期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 114, 期 18, 页码 4661-4666出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1701420114
关键词
allosteric regulation; calcium channel; IP3 receptor; X-ray crystallography; gating mechanism
资金
- Japan Society for the Promotion of Science [15K06791, 15H01572, 24926012, 25221002]
- Japan Science and Technology Agency
- RIKEN Brain Science Institute
- Nanotechnology Platform [12024046]
- Grants-in-Aid for Scientific Research [17H05711, 15H01572, 24926012, 15K06791] Funding Source: KAKEN
The inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) is an IP3-gated ion channel that releases calcium ions (Ca2+) from the endoplasmic reticulum. The IP3-binding sites in the large cytosolic domain are distant from the Ca2+ conducting pore, and the allosteric mechanism of how IP3 opens the Ca2+ channel remains elusive. Here, we identify a long-range gating mechanism uncovered by channel mutagenesis and X-ray crystallography of the large cytosolic domain of mouse type 1 IP3R in the absence and presence of IP3. Analyses of two distinct space group crystals uncovered an IP3-dependent global translocation of the curvature a-helical domain interfacing with the cytosolic and channel domains. Mutagenesis of the IP3R channel revealed an essential role of a leaflet structure in the a-helical domain. These results suggest that the curvature a-helical domain relays IP3-controlled global conformational dynamics to the channel through the leaflet, conferring long-range allosteric coupling from IP3 binding to the Ca2+ channel.
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