Structure of the quaternary complex of interleukin-2 with its alpha, beta, and gamma(c) receptors

摘要

Interleukin-2 (IL-2) is an immunoregulatory cytokine that acts through a quaternary receptor signaling complex containing alpha (IL-2R alpha), beta (IL-2R beta), and common gamma chain (gamma(c)) receptors. In the structure of the quaternary ectodomain complex as visualized at a resolution of 2.3 angstroms, the binding of IL-2R alpha to IL-2 stabilizes a secondary binding site for presentation to IL-2R beta. gamma(c) is then recruited to the composite surface formed by the IL-2/IL-2R beta complex. Consistent with its role as a shared receptor for IL-4, IL-7, IL-9, IL-15, and IL-21, gamma(c) forms degenerate contacts with IL-2. The structure of gamma(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 gamma(c)-dependent cytokine-receptor interactions and for the engineering of improved IL-2 therapeutics..