Polymerization of MIP-1 chemokine (CCL3 and CCL4) and clearance of MIP-1 by insulin-degrading enzyme.

Abstract

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.

• Authors: 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
• Journal: The EMBO journal (EMBO J) Vol. 29 Issue 23 Pg. 3952-66 (Dec 01 2010) ISSN: 1460-2075 [Electronic] England
• PMID: 20959807 (Publication 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.)

Chemical References

• Chemokine CCL3
• Chemokine CCL4
• Macrophage Inflammatory Proteins
• Insulysin

Topics

• 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