Structures of Human CCL18, CCL3, and CCL4 Reveal Molecular Determinants for Quaternary Structures and Sensitivity to Insulin-Degrading Enzyme
- Univ. of Chicago, IL (United States). Ben-May Dept. for Cancer Research
CC chemokine ligands (CCL) are 8-14 kDa signaling proteins involved in diverse immune functions. While CCLs share similar tertiary structures, oligomerization produces highly diverse quaternary structures that protect chemokines from proteolytic degradation and modulate their functions. CCL18 is closely related to CCL3 and CCL4 with respect to both protein sequence and genomic location, yet CCL18 has distinct biochemical and biophysical properties. Here in this paper, we report a crystal structure of human CCL18 and its oligomerization states in solution based on crystallographic and small angle X-ray scattering (SAXS) analyses. Our data shows that CCL18 adopts an α-helical conformation at its N-terminus that weakens its dimerization, explaining CCL18’s preference for the monomeric state. Multiple contacts between monomers allow CCL18 to reversibly form a unique open-ended oligomer different from those of CCL3, CCL4, and CCL5. Furthermore, these differences hinge on proline 8, which is conserved in CCL3 and CCL4, but is replaced by lysine in human CCL18. Our structural analyses suggest that a proline 8 to alanine mutation stabilizes a type I β-turn at the N-terminus of CCL4 to prevent dimerization but prevents dimers from making key contacts with each other in CCL3. Thus, the P8A mutation induces depolymerization of CCL3 and CCL4 by distinct mechanisms. Finally, we used structural, biochemical, and functional analyses to unravel why insulin-degrading enzyme (IDE) degrades CCL3 and CCL4 but not CCL18. Lastly, our results elucidate the molecular basis for the oligomerization of three closely related CC chemokines and suggest how oligomerization shapes CCL chemokine function.
- Research Organization:
- Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Organization:
- USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH)
- Grant/Contract Number:
- AC02-06CH11357
- OSTI ID:
- 1194229
- Alternate ID(s):
- OSTI ID: 1233993
- Journal Information:
- Journal of Molecular Biology, Vol. 427, Issue 6B; ISSN 0022-2836
- Publisher:
- ElsevierCopyright Statement
- Country of Publication:
- United States
- Language:
- ENGLISH
Web of Science
Discovery of CCL18 antagonist blocking breast cancer metastasis
|
journal | May 2019 |
Structural basis for oligomerization and glycosaminoglycan binding of CCL5 and CCL3
|
journal | April 2016 |
PClass: Protein Quaternary Structure Classification by Using Bootstrapping Strategy as Model Selection
|
journal | February 2018 |
Chemokine CXCL7 Heterodimers: Structural Insights, CXCR2 Receptor Function, and Glycosaminoglycan Interactions
|
journal | April 2017 |
SNPs in inflammatory genes CCL11, CCL4 and MEFV in a fibromyalgia family study
|
journal | June 2018 |
Similar Records
Polymerization of MIP-1 chemokine (CCL3 and CCL4) and clearance of MIP-1 by insulin-degrading enzyme
Coagulin-L ameliorates TLR4 induced oxidative damage and immune response by regulating mitochondria and NOX-derived ROS