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Structural basis of receptor sharing by interleukin 17 cytokines

Nature Immunology volume 10, pages 1245–1251 (2009)Cite this article

Abstract

Interleukin 17 (IL-17)-producing helper T cells (TH-17 cells), together with their effector cytokines, including members of the IL-17 family, are emerging as key mediators of chronic inflammatory and autoimmune disorders. Here we present the crystal structure of a complex of IL-17 receptor A (IL-17RA) bound to IL-17F in a 1:2 stoichiometry. The mechanism of complex formation was unique for cytokines and involved the engagement of IL-17 by two fibronectin-type domains of IL-17RA in a groove between the IL-17 homodimer interface. Binding of the first receptor to the IL-17 cytokines modulated the affinity and specificity of the second receptor-binding event, thereby promoting heterodimeric versus homodimeric complex formation. IL-17RA used a common recognition strategy to bind to several members of the IL-17 family, which allows it to potentially act as a shared receptor in multiple different signaling complexes.

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Figure 1: Structure of the IL-17RA–IL-17F complex.
Figure 2: Binding of IL-17F to IL-17RA is mediated by three distinct interfaces.
Figure 3: Assembly and model of the heterodimeric IL-17 signaling complex.
Figure 4: Binding interface and conserved IL-17 residues.
Figure 5: IL-17RA–IL-17F and homodimeric complexes of cysteine-knot growth factor receptors.

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Acknowledgements

We thank S. Juo for assistance with data collection and structure determination; E. Özkan for discussions; D. Gorman (DNAX) for cDNA reagents; and the beamline staff of the Stanford Synchrotron Radiation Lightsource, Advanced Light Source and Advanced Photon Source for assistance with data collection. Supported by the National Health and Medical Research Council of Australia (L.K.E.), the US National Institutes of Health (AI51321 to K.C.G.) and the Howard Hughes Medical Institute (K.C.G.).

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Authors and Affiliations

  1. Departments of Molecular and Cellular Physiology, Howard Hughes Medical Institute, and Structural Biology, Stanford University School of Medicine, Stanford, California, USA

    Lauren K Ely, Suzanne Fischer & K Christopher Garcia

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  1. Lauren K Ely
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Contributions

K.C.G. initiated studies; L.K.E. and K.C.G. designed experiments; L.K.E. and S.F. did experiments; and L.K.E. and K.C.G. analyzed data and wrote manuscript.

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Correspondence to K Christopher Garcia.

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K.C.G. plans to file a patent to use information gained from this crystal structure to design IL-17 therapeutics.

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Ely, L., Fischer, S. & Garcia, K. Structural basis of receptor sharing by interleukin 17 cytokines. Nat Immunol 10, 1245–1251 (2009). https://doi.org/10.1038/ni.1813

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