Structural titration reveals Ca(2+)-dependent conformational landscape of the IP(3) receptor Journal Article

   


Authors: Paknejad, N.; Sapuru, V.; Hite, R. K.
Article Title: Structural titration reveals Ca(2+)-dependent conformational landscape of the IP(3) receptor
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. © 2023, The Author(s).
Keywords: protein domain; metabolism; image analysis; protein; calcium; endoplasmic reticulum; conformation; molecular conformation; protein domains; concentration (composition); cation; inositol 1,4,5 trisphosphate receptor; calcium signaling; inositol 1,4,5-trisphosphate; inositol 1,4,5-trisphosphate receptors; inositol 1,4,5 trisphosphate; cell component
Journal Title: Nature Communications
Volume: 14
ISSN: 2041-1723
Publisher: Nature Publishing Group  
Date Published: 2023-10-28
Start Page: 6897
Language: English
DOI: 10.1038/s41467-023-42707-3
PUBMED: 37898605
PROVIDER: scopus
PMCID: PMC10613215
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85175206469&doi=10.1038%2fs41467-023-42707-3&partnerID=40&md5=e378870fecfae45c498edc3da84985c1
Notes: The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF. Corresponding MSK author is Richard K. Hite -- Source: Scopus
Altmetric
What is Altmetric?
Citation Impact
What is Dimensions Citation Badge?
BMJ Impact Analytics
MSK Authors
  1. Navid Paknejad
    18 Paknejad
  2. Richard Kevin Hite
    25 Hite
  3. Vinay Kumar Sapuru
    4 Sapuru
Related MSK Work