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Polymerization of MIP‐1 chemokine (CCL3 and CCL4) and clearance of MIP‐1 by insulin‐degrading enzyme
Author(s) -
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 WeiJen
Publication year - 2010
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2010.256
Subject(s) - macrophage inflammatory protein , polymerization , chemokine , biology , proteases , monomer , chemotaxis , biophysics , biochemistry , chemistry , polymer , enzyme , receptor , organic chemistry
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.