Structure of the Quaternary Complex of Interleukin-2 with Its α, ß, and γ c Receptors

Abstract

Interleukin-2 (IL-2) is an immunoregulatory cytokine that acts through a quaternary receptor signaling complex containing alpha (IL-2Rα), beta (IL-2Rβ), and common gamma chain (g c ) receptors. In the structure of the quaternary ectodomain complex as visualized at a resolution of 2.3 angstroms, the binding of IL-2Rα to IL-2 stabilizes a secondary binding site for presentation to IL-2Rβ. γ c is then recruited to the composite surface formed by the IL-2/IL-2Rβ complex. Consistent with its role as a shared receptor for IL-4, IL-7, IL-9, IL-15, and IL-21, γ c forms degenerate contacts with IL-2. The structure of γ c provides a rationale for loss-of-function mutations found in patients with X-linked severe combined immunodeficiency diseases (X-SCID). This complex structure provides a framework for other γ c -dependent cytokine-receptor interactions and for the engineering of improved IL-2 therapeutics.