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The Mapping of the Lyn Kinase Binding Site of the Common ß Subunit of IL-3/Granulocyte-Macrophage Colony- Stimulating Factor/IL-5 Receptor¹

Department of Internal Medicine, Division of Allergy and Immunology, University of Texas Medical Branch, Galveston, TX 77555

It has been shown that a membrane-proximal region within common ß (ßc) receptor of IL-3/granulocyte-macrophage CSF/IL-5 (amino acids 450–517) is important for Lyn binding. We have shown previously that Lyn kinase is physically associated with the IL-5R ßc subunit in unstimulated cells. The result suggests that this association involves binding modules that are not activation or phosphorylation dependent. The objective of this study was to map the exact Lyn binding site on ßc. Using overlapping and/or sequential peptides derived from ßc 450–517, we narrowed down the Lyn binding site to nine amino acid residues, ßc 457–465. The PA mutation in this region abrogated the binding to Lyn, indicating a critical role of proline residues. We created a cell-permeable Lyn-binding peptide by N-stearation. This cell-permeable peptide blocked the association of Lyn, but not Jak2 with ßc in situ. We also investigated the ßc binding site of Lyn kinase. Our results suggest that the N-terminal unique domain of Lyn kinase is important for binding to ßc receptor. To our knowledge, this is the first molecular identification of the Lyn binding site of ßc receptor. This finding may help develop specific inhibitors of Lyn-coupled signaling pathways.