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Science 310 (5751): 1159-1163

Copyright © 2005 by the American Association for the Advancement of Science

Structure of the Quaternary Complex of Interleukin-2 with Its {alpha}, ß, and {gamma}c Receptors

Xinquan Wang,* Mathias Rickert,* K. Christopher Garcia{dagger}

Abstract: Interleukin-2 (IL-2) is an immunoregulatory cytokine that acts through a quaternary receptor signaling complex containing alpha (IL-2R{alpha}), beta (IL-2Rß), and common gamma chain (gc) 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-2Rß. {gamma}c is then recruited to the composite surface formed by the IL-2/IL-2Rß 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.

Howard Hughes Medical Institute, Department of Microbiology and Immunology, and Department of Structural Biology, Stanford University School of Medicine, 299 Campus Drive, Fairchild D319, Stanford, CA 94305, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: kcgarcia{at}stanford.edu

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