Calcium stabilization of a flexible N-terminal domain in a pentameric ligand-gated ion channel

• DOI: 10.1101/2025.02.24.640012
• Publication Date: 2025-02-28T03:45:17Z
• Authors: Chen Fan; Marie Lycksell; Yuxuan Zhuang; Rebecca J. Howard; Erik Lindahl

Pentameric ligand-gated ion channels (pLGICs) are responsible for the rapid conversion of chemical to electrical signals. In addition canonical extracellular and transmembrane domains, some prokaryotic pLGICs contain an N-terminal domain (NTD) unclear structure function. one such case, calcium-sensitive channel DeCLIC, NTD appears accelerate gating; however, its evident flexibility has posed a challenge model building, role in calcium sensitivity is unclear. Here we report cryo-EM structures DeCLIC highest resolutions thus far, circularized lipid nanodiscs. Application refinement tools enabled definition multiple calcium-binding sites each symmetric subunit. Under calcium-free conditions, both asymmetric classes could be reconstructed, implicating heterogeneous ensemble. Behavior these molecular dynamics simulations was consistent with stabilization NTD, effect that may conserved structurally homologous domains across evolution.