Structural basis for the regulation of inositol trisphosphate receptors by Ca 2+ and IP 3

Nat Struct Mol Biol. 2018 Aug;25(8):660-668. doi: 10.1038/s41594-018-0089-6. Epub 2018 Jul 16.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Calcium / metabolism*
  • Cryoelectron Microscopy
  • Humans
  • Inositol 1,4,5-Trisphosphate Receptors / chemistry*
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism*
  • Inositol Phosphates / metabolism*
  • Protein Conformation

Substances

  • Inositol 1,4,5-Trisphosphate Receptors
  • Inositol Phosphates
  • Calcium