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Prepublished online as a Blood First Edition Paper on October 10, 2002; DOI 10.1182/blood-2002-06-1903.
Submitted June 27, 2002
Accepted September 10, 2002
Molecular assembly of the ternary granulocyte-macrophage colony-stimulating factor receptor complex
Barbara J McClure, Timothy R Hercus, Bronwyn A Cambareri, Joanna M Woodcock, Christopher J Bagley, Geoff J Howlett, and Angel F Lopez*
Cytokine Receptor Laboratory, Division of Human Immunology, Institute of Medical and Veterinary Science, Adelaide, SA, Australia
Protein Laboratory, Division of Human Immunology, Institute of Medical and Veterinary Science, Adelaide, SA, Australia
Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, VIC, Australia
* Corresponding author; email: angel.lopez{at}imvs.sa.gov.au.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a hematopoietic cytokine that stimulates the production and functional activity of granulocytes and macrophages, properties that have encouraged its clinical use in bone marrow transplantation and in certain infectious diseases. Despite the importance of GM-CSF in regulating myeloid cell numbers and function little is known about the exact composition and mechanism of assembly of the GM-CSF receptor complex. We have now produced soluble forms of the GM-CSF receptor  chain (sGMR) and ßchain (sßc) and utilised GM-CSF, the GM-CSF antagonist E21R and the ßc-blocking monoclonal antibody BION-1 to define the molecular assembly of the GM-CSF receptor complex. We found that GM-CSF and E21R were able to form low affinity, binary complexes with sGMR, each having a stoichiometry of 1:1. Importantly, GM-CSF but not E21R, formed a ternary complex with sGMRand sßc and this complex could be disrupted by E21R. Significantly, size exclusion chromatography, analytical ultracentrifugation and radioactive tracer experiments indicated that the ternary complex is composed of one sßc dimer with a single molecule each of sGMRand of GM-CSF. In addition, a hitherto unrecognised direct interaction between ßc and GM-CSF was detected which was absent with E21R and was abolished by BION-1. These results demonstrate a novel mechanism of cytokine receptor assembly likely to apply also to interleukin (IL) -3 and IL-5, and have implications for our molecular understanding and potential manipulation of GM-CSF activation of its receptor.
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