Gating machinery of InsP3R channels revealed by electron cryomicroscopy

Guizhen Fan, Matthew L. Baker, Zhao Wang, Mariah R. Baker, Pavel A. Sinyagovskiy, Wah Chiu, Steven J. Ludtke and Irina I. Serysheva ()
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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

Nature, 2015, vol. 527, issue 7578, 336-341

Abstract: 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.

Date: 2015
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DOI: 10.1038/nature15249

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