Journal
NATURE
Volume 527, Issue 7578, Pages 336-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature15249
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Funding
- National Institutes of Health [R01GM072804, R21AR063255, S10OD016279, P41GM103832, R01GM079429, R01GM080139, R21GM100229]
- American Heart Association [14RNT1980029]
- Muscular Dystrophy Association [295138]
- National Science Foundation [DBI-1356306]
- Direct For Biological Sciences
- Div Of Biological Infrastructure [1356388] Funding Source: National Science Foundation
- Div Of Biological Infrastructure
- Direct For Biological Sciences [1356306] Funding Source: National Science Foundation
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Inositol-1,4,5-trisphosphate receptors (InsP(3)Rs) 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 InsP(3)Rs, a mechanistic understanding of their structure-function relationship is lacking. Here we present the first, to our knowledge, near-atomic (4.7 angstrom) resolution electron cryomicroscopy structure of the tetrameric mammalian type 1 InsP(3)R channel in its apo-state. At this resolution, we are able to trace unambiguously similar to 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 a-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.
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