title: Human IL-34 and CSF-1 establish structurally similar extracellular assemblies with their common hematopoietic receptor.
abstract: 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.
authors.affiliation: Unit for Structural Biology, Laboratory for Protein Biochemistry and Biomolecular Engineering (L-ProBE), Ghent University, K.L. Ledeganckstraat 35, 9000 Ghent, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Felix
authors.forename: Jonathan
authors.initials: J
authors.lastname: Elegheert
authors.forename: Irina
authors.initials: I
authors.lastname: Gutsche
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Shkumatov
authors.forename: Yurong
authors.initials: Y
authors.lastname: Wen
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bracke
authors.forename: Erwin
authors.initials: E
authors.lastname: Pannecoucke
authors.forename: Isabel
authors.initials: I
authors.lastname: Vandenberghe
authors.forename: Bart
authors.initials: B
authors.lastname: Devreese
authors.forename: Dmitri I
authors.initials: DI
authors.lastname: Svergun
authors.forename: Ewald
authors.initials: E
authors.lastname: Pauwels
authors.forename: Bjorn
authors.initials: B
authors.lastname: Vergauwen
authors.forename: Savvas N
authors.initials: SN
authors.lastname: Savvides
mesh_terms: D006801:Humans; D007378:Interleukins / Q000737:chemistry*; D016173:Macrophage Colony-Stimulating Factor / Q000737:chemistry*; D008854:Microscopy, Electron; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000737:chemistry*; D011487:Protein Conformation; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000737:chemistry*; D053838:Scattering, Small Angle; D053719:Tandem Mass Spectrometry
chemical_list: C529076:IL34 protein, human; D007378:Interleukins; D046912:Multiprotein Complexes; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor