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Discovery of Chemokine Substrates for Matrix Metalloproteinases by Exosite Scanning: A New Tool for Degradomics

Discovery of Chemokine Substrates for Matrix Metalloproteinases by Exosite Scanning: A New Tool... Abstract Increasingly it is being recognized that matrix metalloproteinases (MMPs) are important processing enzymes that regulate cellular behaviour and immune cell function by selective proteolysis of cell surface receptors and adhesion molecules, cytokines and growth factors. These functions will likely prove to be as important in vivo as the proposed roles of MMPs in pathological matrix degradation. To screen for new protease substrates we have reported a novel exosite scanning strategy that utilizes protease substrate binding exosite domains as yeast twohybrid baits. We discovered that the chemokine monocyte chemoattractant protein-3 (MCP-3) binds the hemopexin C domain of gelatinase A (MMP-2) leading to its efficient cleavage, converting an agonist to a potent receptor antagonist. We have now found that other MMPs cleave MCP-1, MCP-2, MCP-3, MCP-4, SDF 1α and SDF-1β indicating that the intersection between the chemokine and MMP families is broad with important implications for the control of inflammatory and immune processes. Use of engineered substrates with altered exosite binding affinities further revealed the power of exosites in dictating proteolytic specificity either directing cleavage of nonpreferred sites or in other cases virtually eliminating proteolysis of readily accessible scissile bonds. Hence, bioinformatic searches for protease substrates based on scissile bond preference will only reveal a subset of substrates unless the influence of exosites is considered. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Biological Chemistry de Gruyter

Discovery of Chemokine Substrates for Matrix Metalloproteinases by Exosite Scanning: A New Tool for Degradomics

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References (43)

Publisher
de Gruyter
Copyright
Copyright © 2002 by the
ISSN
1431-6730
DOI
10.1515/BC.2002.114
pmid
12437088
Publisher site
See Article on Publisher Site

Abstract

Abstract Increasingly it is being recognized that matrix metalloproteinases (MMPs) are important processing enzymes that regulate cellular behaviour and immune cell function by selective proteolysis of cell surface receptors and adhesion molecules, cytokines and growth factors. These functions will likely prove to be as important in vivo as the proposed roles of MMPs in pathological matrix degradation. To screen for new protease substrates we have reported a novel exosite scanning strategy that utilizes protease substrate binding exosite domains as yeast twohybrid baits. We discovered that the chemokine monocyte chemoattractant protein-3 (MCP-3) binds the hemopexin C domain of gelatinase A (MMP-2) leading to its efficient cleavage, converting an agonist to a potent receptor antagonist. We have now found that other MMPs cleave MCP-1, MCP-2, MCP-3, MCP-4, SDF 1α and SDF-1β indicating that the intersection between the chemokine and MMP families is broad with important implications for the control of inflammatory and immune processes. Use of engineered substrates with altered exosite binding affinities further revealed the power of exosites in dictating proteolytic specificity either directing cleavage of nonpreferred sites or in other cases virtually eliminating proteolysis of readily accessible scissile bonds. Hence, bioinformatic searches for protease substrates based on scissile bond preference will only reveal a subset of substrates unless the influence of exosites is considered.

Journal

Biological Chemistry – de Gruyter

Published: Aug 27, 2002

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