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

Abstract

The transmembrane (TM) region of the Fc receptor-γ (FcRγ) chain is responsible for the association of this ubiquitous signal transduction subunit with many immunoreceptor ligand binding chains, making FcRγ 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 FcRγ subunit, but otherwise the molecular basis for the FcRγ subunit interactions is largely unknown. This study reports residues in the TM region of the FcRγ subunit are important for association with the high affinity IgE receptor FcεRI and a leukocyte receptor cluster member, the IgA receptor FcαRI. FcRγ residue Leu-21 was essential for surface expression of FcεRIα/γ2 and Tyr-8, Leu-14, and Phe-15 contributed to expression. Likewise, detergent-stable FcRγ association with FcαRI 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 FcRγ dimer indicated these residues interacting with both FcαRI and FcεRI are near the interface between the two FcRγ TM helices. Furthermore, the FcRγ residues interacting with FcαRI form a leucine zipper-like interface with mutagenesis confirming a complementary interface comprising FcαRI residues Leu-217, Leu-220, and Leu-224. The dependence of these two nonhomologous receptor interactions on FcRγ 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 FcRγ subunit. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.