2X69

X-ray Structure of Macrophage Inflammatory Protein-1 alpha polymer

Summary for 2X69

• Entry DOI: 10.2210/pdb2x69/pdb
• Related: 1B50 1B53 2X6G
• Descriptor: C-C MOTIF CHEMOKINE 3 (2 entities in total)
• Functional Keywords: immune system, inflammatory response, cytokine, chemotaxis
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Secreted: P10147
• Total number of polymer chains: 5
• Total formula weight: 38968.32

Authors

Guo, Q.,Ren, M.,Tang, W. (deposition date: 2010-02-15, release date: 2010-11-03, Last modification date: 2024-11-06)

Primary citation

Ren, M.,Guo, Q.,Guo, L.,Lenz, M.,Qian, F.,Koenen, R.R.,Xu, H.,Schilling, A.B.,Weber, C.,Ye, R.D.,Dinner, A.R.,Tang, W.
Polymerization of Mip-1 Chemokine (Ccl3 and Ccl4) and Clearance of Mip-1 by Insulin-Degrading Enzyme.
Embo J., 29:3952-, 2010

PubMed Abstract: 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.

PubMed: 20959807
DOI: 10.1038/EMBOJ.2010.256

Experimental method

X-RAY DIFFRACTION (2.65 Å)