Human IL-34 and CSF-1 Establish Structurally Similar Extracellular Assemblies with Their Common Hematopoietic Receptor

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• 作者：Jan Felix¹ ; ⁵ ; Jonathan Elegheert¹ ; ⁶ ; Irina Gutsche³ ; Alexander V. Shkumatov⁴ ; Yurong Wen² ; Nathalie Bracke¹ ; ⁷ ; Erwin Pannecoucke¹ ; Isabel Vandenberghe² ; Bart Devreese² ; Dmitri I. Svergun⁴ ; Ewald Pauwels⁵ ; Bjorn Vergauwen¹ ; Savvas N. Savvides¹ ; ^{savvas.savvides@ugent.be}
• 刊名：Structure
• 出版年：2013
• 出版时间：2 April, 2013
• 年：2013
• 卷：21
• 期：4
• 页码：528-539
• 全文大小：1539 K

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Summary

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.