Plasticity of the selectivity filter is essential for permeation in lysosomal TPC2 channels.

ABSTRACT: Two-pore channels are pathophysiologically important Na⁺- and Ca²⁺-permeable channels expressed in lysosomes and other acidic organelles. Unlike most other ion channels, their permeability is malleable and ligand-tuned such that when gated by the signaling lipid PI(3,5)P₂, they are more Na⁺-selective than when gated by the Ca²⁺ mobilizing messenger nicotinic acid adenine dinucleotide phosphate. However, the structural basis that underlies such plasticity and single-channel behavior more generally remains poorly understood. A recent Cryo-electron microscopy (cryo-EM) structure of TPC2 bound to PI(3,5)P₂ in a proposed open-channel conformation provided an opportunity to address this via molecular dynamics (MD) simulation. To o

SUBMITTER: Zaki AM 

PROVIDER: S-EPMC11317647 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature