title: High-Throughput Multiplexed Peptide-Centric Profiling Illustrates Both Substrate Cleavage Redundancy and Specificity in the MMP Family.
abstract: Matrix metalloproteinases (MMPs) play incompletely understood roles in health and disease. Knowing the MMP cleavage preferences is essential for a better understanding of the MMP functions and design of selective inhibitors. To elucidate the cleavage preferences of MMPs, we employed a high-throughput multiplexed peptide-centric profiling technology involving the cleavage of 18,583 peptides by 18 proteinases from the main sub-groups of the MMP family. Our results enabled comparison of the MMP substrates on a global scale, leading to the most efficient and selective substrates. The data validated the accuracy of our cleavage prediction software. This software allows us and others to locate, with nearly 100% accuracy, the MMP cleavage sites in the peptide sequences. In addition to increasing our understanding of both the selectivity and the redundancy of the MMP family, our study generated a roadmap for the subsequent MMP structural-functional studies and efficient substrate and inhibitor design.
authors.affiliation: Prognosys Biosciences Inc., San Diego, CA 92121, USA.
authors.forename: Muskan
authors.initials: M
authors.lastname: Kukreja
authors.affiliation: Infectious and Inflammatory Disease Center/Cancer Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Sergey A
authors.initials: SA
authors.lastname: Shiryaev
authors.affiliation: Infectious and Inflammatory Disease Center/Cancer Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Piotr
authors.initials: P
authors.lastname: Cieplak
authors.affiliation: Prognosys Biosciences Inc., San Diego, CA 92121, USA.
authors.forename: Norihito
authors.initials: N
authors.lastname: Muranaka
authors.affiliation: Prognosys Biosciences Inc., San Diego, CA 92121, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Routenberg
authors.affiliation: Infectious and Inflammatory Disease Center/Cancer Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Chernov
authors.affiliation: Infectious and Inflammatory Disease Center/Cancer Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Sonu
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Infectious and Inflammatory Disease Center/Cancer Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Albert G
authors.initials: AG
authors.lastname: Remacle
authors.affiliation: Infectious and Inflammatory Disease Center/Cancer Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Smith
authors.affiliation: Prognosys Biosciences Inc., San Diego, CA 92121, USA.
authors.forename: Igor A
authors.initials: IA
authors.lastname: Kozlov
authors.affiliation: Infectious and Inflammatory Disease Center/Cancer Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: strongin@sanfordburnham.org.
authors.forename: Alex Y
authors.initials: AY
authors.lastname: Strongin
mesh_terms: D000595:Amino Acid Sequence; D002384:Catalysis; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D006868:Hydrolysis; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism; D045726:Metalloproteases / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D010455:Peptides; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D007527:Isoenzymes; D010455:Peptides; D045726:Metalloproteases