title: The mechanism of shared but distinct CSF-1R signaling by the non-homologous cytokines IL-34 and CSF-1.
abstract: Interleukin-34 (IL-34) and colony stimulating factor-1 (CSF-1) both signal through the CSF-1R receptor tyrosine kinase, but they have no sequence homology, and their functions and signaling activities are not identical. We report the crystal structures of mouse IL-34 alone and in complex with the N-terminal three immunoglobulin-like domains (D1-D3) of mouse CSF-1R. IL-34 is structurally related to other helical hematopoietic cytokines, but contains two additional helices integrally associated with the four shared helices. The non-covalently linked IL-34 homodimer recruits two copies of CSF-1R on the sides of the helical bundles, with an overall shape similar to the CSF-1:CSF-1R complex, but the flexible linker between CSF-1R D2 and D3 allows these domains to clamp IL-34 and CSF-1 at different angles. Functional dissection of the IL-34:CSF-1R interface indicates that the hydrophobic interactions, rather than the salt bridge network, dominate the biological activity of IL-34. To degenerately recognize two ligands with completely different surfaces, CSF-1R apparently takes advantage of different subsets of a chemically inert surface that can be tuned to fit different ligand shapes. Differentiated signaling between IL-34 and CSF-1 is likely achieved by the relative thermodynamic independence of IL-34 vs. negative cooperativity of CSF-1 at the receptor-recognition sites, in combination with the difference in hydrophobicity which dictates a more stable IL-34:CSF-1R complex compared to the CSF-1:CSF-1R complex.
authors.affiliation: Department of Molecular Pharmacology & Biological Chemistry, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Heli
authors.initials: H
authors.lastname: Liu
authors.forename: Cindy
authors.initials: C
authors.lastname: Leo
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Chen
authors.forename: Brian R
authors.initials: BR
authors.lastname: Wong
authors.forename: Lewis T
authors.initials: LT
authors.lastname: Williams
authors.forename: Haishan
authors.initials: H
authors.lastname: Lin
authors.forename: Xiaolin
authors.initials: X
authors.lastname: He
mesh_terms: D000818:Animals; D016367:Baculoviridae / Q000235:genetics; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015870:Gene Expression; D005822:Genetic Vectors; D057927:Hydrophobic and Hydrophilic Interactions; D007378:Interleukins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D008024:Ligands; D016173:Macrophage Colony-Stimulating Factor / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D061987:Sf9 Cells / Q000166:cytology / Q000378:metabolism; D015398:Signal Transduction; D018411:Spodoptera; D013816:Thermodynamics
chemical_list: D007378:Interleukins; D008024:Ligands; D011994:Recombinant Proteins; C552364:interleukin-34, mouse; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor