title: Structural basis for the dual recognition of helical cytokines IL-34 and CSF-1 by CSF-1R.
abstract: Lacking any discernible sequence similarity, interleukin-34 (IL-34) and colony stimulating factor 1 (CSF-1) signal through a common receptor CSF-1R on cells of mononuclear phagocyte lineage. Here, the crystal structure of dimeric IL-34 reveals a helical cytokine fold homologous to CSF-1, and we further show that the complex architecture of IL-34 bound to the N-terminal immunoglobulin domains of CSF-1R is similar to the CSF-1/CSF-1R assembly. However, unique conformational adaptations in the receptor domain geometry and intermolecular interface explain the cross-reactivity of CSF-1R for two such distantly related ligands. The docking adaptations of the IL-34 and CSF-1 quaternary complexes, when compared to the stem cell factor assembly, draw a common evolutionary theme for transmembrane signaling. In addition, the structure of IL-34 engaged by a Fab fragment reveals the mechanism of a neutralizing antibody that can help deconvolute IL-34 from CSF-1 biology, with implications for therapeutic intervention in diseases with myeloid pathogenic mechanisms.
authors.affiliation: Department of Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Ma
authors.forename: Wei Yu
authors.initials: WY
authors.lastname: Lin
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Chen
authors.forename: Scott
authors.initials: S
authors.lastname: Stawicki
authors.forename: Kiran
authors.initials: K
authors.lastname: Mukhyala
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.forename: Flavius
authors.initials: F
authors.lastname: Martin
authors.forename: J Fernando
authors.initials: JF
authors.lastname: Bazan
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Starovasnik
mesh_terms: D057134:Antibodies, Neutralizing / Q000737:chemistry*; D016367:Baculoviridae; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry; D007378:Interleukins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000737:chemistry* / Q000235:genetics; D008958:Models, Molecular; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D019009:Proto-Oncogene Proteins c-kit / Q000737:chemistry; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000737:chemistry* / Q000235:genetics; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D019089:Stem Cell Factor / Q000737:chemistry; D040681:Structural Homology, Protein; D013816:Thermodynamics
chemical_list: D057134:Antibodies, Neutralizing; C529076:IL34 protein, human; D007140:Immunoglobulin Fab Fragments; D007378:Interleukins; D011994:Recombinant Proteins; D019089:Stem Cell Factor; D016173:Macrophage Colony-Stimulating Factor; D019009:Proto-Oncogene Proteins c-kit; D016186:Receptor, Macrophage Colony-Stimulating Factor