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Proc Natl Acad Sci U S A. 2017 May 2;114(18):4661-4666. doi: 10.1073/pnas.1701420114. Epub 2017 Apr 17.

IP3-mediated gating mechanism of the IP3 receptor revealed by mutagenesis and X-ray crystallography.

Author information

1
Laboratory for Developmental Neurobiology, Brain Science Institute, RIKEN, Saitama 351-0198, Japan.
2
Nano Medical Engineering Laboratory, RIKEN, Saitama 351-0198, Japan.
3
Laboratory for Developmental Neurobiology, Brain Science Institute, RIKEN, Saitama 351-0198, Japan; mikosiba@brain.riken.jp.

Abstract

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 α-helical domain interfacing with the cytosolic and channel domains. Mutagenesis of the IP3R channel revealed an essential role of a leaflet structure in the α-helical domain. These results suggest that the curvature α-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.

KEYWORDS:

IP3 receptor; X-ray crystallography; allosteric regulation; calcium channel; gating mechanism

PMID:
28416699
PMCID:
PMC5422816
DOI:
10.1073/pnas.1701420114
[Indexed for MEDLINE]
Free PMC Article

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