Dataset Information

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

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.

SUBMITTER: Ren M

PROVIDER: S-EPMC3020635 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Publications

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

Ren Min M Guo Qing Q Guo Liang L Lenz Martin M Qian Feng F Koenen Rory R RR Xu Hua H Schilling Alexander B AB Weber Christian C Ye Richard D RD Dinner Aaron R AR Tang Wei-Jen WJ

The EMBO journal 20101019 23

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 ...[more]

PMID: 20959807

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Project description:CCL3 (MIP-1 alpha), CCL4 (MIP-1 beta), and CCL18 (DC-CK1/PARC/AMAC-1) are potent chemoattractants produced by macrophages, natural killer cells, fibroblasts, mast cells, CD4(+) T cells, and CD8(+) T cells. CCL3 and CCL4 are natural ligands for the primary human immunodeficiency virus type 1 (HIV-1) coreceptor CCR5 and are also known to activate and enhance the cytotoxicity of natural killer cells. Genomic DNAs from >3,000 participants enrolled in five United States-based natural-history cohorts with acquired immunodeficiency syndrome (AIDS) were genotyped for 21 single-nucleotide polymorphisms (SNPs) in a 47-kb interval on chromosome 17q12 containing the genes CCL3, CCL4, and CCL18. All 21 SNPs were polymorphic in African Americans (AAs), whereas 7 of the 21 had minor-allele frequencies <0.01 in European Americans (EAs). Substantial linkage disequilibrium was observed in a 37-kb interval containing 17 SNPs where many pairwise D' values exceeded 0.70 in both racial groups, but particularly in EAs. Four and three haplotype blocks were observed in AAs and EAs, respectively. Blocks were strongly correlated with each other, and common haplotype diversity within blocks was limited. Two significant associations are reported that replicate an earlier study. First, among AA members of the AIDS Link to the Intravenous Experience cohort of injection drug users, frequencies of three correlated SNPs covering 2,231 bp in CCL3 were significantly elevated among highly exposed, persistently HIV-1-uninfected individuals compared with HIV-1-infected seroconvertors (P = .02-.03). Second, seven highly correlated SNPs spanning 36 kb and containing all three genes were significantly associated with more-rapid disease progression among EAs enrolled in the Multicenter AIDS Cohort Study cohort (P = .01-.02). These results reiterate the importance of chemokine gene variation in HIV-1/AIDS pathogenesis and emphasize that localized linkage disequilibrium makes the identification of causal mutations difficult.

Dataset Information

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

Publications

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

Similar Datasets

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