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

• Published in: The EMBO journal 2010-12, Vol.29 (23), p.3952-3966
• Main Authors: Ren, Min, Guo, Qing, Guo, Liang, Lenz, Martin, Qian, Feng, Koenen, Rory R, Xu, Hua, Schilling, Alexander B, Weber, Christian, Ye, Richard D, Dinner, Aaron R, Tang, Wei-Jen
• Format: Article
• Language: English
• Subjects: Aggregates; Amino Acid Sequence; Animals; Cell Line; chemokine; Chemokine CCL3 - chemistry; Chemokine CCL3 - genetics; Chemokine CCL3 - immunology; Chemokine CCL3 - metabolism; Chemokine CCL4 - chemistry; Chemokine CCL4 - genetics; Chemokine CCL4 - immunology; Chemokine CCL4 - metabolism; chemotactic gradient; CLEARANCE; CRYSTAL STRUCTURE; Crystallography, X-Ray; Cytokines; DEPOLYMERIZATION; DISTRIBUTION; EMBO37; EMBO40; ENDOTHELIUM; ENZYMES; Humans; Immunology; INACTIVATION; INFLAMMATION; Insulin; insulin-degrading enzyme; Insulysin - chemistry; Insulysin - metabolism; Macrophage Inflammatory Proteins - chemistry; Macrophage Inflammatory Proteins - genetics; Macrophage Inflammatory Proteins - immunology; Macrophage Inflammatory Proteins - metabolism; MACROPHAGES; Male; MATERIALS SCIENCE; Mice; Mice, Inbred C57BL; MIP-1 polymerization; Models, Molecular; Molecular biology; Molecular Sequence Data; MONOCYTES; MONOMERS; Mutation; MUTATIONS; POLYMERIZATION; POLYMERS; Protein Binding; Protein Conformation; Protein Multimerization; X-ray crystallography
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/emboj.2010.256

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. The two closely related MIP chemokines, CCL3 and CCL4, assemble into high‐order polymers that are protected from degradation. MIP‐1 polymers can dissociate into active MIP‐1 monomers that in turn are selectively degraded by the insulin‐degrading enzyme.