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

Journal Article · Tue Dec 07 04:00:00 EST 2010 · EMBO J.

DOI:https://doi.org/10.1038/emboj.2010.256· OSTI ID:1002901

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 ^[1]

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1. IIT

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.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: USDOE
• OSTI ID: 1002901
• Journal Information: EMBO J., Journal Name: EMBO J. Journal Issue: (23) ; 2010 Vol. 29; ISSN EMJODG; ISSN 0261-4189
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

36 MATERIALS SCIENCE
CLEARANCE
CRYSTAL STRUCTURE
DEPOLYMERIZATION
DISTRIBUTION
ENDOTHELIUM
ENZYMES
INACTIVATION
INFLAMMATION
MACROPHAGES
MONOCYTES
MONOMERS
MUTATIONS
POLYMERIZATION
POLYMERS