Structure of the quaternary complex of interleukin-2 with its alpha, beta, and gammac receptors.
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.
Wang
Xinquan
X
Howard Hughes Medical Institute, Department of Microbiology and Immunology, Stanford University School of Medicine, 299 Campus Drive, Fairchild D319, Stanford, CA 94305, USA.
Rickert
Mathias
M
Garcia
K Christopher
KC
D018360:Crystallography, X-Ray; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit; D007376:Interleukin-2 / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D053645:Interleukin-2 Receptor alpha Subunit; D053646:Interleukin-2 Receptor beta Subunit; D008958:Models, Molecular; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D018123:Receptors, Interleukin / Q000737:chemistry* / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000627:therapeutic use; D016511:Severe Combined Immunodeficiency / Q000235:genetics
C508017:IL2RA protein, human; C508020:IL2RB protein, human; C507941:IL2RG protein, human; D053631:Interleukin Receptor Common gamma Subunit; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D053646:Interleukin-2 Receptor beta Subunit; D018123:Receptors, Interleukin; D015375:Receptors, Interleukin-2; D011994:Recombinant Proteins