In silico characterization of the gating and selectivity mechanism of the human TPC2 cation channel.

ABSTRACT: Two-pore channels (TPCs) are twofold symmetric endolysosomal cation channels forming important drug targets, especially for antiviral drugs. They are activated by calcium, ligand binding, and membrane voltage, and to date, they are the only ion channels shown to alter their ion selectivity depending on the type of bound ligand. However, despite their importance, ligand activation of TPCs and the molecular mechanisms underlying their ion selectivity are still poorly understood. Here, we set out to elucidate the mechanistic basis for the ion selectivity of human TPC2 (hTPC2) and the molecular mechanism of ligand-induced channel activation by the lipid PI(3,5)P2. We performed all-atom in silico electrophysiology simulations to study Na+ and Ca2+ permeation across full-length hTPC2 on the time

SUBMITTER: Sahin AT 

PROVIDER: S-EPMC11844439 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature