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Signaling conformations of the tall cytokine receptor gp130 when in complex with IL-6 and IL-6 receptor

Nature Structural & Molecular Biology volume 12, pages 545–551 (2005)Cite this article

Abstract

gp130 is a shared cytokine signaling receptor and the founding member of the 'tall' class of cytokine receptors. A crystal structure of the ligand-binding domains of gp130 in complex with human interleukin-6 (IL-6) and its a-receptor (IL-6Rα) revealed a hexameric architecture in which the gp130 membrane-distal regions were ∼100 Å apart, in contrast to the close apposition seen between short cytokine receptor complexes. Here we used single-particle EM to visualize the entire extracellular hexameric IL-6–IL-6Rα–gp130 complex, containing all six gp130 domains. The structure reveals that gp130 is bent such that the membrane-proximal domains of gp130 are close together at the cell surface, enabling activation of intracellular signaling. Variation in the receptor bend angles suggests a possible conformational transition from open to closed states upon ligand binding; this transition is probably representative of the other tall cytokine receptors.

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Figure 1: The components of the gp130–IL-6 system.
Figure 2: EM of the IL-6–IL-6Rα–gp130 complex.
Figure 3: Three-dimensional map and fit crystal structures of the IL-6–IL-6Rα–gp130 complex.
Figure 4: Structural comparison of short and tall cytokine receptor complexes.

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Acknowledgements

We acknowledge D. Chow, N. Goriatcheva, M. Martick and L. Brevnova for assistance and helpful discussions, and Y. Cheng for support in data collection and image processing. We also acknowledge the Keck Foundation (K.C.G.), Pew Trust (K.C.G.) and US National Institutes of Health (NIH) AI51321 (K.C.G.) for support. The molecular EM facility at Harvard Medical School was established by a generous donation from the Giovanni Armenise Harvard Center for Structural Biology and is maintained by funds from NIH GM62580 (T.W.). G.S. is a Damon Runyon Fellow, supported by the Damon Runyon Cancer Research Foundation (DRG-#1824-04).

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Authors and Affiliations

  1. Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Georgios Skiniotis & Thomas Walz

  2. Departments of Microbiology and Immunology, Structural Biology, Stanford University School of Medicine, Stanford, 94305, California, USA

    Martin J Boulanger & K Christopher Garcia

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  1. Georgios Skiniotis
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  2. Martin J Boulanger
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Correspondence to K Christopher Garcia or Thomas Walz.

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Supplementary information

Supplementary Fig. 1

Class averages. (PDF 1254 kb)

Supplementary Fig. 2

Angular distribution plots and Fourier shell correlation curve. (PDF 307 kb)

Supplementary Fig. 3

Improvement of the density map for the IL-6–IL-6Rα–gp130 complex. (PDF 2739 kb)

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Skiniotis, G., Boulanger, M., Garcia, K. et al. Signaling conformations of the tall cytokine receptor gp130 when in complex with IL-6 and IL-6 receptor. Nat Struct Mol Biol 12, 545–551 (2005). https://doi.org/10.1038/nsmb941

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