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

Abstract

Inositol trisphosphate receptors (IP3R) are ubiquitous Ca2+-permeable channels that mediate release of Ca2+ from the endoplasmic reticulum to regulate numerous processes including cell division, cell death, differentiation and fertilization. IP3R is activated by both IP3 and its permeant ion Ca2+. At high concentrations, however, Ca2+ inhibits activity ensuring precise spatiotemporal control over intracellular Ca2+. Despite extensive characterization of IP3R, the mechanisms by which these molecules control channel gating have remained elusive. Here, we present structures of full-length human type 3 IP3R 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 begin to provide a mechanistic basis for understanding the regulation of IP3R.