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

Macrophage inflammatory protein-1 (MIP-1), MIP-1 alpha (CCL3) and MIP-1 beta (CCL4) are chemokines crucial for immune responses towards infection and inflammation. Both MIP-1 alpha and MIP-1 beta form high-molecular-weight aggregates. Our crystal structures reveal that MIP-1 aggregation is a polymerization process and human MIP-1 alpha and MIP-1 beta 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-1 alpha, thus depolymerization mutations enhance MIP-1 alpha to arrest monocytes onto activated human endothelium. However, same depolymerization mutations render MIP-1 alpha 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 EMBO Journal (2010) 29, 3952-3966. doi:10.1038/emboj.2010.256; Published online 19 October 2010