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

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

SUBMITTER: Hamada K

PROVIDER: S-EPMC5422816 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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

Hamada Kozo K Miyatake Hideyuki H Terauchi Akiko A Mikoshiba Katsuhiko K

Proceedings of the National Academy of Sciences of the United States of America 20170417 18

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-r ...[more]

PMID: 28416699

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

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