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Structural basis for the regulation of inositol trisphosphate receptors by Ca2+ and IP3.


ABSTRACT: Inositol trisphosphate receptors (IP3Rs) are ubiquitous Ca2+-permeable channels that mediate release of Ca2+ from the endoplasmic reticulum, thereby regulating numerous processes including cell division, cell death, differentiation and fertilization. IP3Rs are jointly activated by inositol trisphosphate (IP3) and their permeant ion, Ca2+. At high concentrations, however, Ca2+ inhibits activity, ensuring precise spatiotemporal control over intracellular Ca2+. Despite extensive characterization of IP3R, the mechanisms through which these molecules control channel gating have remained elusive. Here, we present structures of full-length human type 3 IP3Rs in ligand-bound and ligand-free states. Multiple IP3-bound structures demonstrate that the large cytoplasmic domain provides a platform for propagation of long-range conformational changes to the ion-conduction gate. Structures in the presence of Ca2+ reveal two Ca2+-binding sites that induce the disruption of numerous interactions between subunits, thereby inhibiting IP3R. These structures thus provide a mechanistic basis for beginning to understand the regulation of IP3R.

SUBMITTER: Paknejad N 

PROVIDER: S-EPMC6082148 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Structural basis for the regulation of inositol trisphosphate receptors by Ca<sup>2+</sup> and IP<sub>3</sub>.

Paknejad Navid N   Hite Richard K RK  

Nature structural & molecular biology 20180716 8


Inositol trisphosphate receptors (IP<sub>3</sub>Rs) are ubiquitous Ca<sup>2+</sup>-permeable channels that mediate release of Ca<sup>2+</sup> from the endoplasmic reticulum, thereby regulating numerous processes including cell division, cell death, differentiation and fertilization. IP<sub>3</sub>Rs are jointly activated by inositol trisphosphate (IP<sub>3</sub>) and their permeant ion, Ca<sup>2+</sup>. At high concentrations, however, Ca<sup>2+</sup> inhibits activity, ensuring precise spatiote  ...[more]

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