Observation of an unexpected third receptor molecule in the crystal structure of human interferon-γ receptor complex

Abstract

Background: Molecular interactions among cytokines and cytokine receptors form the basis of many cell-signaling pathways relevant to immune function. Interferon-γ (IFN-γ) signals through a multimeric receptor complex consisting of two different but structurally related transmembrane chains: the high-affinity receptor-binding subunit (IFN-γRα) and a species-specific accessory factor (AF-1 or IFN-γRβ). In the signaling complex, the two receptors probably interact with one another through their extracellular domains. Understanding the atomic interactions of signaling complexes enhances the ability to control and alter cell signaling and also provides a greater understanding of basic biochemical processes. Results: The crystal structure of the complex of human IFN-γ with the soluble, glycosylated extracellular part of IFN-γRα has been determined at 2.9 Å resolution using multiwavelength anomalous diffraction methods. In addition to the expected 2:1 complex, the crystal structure reveals the presence of a third receptor molecule not directly associated with the IFN-γ dimer. Two distinct intermolecular contacts, involving the edge strands of the C-terminal domains, are observed between this extra receptor and the 2:1 receptor–ligand complex thereby forming a 3:1 complex. Conclusions: The observed interactions in the 2:1 complex of the high-affinity cell-surface receptor with the IFN-γ cytokine are similar to those seen in a previously reported structure where the receptor chains were not glycosylated. The formation of β-sheet packing interactions between pairs of IFN-γRα receptors in these crystals suggests a possible model for receptor oligomerization of Rα and the structurally homologous Rβ receptors in the fully active IFN-γ signaling complex.