2X69: X-Ray Structure Of Macrophage Inflammatory Protein-1 Alpha Polymer

Citation:
Abstract
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.
PDB ID: 2X69Download
MMDB ID: 85859
PDB Deposition Date: 2010/2/15
Updated in MMDB: 2010/11
Experimental Method:
x-ray diffraction
Resolution: 2.65  Å
Source Organism:
Similar Structures:
Biological Unit for 2X69: dimeric; determined by author and by software (PISA)
Molecular Components in 2X69
Label Count Molecule
Proteins (2 molecules)
2
C-C Motif Chemokine 3(Gene symbol: CCL3)
Molecule annotation
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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