Polymerization of MIP-1 chemokine (CCL3 and CCL4) and clearance of MIP-1 by insulin-degrading enzyme.
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.
Ben-May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
Min
M
Ren
Qing
Q
Guo
Liang
L
Guo
Martin
M
Lenz
Feng
F
Qian
Rory R
RR
Koenen
Hua
H
Xu
Alexander B
AB
Schilling
Christian
C
Weber
Richard D
RD
Ye
Aaron R
AR
Dinner
Wei-Jen
WJ
Tang
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D054405:Chemokine CCL3 / Q000737:chemistry* / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D054407:Chemokine CCL4 / Q000737:chemistry* / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006801:Humans; D007339:Insulysin / Q000737:chemistry / Q000378:metabolism*; D019402:Macrophage Inflammatory Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D058105:Polymerization; D011485:Protein Binding; D011487:Protein Conformation; D055503:Protein Multimerization
D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019402:Macrophage Inflammatory Proteins; D007339:Insulysin