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Nature. 2015 Nov 19;527(7578):336-41. doi: 10.1038/nature15249. Epub 2015 Oct 12.

Gating machinery of InsP3R channels revealed by electron cryomicroscopy.

Author information

1
Department of Biochemistry and Molecular Biology, Structural Biology Imaging Center, The University of Texas Medical School at Houston, 6431 Fannin Street, Houston, Texas 77030, USA.
2
National Center for Macromolecular Imaging, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.

Abstract

Inositol-1,4,5-trisphosphate receptors (InsP3Rs) are ubiquitous ion channels responsible for cytosolic Ca(2+) 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 Ca(2+)-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.

PMID:
26458101
PMCID:
PMC4804758
DOI:
10.1038/nature15249
[Indexed for MEDLINE]
Free PMC Article

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