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Discovery of Chemokine Substrates for Matrix Metalloproteinases by Exosite Scanning: A New Tool for Degradomics
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C. M. Overall
Published/Copyright:
June 1, 2005
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.
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Published Online: 2005-06-01
Published in Print: 2002-08-27
Copyright © 2002 by Walter de Gruyter GmbH & Co. KG
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Articles in the same Issue
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- Proteases and Their Inhibitors: Traditional Research Subjects in the Munich Area
- Apoptotic Pathways: Involvement of Lysosomal Proteases
- Human Tissue Kallikreins: A New Enzymatic Cascade Pathway?
- Discovery of Chemokine Substrates for Matrix Metalloproteinases by Exosite Scanning: A New Tool for Degradomics
- Novel Secretory Vesicle Serpins, Endopin 1 and Endopin 2: Endogenous Protease Inhibitors with Distinct Target Protease Specificities
- Extracellular Proteases of Staphylococcus spp.
- Secreted Aspartic Proteases as Virulence Factors of Candida Species
- Triple-Helical Peptide Analysis of Collagenolytic Protease Activity
- Phage Display Substrate: A Blind Method for Determining Protease Specificity
- Evolution of Placental Proteases
- Factor VII Activating Protease (FSAP): A Novel Protease in Hemostasis
- Cold-Adapted and Mesophilic Brachyurins
- The Role of Dipeptidyl Peptidase IV (DP IV) Enzymatic Activity in T Cell Activation and Autoimmunity
- Biochemical Features, Molecular Biology and Clinical Relevance of the Human 15-Domain Serine Proteinase Inhibitor LEKTI
- Interaction of Plasminogen Activator Inhibitor Type-1 (PAI-1) with Vitronectin (Vn): Mapping the Binding Sites on PAI-1 and Vn
- Structure-Function Relationship of Bromelain Isoinhibitors from Pineapple Stem
- Structural Basis for the Processive Protein Degradation by Tricorn Protease
- Zinc Ligands in an Astacin Family Metalloprotease Meprin A
- Probing the Active Sites and Mechanisms of Rat Metalloproteases Meprin A and B
- (R)-3-Amidinophenylalanine-Derived Inhibitors of Factor Xa with a Novel Active-Site Binding Mode
- Inhibition of Arginine Gingipains (RgpB and HRgpA) with Benzamidine Inhibitors: Zinc Increases Inhibitory Potency
- Cathepsin B Stability, But Not Activity, Is Affected in Cysteine:Cystine Redox Buffers
- Inhibition of Mammalian Legumain by Michael Acceptors and AzaAsn-Halomethylketones
- Role of the Prosegment of Fasciola hepatica Cathepsin L1 in Folding of the Catalytic Domain
- Roles for Arg- and Lys-Gingipains in the Disruption of Cytokine Responses and Loss of Viability of Human Endothelial Cells by Porphyromonas gingivalis Infection
- Aberrant Expression of Serpin Squamous Cell Carcinoma Antigen 2 in Human Tumor Tissues and Cell Lines: Evidence of Protection from Tumor Necrosis Factor-Mediated Apoptosis
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- Functional Consequences of Cathepsin L Deficiency in Human Lung Epithelial Cells
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