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Vol. 273, Issue 2, 1192-1199, January 9, 1998

Identification of a Cys Motif in the Common  Chain of the Interleukin 3, Granulocyte-Macrophage Colony-stimulating Factor, and Interleukin 5 Receptors Essential for Disulfide-linked Receptor Heterodimerization and Activation of All Three Receptors

From the Cytokine Receptor Laboratory, The Hanson Centre for Cancer Research, The Institute of Medical and Veterinary Science, Adelaide 5000, South Australia, Australia

The human interleukin 3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) receptors undergo covalent dimerization of the respective specific  chains with the common  subunit (_c) in the presence of the cognate ligand. We have now performed alanine substitutions of individual Cys residues in _c to identify the Cys residues involved and their contribution to activation of the IL-3, GM-CSF, and IL-5 receptors. We found that substitution of Cys-86, Cys-91, and Cys-96 in _c but not of Cys-100 or Cys-234 abrogated disulfide-linked IL-3 receptor dimerization. However, although Cys-86 and Cys-91 _c mutants retained their ability to form non-disulfide-linked dimers with IL-3R, substitution of Cys-96 eliminated this interaction. Binding studies demonstrated that all _c mutants with the exception of C96A supported high affinity binding of IL-3 and GM-CSF. In receptor activation experiments, we found that _c mutants C86A, C91A, and C96A but not C100A or C234A abolished phosphorylation of _c in response to IL-3, GM-CSF, or IL-5. These data show that although Cys-96 is important for the structural integrity of _c, Cys-86 and Cys-91 participate in disulfide-linked receptor heterodimerization and that this linkage is essential for tyrosine phosphorylation of _c. Sequence alignment of _c with other cytokine receptor signaling subunits in light of these data shows that Cys-86 and Cys-91 represent a motif restricted to human and mouse  chains, suggesting a unique mechanism of activation utilized by the IL-3, GM-CSF, and IL-5 receptors.

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