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Gating machinery of InsP3R channels revealed by electron cryomicroscopy

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  • Guizhen Fan

    (Structural Biology Imaging Center, The University of Texas Medical School at Houston)

  • Matthew L. Baker

    (National Center for Macromolecular Imaging, Baylor College of Medicine)

  • Zhao Wang

    (National Center for Macromolecular Imaging, Baylor College of Medicine)

  • Mariah R. Baker

    (Structural Biology Imaging Center, The University of Texas Medical School at Houston)

  • Pavel A. Sinyagovskiy

    (Structural Biology Imaging Center, The University of Texas Medical School at Houston)

  • Wah Chiu

    (National Center for Macromolecular Imaging, Baylor College of Medicine)

  • Steven J. Ludtke

    (National Center for Macromolecular Imaging, Baylor College of Medicine)

  • Irina I. Serysheva

    (Structural Biology Imaging Center, The University of Texas Medical School at Houston)

Abstract

Inositol-1,4,5-trisphosphate receptors (InsP3Rs) are ubiquitous ion channels responsible for cytosolic Ca2+ signalling and essential for a broad array of cellular processes ranging from contraction to secretion, and from proliferation to cell death. Despite decades of research on InsP3Rs, a mechanistic understanding of their structure–function relationship is lacking. Here we present the first, to our knowledge, near-atomic (4.7 Å) resolution electron cryomicroscopy structure of the tetrameric mammalian type 1 InsP3R channel in its apo-state. At this resolution, we are able to trace unambiguously ∼85% of the protein backbone, allowing us to identify the structural elements involved in gating and modulation of this 1.3-megadalton channel. Although the central Ca2+-conduction pathway is similar to other ion channels, including the closely related ryanodine receptor, the cytosolic carboxy termini are uniquely arranged in a left-handed α-helical bundle, directly interacting with the amino-terminal domains of adjacent subunits. This configuration suggests a molecular mechanism for allosteric regulation of channel gating by intracellular signals.

Suggested Citation

  • Guizhen Fan & Matthew L. Baker & Zhao Wang & Mariah R. Baker & Pavel A. Sinyagovskiy & Wah Chiu & Steven J. Ludtke & Irina I. Serysheva, 2015. "Gating machinery of InsP3R channels revealed by electron cryomicroscopy," Nature, Nature, vol. 527(7578), pages 336-341, November.
    • Handle: RePEc:nat:nature:v:527:y:2015:i:7578:d:10.1038_nature15249
    DOI: 10.1038/nature15249
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    Cited by:

    1. Navid Paknejad & Vinay Sapuru & Richard K. Hite, 2023. "Structural titration reveals Ca2+-dependent conformational landscape of the IP3 receptor," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    2. Guizhen Fan & Mariah R. Baker & Lara E. Terry & Vikas Arige & Muyuan Chen & Alexander B. Seryshev & Matthew L. Baker & Steven J. Ludtke & David I. Yule & Irina I. Serysheva, 2022. "Conformational motions and ligand-binding underlying gating and regulation in IP3R channel," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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