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Identification of residues in the first and fourth helices of human
granulocyte-macrophage colony-stimulating factor involved in biologic
activity and in binding to the alpha- and beta-chains of its receptor
TR Hercus, B Cambareri, M Dottore, J Woodcock, CJ Bagley, MA Vadas, MF Shannon and AF Lopez
Division of Human Immunology, Hanson Centre for Cancer Research, Institute
of Medical and Veterinary Science, Adelaide, South Australia.
Residues within the first and fourth helices of human granulocyte-
macrophage colony-stimulating factor (hGM-CSF) were analyzed for their role
in biologic activity and interaction with the alpha- and beta- chains of
the hGM-CSF receptor. Within the first helix substitution of the surface
residues Glu14, Asn17, Gln20, Arg23, Arg24, and Asn27 or the buried
residues Ala18, Leu25, and Leu28 did not significantly impair bioactivity
or receptor binding. Substitutions at the buried residues Ala22 and Leu26
had intermediate bioactivity. However, substitutions of the surface residue
Glu21 or the buried residue Ile19 reduced the relative bioactivity of the
analogues to as little as 0.45% and 0.3%, respectively. Substitution of the
charged surface residues of the fourth helix showed that substitution at
Glu104, Lys107, and Lys111 had no significant effect on bioactivity, but
substitution at Glu108 and Asp112 reduced the potency of the analogues to
34% and 7%, respectively. Receptor binding studies showed that, whereas
Glu21 is the critical residue for binding to the hGM-CSF-receptor
beta-chain, Asp112 is likely to be involved in binding to the
GM-CSF-receptor alpha- chain. These results establish the relative
contribution of residues in the first and fourth helices for GM-CSF
bioactivity and receptor binding, and support a model where the fourth
helix of GM-CSF interacts with the alpha-chain, and the first helix with
the beta-chain of the GM- CSF receptor.
Volume 83,
Issue 12,
pp. 3500-3508,
06/15/1994
Copyright © 1994 by The American Society of Hematology
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