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Prepublished online as a Blood First Edition Paper on October 10, 2002; DOI 10.1182/blood-2002-06-1903.
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Blood, 15 February 2003, Vol. 101, No. 4, pp. 1308-1315
HEMATOPOIESIS
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
From the Cytokine Receptor Laboratory and Protein
Laboratory, Division of Human Immunology, Institute of Medical and
Veterinary Science (IMVS), Adelaide, South
Australia; and Department of Biochemistry and Molecular Biology,
University of Melbourne, Parkville, Australia.
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  chain (sc) and utilized GM-CSF, the GM-CSF
antagonist E21R (Glu21Arg), and the c-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 sGMR
and sc, 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 sc dimer with a single molecule each of
sGMR and of GM-CSF. In addition, a hitherto unrecognized direct interaction between c and GM-CSF was detected that 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-3 (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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