Abstract
Interleukin-2 (IL-2) is an immunoregulatory cytokine that acts through a quaternary receptor signaling complex containing alpha (IL-2Ralpha), beta (IL-2Rbeta), 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-2Ralpha to IL-2 stabilizes a secondary binding site for presentation to IL-2Rbeta. gammac is then recruited to the composite surface formed by the IL-2/IL-2Rbeta complex. Consistent with its role as a shared receptor for IL-4, IL-7, IL-9, IL-15, and IL-21, gammac forms degenerate contacts with IL-2. The structure of gammac 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 gammac-dependent cytokine-receptor interactions and for the engineering of improved IL-2 therapeutics.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Crystallography, X-Ray
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Humans
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Interleukin Receptor Common gamma Subunit
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Interleukin-2 / chemistry*
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Interleukin-2 / metabolism
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Interleukin-2 / therapeutic use
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Interleukin-2 Receptor alpha Subunit
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Interleukin-2 Receptor beta Subunit
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Models, Molecular
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Mutation
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Protein Binding
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Protein Conformation
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Receptors, Interleukin / chemistry*
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Receptors, Interleukin / metabolism
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Receptors, Interleukin-2 / chemistry*
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Receptors, Interleukin-2 / genetics
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Receptors, Interleukin-2 / metabolism
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Recombinant Proteins / therapeutic use
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Severe Combined Immunodeficiency / genetics
Substances
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IL2RA protein, human
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IL2RB protein, human
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IL2RG protein, human
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Interleukin Receptor Common gamma Subunit
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Interleukin-2
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Interleukin-2 Receptor alpha Subunit
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Interleukin-2 Receptor beta Subunit
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Receptors, Interleukin
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Receptors, Interleukin-2
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Recombinant Proteins