Cryo-EM structure of type 1 IP3R channel in a lipid bilayer

TLDR

IP3R1 is the predominant neuronal Ca²⁺ release channel that mobilizes ER calcium into the cytosol and participates in many physiological processes. The study aims to determine ligand‑free closed cryo‑EM structures of full‑length rat IP3R1 reconstituted in lipid nanodiscs and solubilized in phosphatidylcholine‑containing detergent. Using single‑particle cryo‑EM, the authors resolved full‑length IP3R1 in both lipid nanodiscs and detergent, capturing the channel in ligand‑free closed states. The resulting structures exhibit the canonical IP3R1 fold with extensive lipid occupancy, allowing atomic models that reveal two previously unresolved transmembrane helices and suggest conserved lipid binding sites critical for channel integrity.

Abstract

Abstract Type 1 inositol 1,4,5-trisphosphate receptor (IP 3 R1) is the predominant Ca 2+ -release channel in neurons. IP 3 R1 mediates Ca 2+ release from the endoplasmic reticulum into the cytosol and thereby is involved in many physiological processes. Here, we present the cryo-EM structures of full-length rat IP 3 R1 reconstituted in lipid nanodisc and detergent solubilized in the presence of phosphatidylcholine determined in ligand-free, closed states by single-particle electron cryo-microscopy. Notably, both structures exhibit the well-established IP 3 R1 protein fold and reveal a nearly complete representation of lipids with similar locations of ordered lipids bound to the transmembrane domains. The lipid-bound structures show improved features that enabled us to unambiguously build atomic models of IP 3 R1 including two membrane associated helices that were not previously resolved in the TM region. Our findings suggest conserved locations of protein-bound lipids among homotetrameric ion channels that are critical for their structural and functional integrity despite the diversity of structural mechanisms for their gating.