6drc

Publication Abstract from PubMed

Inositol trisphosphate receptors (IP3Rs) are ubiquitous Ca(2+)-permeable channels that mediate release of Ca(2+) 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, Ca(2+). At high concentrations, however, Ca(2+) inhibits activity, ensuring precise spatiotemporal control over intracellular Ca(2+). 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 Ca(2+) reveal two Ca(2+)-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.

Structural basis for the regulation of inositol trisphosphate receptors by Ca(2+) and IP3.,Paknejad N, Hite RK Nat Struct Mol Biol. 2018 Jul 16. pii: 10.1038/s41594-018-0089-6. doi:, 10.1038/s41594-018-0089-6. PMID:30013099^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.