A common site of the Fc receptor γ subunit interacts with the unrelated immunoreceptors FcαRI and FcεRI

The transmembrane (TM) region of the Fc receptor-gamma (FcR gamma) chain is responsible for the association of this ubiquitous signal transduction subunit with many immunoreceptor ligand binding chains, making FcR gamma key to a number of leukocyte activities in immunity and disease. Some receptors contain a TM arginine residue that interacts with Asp-11 of the FcR gamma subunit, but otherwise the molecular basis for the FcR gamma subunit interactions is largely unknown. This study reports residues in the TM region of the FcR gamma subunit are important for association with the high affinity IgE receptor Fc epsilon RI and a leukocyte receptor cluster member, the IgA receptor Fc alpha RI. FcR gamma residue Leu-21 was essential for surface expression of Fc epsilon RI alpha/gamma(2) and Tyr-8, Leu-14, and Phe-15 contributed to expression. Likewise, detergent-stable FcR gamma association with Fc alpha RI was also dependent on Leu-14 and Leu-21 and in addition required residues Tyr-17, Tyr-25, and Cys-26. Modeling the TM regions of the FcR gamma dimer indicated these residues interacting with both Fc alpha RI and Fc epsilon RI are near the interface between the two FcR gamma TM helices. Furthermore, the FcR gamma residues interacting with Fc alpha RI form a leucine zipper-like interface with mutagenesis confirming a complementary interface comprising Fc alpha RI residues Leu-217, Leu-220, and Leu-224. The dependence of these two nonhomologous receptor interactions on FcR gamma Leu-14 and Leu-21 suggests that all the associated Fc receptors and the activating leukocyte receptor cluster members interact with this one site. Taken together these data provide a molecular basis for understanding how disparate receptor families assemble with the FcR gamma subunit.