratnikov
authors.affiliation: The Cancer Center and.
authors.forename: Piotr
authors.initials: P
authors.lastname: Cieplak
authors.affiliation: The Cancer Center and.
authors.forename: Kosi
authors.initials: K
authors.lastname: Gramatikoff
authors.affiliation: The Cancer Center and.
authors.forename: James
authors.initials: J
authors.lastname: Pierce
authors.affiliation: The Cancer Center and.
authors.forename: Alexey
authors.initials: A
authors.lastname: Eroshkin
authors.affiliation: The Cancer Center and.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Igarashi
authors.affiliation: Research and Training Center on Bioinformatics, Institute for Information Transmission Problems, Russian Academy of Sciences, Moscow 127994, Russia.
authors.forename: Marat
authors.initials: M
authors.lastname: Kazanov
authors.affiliation: The Cancer Center and.
authors.forename: Qing
authors.initials: Q
authors.lastname: Sun
authors.affiliation: The Cancer Center and The Inflammatory and Infectious Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037; and.
authors.forename: Adam
authors.initials: A
authors.lastname: Godzik
authors.affiliation: The Cancer Center and The Inflammatory and Infectious Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037; and.
authors.forename: Andrei
authors.initials: A
authors.lastname: Osterman
authors.affiliation: The Cancer Center and.
authors.forename: Boguslaw
authors.initials: B
authors.lastname: Stec
authors.affiliation: The Cancer Center and The Inflammatory and Infectious Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037; and.
authors.forename: Alex
authors.initials: A
authors.lastname: Strongin
authors.affiliation: The Cancer Center and jsmith@sanfordburnham.org.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Smith
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D001665:Binding Sites / Q000235:genetics; D055162:Biocatalysis; D020134:Catalytic Domain; D006801:Humans; D007700:Kinetics; D020782:Matrix Metalloproteinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010455:Peptides / Q000378:metabolism*; D010802:Phylogeny; D059748:Proteolysis; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity
chemical_list: D010455:Peptides; D020782:Matrix Metalloproteinases
keywords: MMPs; protease; specificity-determining positions