Felix, Jan; Elegheert, Jonathan; Gutsche, Irina; Shkumatov, Alexander V.; Wen, Yurong; Bracke, Nathalie; Pannecoucke, Erwin; Vandenberghe, Isabel; Devreese, Bart; Svergun, Dmitri I.; Pauwels, Ewald; Vergauwen, Bjorn; Savvides, Savvas N.
Human IL-34 and CSF-1 Establish Structurally Similar Extracellular Assemblies with Their Common Hematopoietic Receptor
STRUCTURE, 21:528-539, APR 2 2013

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.

DOI:10.1016/j.str.2013.01.018

Find full text with Google Scholar.