title: Structure and Assembly Mechanism of the Signaling Complex Mediated by Human CSF-1.
abstract: Human colony-stimulating factor 1 receptor (hCSF-1R) is unique among the hematopoietic receptors because it is activated by two distinct cytokines, CSF-1 and interleukin-34 (IL-34). Despite ever-growing insights into the central role of hCSF-1R signaling in innate and adaptive immunity, inflammatory diseases, and cancer, the structural basis of the functional dichotomy of hCSF-1R has remained elusive. Here, we report crystal structures of ternary complexes between hCSF-1 and hCSF-1R, including their complete extracellular assembly, and propose a mechanism for the cooperative human CSF-1:CSF-1R complex that relies on the adoption by dimeric hCSF-1 of an active conformational state and homotypic receptor interactions. Furthermore, we trace the cytokine-binding duality of hCSF-1R to a limited set of conserved interactions mediated by functionally equivalent residues on CSF-1 and IL-34 that play into the geometric requirements of hCSF-1R activation, and map the possible mechanistic consequences of somatic mutations in hCSF-1R associated with cancer.
authors.affiliation: Laboratory for Protein Biochemistry and Biomolecular Engineering (L-ProBE), Department of Biochemistry and Microbiology, Ghent University, 9000 Ghent, Belgium; Unit for Structural Biology, VIB Inflammation Research Center, 9052 Ghent, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Felix
authors.affiliation: Laboratory for Protein Biochemistry and Biomolecular Engineering (L-ProBE), Department of Biochemistry and Microbiology, Ghent University, 9000 Ghent, Belgium; Unit for Structural Biology, VIB Inflammation Research Center, 9052 Ghent, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: De Munck
authors.affiliation: Laboratory for Protein Biochemistry and Biomolecular Engineering (L-ProBE), Department of Biochemistry and Microbiology, Ghent University, 9000 Ghent, Belgium; Unit for Structural Biology, VIB Inflammation Research Center, 9052 Ghent, Belgium.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Verstraete
authors.affiliation: Laboratory for Protein Biochemistry and Biomolecular Engineering (L-ProBE), Department of Biochemistry and Microbiology, Ghent University, 9000 Ghent, Belgium; VIB Medical Biotechnology Center, 9052 Ghent, Belgium.
authors.forename: Leander
authors.initials: L
authors.lastname: Meuris
authors.affiliation: Laboratory for Protein Biochemistry and Biomolecular Engineering (L-ProBE), Department of Biochemistry and Microbiology, Ghent University, 9000 Ghent, Belgium; VIB Medical Biotechnology Center, 9052 Ghent, Belgium.
authors.forename: Nico
authors.initials: N
authors.lastname: Callewaert
authors.affiliation: Laboratory for Protein Biochemistry and Biomolecular Engineering (L-ProBE), Department of Biochemistry and Microbiology, Ghent University, 9000 Ghent, Belgium.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Elegheert
authors.affiliation: Laboratory for Protein Biochemistry and Biomolecular Engineering (L-ProBE), Department of Biochemistry and Microbiology, Ghent University, 9000 Ghent, Belgium; Unit for Structural Biology, VIB Inflammation Research Center, 9052 Ghent, Belgium. Electronic address: savvas.savvides@ugent.be.
authors.forename: Savvas N
authors.initials: SN
authors.lastname: Savvides
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D010766:Phosphorylation; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000737:chemistry* / Q000378:metabolism*; D053838:Scattering, Small Angle; D015398:Signal Transduction; D014961:X-Ray Diffraction
chemical_list: D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor