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

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*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

101 Citations (Web of Science)

Abstract

Macrophage inflammatory protein-1 (MIP-1), MIP-1? (CCL3) and MIP-1? (CCL4) are chemokines crucial for immune responses towards infection and inflammation. Both MIP-1? and MIP-1? form high-molecular-weight aggregates. Our crystal structures reveal that MIP-1 aggregation is a polymerization process and human MIP-1? and MIP-1? 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?, thus depolymerization mutations enhance MIP-1? to arrest monocytes onto activated human endothelium. However, same depolymerization mutations render MIP-1? 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.
Original languageEnglish
Pages (from-to)3952-3966
JournalThe Embo Journal
Volume29
Issue number23
DOIs
Publication statusPublished - 1 Dec 2010

Keywords

  • chemokine
  • chemotactic gradient
  • insulin-degrading enzyme
  • MIP-1 polymerization
  • X-ray crystallography

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