title: Conformational Changes in the GM-CSF Receptor Suggest a Molecular Mechanism for Affinity Conversion and Receptor Signaling.
abstract: The GM-CSF, IL-3, and IL-5 receptors constitute the βc family, playing important roles in inflammation, autoimmunity, and cancer. Typical of heterodimeric type I cytokine receptors, signaling requires recruitment of the shared subunit to the initial cytokine:α subunit binary complex through an affinity conversion mechanism. This critical process is poorly understood due to the paucity of crystal structures of both binary and ternary receptor complexes for the same cytokine. We have now solved the structure of the binary GM-CSF:GMRα complex at 2.8-Å resolution and compared it with the structure of the ternary complex, revealing distinct conformational changes. Guided by these differences we performed mutational and functional studies that, importantly, show GMRα interactions playing a major role in receptor signaling while βc interactions control high-affinity binding. These results support the notion that conformational changes underlie the mechanism of GM-CSF receptor activation and also suggest how related type I cytokine receptors signal.
authors.affiliation: ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, VIC 3065, Australia.
authors.forename: Sophie E
authors.initials: SE
authors.lastname: Broughton
authors.affiliation: The Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, SA 5000, Australia.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Hercus
authors.affiliation: ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, VIC 3065, Australia.
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Nero
authors.affiliation: The Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, SA 5000, Australia.
authors.forename: Mara
authors.initials: M
authors.lastname: Dottore
authors.affiliation: The Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, SA 5000, Australia.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: McClure
authors.affiliation: ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, VIC 3065, Australia.
authors.forename: Urmi
authors.initials: U
authors.lastname: Dhagat
authors.affiliation: The Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, SA 5000, Australia.
authors.forename: Houng
authors.initials: H
authors.lastname: Taing
authors.affiliation: ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, VIC 3065, Australia.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Gorman
authors.affiliation: ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, VIC 3065, Australia.
authors.forename: Jack
authors.initials: J
authors.lastname: King-Scott
authors.affiliation: The Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, SA 5000, Australia. Electronic address: angel.lopez@sa.gov.au.
authors.forename: Angel F
authors.initials: AF
authors.lastname: Lopez
authors.affiliation: ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, VIC 3065, Australia; Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: mparker@svi.edu.au.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Parker
mesh_terms: D020816:Amino Acid Motifs; D001665:Binding Sites; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009154:Mutation; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D021122:Protein Subunits / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D021122:Protein Subunits; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D011994:Recombinant Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor