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Structural insights into the assembly and activation of IL-1β with its receptors

Nature Immunology volume 11, pages 905–911 (2010)Cite this article

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Abstract

Interleukin 1β (IL-1β) is a key orchestrator of inflammation and host defense that exerts its effects through IL-1 receptor type I (IL-1RI) and IL-1 receptor accessory protein (IL-1RAcP). How IL-1RAcP is recruited by IL-1β–IL-1RI to form the signaling-competent complex remains elusive. Here we present the crystal structure of IL-1β bound to IL-1 receptor type II (IL-1RII) and IL-1RAcP. IL-1β–IL-1RII generated a composite binding surface to recruit IL-1RAcP. Biochemical analysis demonstrated that IL-1β–IL-1RI and IL-1β–IL-1RII interacted similarly with IL-1RAcP. It also showed the importance of two loops of IL-1 receptor antagonist (IL-1Ra) in determining its antagonism. Our results provide a structural basis for assembly and activation of the IL-1 receptor and offer a general cytokine-receptor architecture that governs the IL-1 family of cytokines.

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Figure 1: Structure of IL-1β bound to the ectodomains of IL-1RII and IL-1RAcP.
Figure 2: Structure comparison of IL-1RI, IL-1RII and IL-1RAcP.
Figure 3: Binding interface between IL-1 and IL-1RII.
Figure 4: Binding interface between IL-1β–IL-1RII and IL-1RAcP.
Figure 5: Effect of loop substitution on the binding of IL-1RAcP by IL-1β–IL-1RI, IL-1β–IL-1RII and IL-1Ra–IL-1RI.
Figure 6: Superimposition of IL-1β–IL-1RI and IL-1Ra–IL-1RI onto IL-1β–IL-1RII–IL-1RAcP based on bound ligand.

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Acknowledgements

We thank J.W. Wang and H.P. Gong for assistance with structure determination; J.H. He, S. Huang and L. Tang at Shanghai Synchrotron Research Facility beamline BL-17U for help with data collection; Y.Y. Chen and X.D. Zhao for technical help with BIAcore 3000 at the Institute of Biophysics, Chinese Academy of Sciences; and Y.G. Shi, H.T. Li, L. Yu, N. Yan, M.J. Yang, J.W. Wu, Y.H. Chen and Z. Wang for discussion. Supported by Tsinghua University 985 Phase II funds, the Ministry of Science and Technology (2010CB912402), the Ministry of Health (2008ZX10001-011) and the Fok Ying Tung Education Foundation.

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  1. Center for Structural Biology, School of Life Sciences, Ministry of Education Key Laboratory of Bioinformatics, Tsinghua University, Beijing, China

    Dongli Wang, Senyan Zhang, Liang Li, Xi Liu, Kunrong Mei & Xinquan Wang

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Contributions

D.W. purified protein, grew crystals, collected diffraction data, did BIAcore experiments, analyzed data and contributed to the writing of the manuscript; S.Z. made baculoviruses and cultured insect cells; L.L., X.L. and K.M. were involved in protein purification; and X.W. collected diffraction data, solved structure, analyzed data and wrote the manuscript.

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Correspondence to Xinquan Wang.

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Wang, D., Zhang, S., Li, L. et al. Structural insights into the assembly and activation of IL-1β with its receptors. Nat Immunol 11, 905–911 (2010). https://doi.org/10.1038/ni.1925

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