First Author | Ren M | Year | 2010 |
Journal | EMBO J | Volume | 29 |
Issue | 23 | Pages | 3952-66 |
PubMed ID | 20959807 | Mgi Jnum | J:167181 |
Mgi Id | MGI:4867374 | Doi | 10.1038/emboj.2010.256 |
Citation | Ren M, et al. (2010) Polymerization of MIP-1 chemokine (CCL3 and CCL4) and clearance of MIP-1 by insulin-degrading enzyme. EMBO J 29(23):3952-66 |
abstractText | Macrophage inflammatory protein-1 (MIP-1), MIP-1alpha (CCL3) and MIP-1beta (CCL4) are chemokines crucial for immune responses towards infection and inflammation. Both MIP-1alpha and MIP-1beta form high-molecular-weight aggregates. Our crystal structures reveal that MIP-1 aggregation is a polymerization process and human MIP-1alpha and MIP-1beta 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-1alpha, thus depolymerization mutations enhance MIP-1alpha to arrest monocytes onto activated human endothelium. However, same depolymerization mutations render MIP-1alpha 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. |