1. IP 3 -mediated gating mechanism of the IP 3 receptor revealed by mutagenesis and X-ray crystallography.
- Author
-
Hamada K, Miyatake H, Terauchi A, and Mikoshiba K
- Subjects
- Allosteric Regulation, Animals, Crystallography, X-Ray, Humans, Inositol 1,4,5-Trisphosphate genetics, Inositol 1,4,5-Trisphosphate metabolism, Inositol 1,4,5-Trisphosphate Receptors genetics, Inositol 1,4,5-Trisphosphate Receptors metabolism, Mice, Protein Domains, Protein Structure, Secondary, Structure-Activity Relationship, Inositol 1,4,5-Trisphosphate chemistry, Inositol 1,4,5-Trisphosphate Receptors chemistry, Ion Channel Gating
- Abstract
The inositol 1,4,5-trisphosphate (IP
3 ) receptor (IP3 R) 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 IP3 R 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 IP3 R 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., Competing Interests: The authors declare no conflict of interest.- Published
- 2017
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