Year: 2023
Type: article
Abstract: Inositol 1,4,5-trisphosphate receptors (IP3Rs) are endoplasmic reticulum Ca2+ channels whose biphasic dependence on cytosolic Ca2+ gives rise to Ca2+ oscillations that regulate fertilization, cell division and cell death. Despite the critical roles of IP3R-mediated Ca2+ responses, the structural underpinnings of the biphasic Ca2+ dependence that underlies Ca2+ oscillations are incompletely understood. Here, we collect cryo-EM images of an IP3R with Ca2+ concentrations spanning five orders of magnitude. Unbiased image analysis reveals that Ca2+ binding does not explicitly induce conformational changes but rather biases a complex conformational landscape consisting of resting, preactivated, activated, and inhibited states. Using particle counts as a proxy for relative conformational free energy, we demonstrate that Ca2+ binding at a high-affinity site allows IP3Rs to activate by escaping a low-energy resting state through an ensemble of preactivated states. At high Ca2+ concentrations, IP3Rs preferentially enter an inhibited state stabilized by a second, low-affinity Ca2+ binding site. Together, these studies provide a mechanistic basis for the biphasic Ca2+-dependence of IP3R channel activity.
Source: Nature Communications
Authors: Navid Paknejad, Vinay Sapuru, Richard K. Hite
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,290
Awards: G1391005062, G2051006376, G289723095, G2911627494, G4102770861, Molecular characterization of the multi-modal regulation of inositol 1,4,5-trisphosphate receptors, G5602527752, Molecular Mechanisms of Apoptosis Regulation Through IP3 Receptors, G8068008632, G9000003249, Cancer Center Support Grant
OpenAlex ID: W4388034097