期刊
STRUCTURE
卷 21, 期 4, 页码 528-539出版社
CELL PRESS
DOI: 10.1016/j.str.2013.01.018
关键词
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资金
- European Commission [226716]
- Research Foundation Flanders (FWO) [3G064307, G059710, G0B7912N]
- Ghent University
- Bundesministerium fur Bildung und Forschung (BMBF) [05K10YEA]
- FWO
- Chinese Scholarship Council (CSC)
The discovery that hematopoietic human colony stimulating factor-1 receptor (CSF-1R) can be activated by two distinct cognate cytokines, colony stimulating factor-1 (CSF-1) and interleukin-34 (IL-34), created puzzling scenarios for the two possible signaling complexes. We here employ a hybrid structural approach based on small-angle X-ray scattering (SAXS) and negative-stain EM to reveal that bivalent binding of human IL-34 to CSF-1R leads to an extracellular assembly hallmarked by striking similarities to the CSF-1:CSF-1R complex, including homotypic receptor-receptor interactions. Thus, IL-34 and CSF-1 have evolved to exploit the geometric requirements of CSF-1R activation. Our models include N-linked oligomannose glycans derived from a systematic approach resulting in the accurate fitting of glycosylated models to the SAXS data. We further show that the C-terminal region of IL-34 is heavily glycosylated and that it can be proteolytically cleaved from the IL-34:hCSF-1R complex, providing insights into its role in the functional nonredundancy of IL-34 and CSF-1.
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