| Polymerization of MIP-1 chemokine (CCL3 and CCL4) and clearance of MIP-1 by insulin-degrading enzyme. | |
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MedLine Citation:
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PMID: 20959807 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Macrophage inflammatory protein-1 (MIP-1), MIP-1α (CCL3) and MIP-1β (CCL4) are chemokines crucial for immune responses towards infection and inflammation. Both MIP-1α and MIP-1β form high-molecular-weight aggregates. Our crystal structures reveal that MIP-1 aggregation is a polymerization process and human MIP-1α and MIP-1β form rod-shaped, double-helical polymers. Biophysical analyses and mathematical modelling show that MIP-1 reversibly forms a polydisperse distribution of rod-shaped polymers in solution. Polymerization buries receptor-binding sites of MIP-1α, thus depolymerization mutations enhance MIP-1α to arrest monocytes onto activated human endothelium. However, same depolymerization mutations render MIP-1α ineffective in mouse peritoneal cell recruitment. Mathematical modelling reveals that, for a long-range chemotaxis of MIP-1, polymerization could protect MIP-1 from proteases that selectively degrade monomeric MIP-1. Insulin-degrading enzyme (IDE) is identified as such a protease and decreased expression of IDE leads to elevated MIP-1 levels in microglial cells. Our structural and proteomic studies offer a molecular basis for selective degradation of MIP-1. The regulated MIP-1 polymerization and selective inactivation of MIP-1 monomers by IDE could aid in controlling the MIP-1 chemotactic gradient for immune surveillance. |
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Authors:
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Min Ren; Qing Guo; Liang Guo; Martin Lenz; Feng Qian; Rory R Koenen; Hua Xu; Alexander B Schilling; Christian Weber; Richard D Ye; Aaron R Dinner; Wei-Jen Tang |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. Date: 2010-10-19 |
Journal Detail:
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Title: The EMBO journal Volume: 29 ISSN: 1460-2075 ISO Abbreviation: EMBO J. Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-12-02 Completed Date: 2011-01-12 Revised Date: 2011-12-21 |
Medline Journal Info:
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Nlm Unique ID: 8208664 Medline TA: EMBO J Country: England |
Other Details:
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Languages: eng Pagination: 3952-66 Citation Subset: IM |
Affiliation:
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Ben-May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Sequence Animals Cell Line Chemokine CCL3 / chemistry*, genetics, immunology, metabolism* Chemokine CCL4 / chemistry*, genetics, immunology, metabolism* Crystallography, X-Ray Humans Insulysin / chemistry, metabolism* Macrophage Inflammatory Proteins / chemistry, genetics, immunology, metabolism Male Mice Mice, Inbred C57BL Models, Molecular Molecular Sequence Data Mutation Polymerization Protein Binding Protein Conformation Protein Multimerization |
| Grant Support | |
ID/Acronym/Agency:
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GM81539/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Chemokine CCL3; 0/Chemokine CCL4; 0/Macrophage Inflammatory Proteins; EC 3.4.24.56/Insulysin |
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