Structural basis of γ-chain family receptor sharing at the membrane level

The common {gamma}-chain ({gamma}c) family of cytokine receptors, including interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21 receptors, are activated upon engagement with the common {gamma}c receptor in ligand dependent manner. Sharing of {gamma}c by the IL receptors (ILRs) is thought to be achieved by concomitant binding of {gamma}c and ILR ectodomains to a cytokine. Here, we found that direct interactions between the transmembrane domain (TMD) of {gamma}c and those of the ILRs are also required for receptor activation, and remarkably, the same {gamma}c TMD can specifically recognize multiple ILR TMDs of diverse sequences. Heterodimer structures of {gamma}c TMD bound to the TMDs of IL-7R and IL-9R, determined in near lipid bilayer environment, reveal a conserved knob-into-hole mechanism of recognition that mediates receptor sharing within the membrane. Functional mutagenesis data indicate the requirement of the heterotypic interactions of TMDs in signaling, which could explain disease mutations within the receptor TMDs. One-Sentence SummaryThe transmembrane anchors of interleukin receptors of the gamma-chain family are critical for receptor sharing and activation.