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

IF 3.3 2区 医学 Q1 PHYSIOLOGY
Journal of General Physiology Pub Date : 2025-05-05 Epub Date: 2025-02-21 DOI:10.1085/jgp.202313506
Alp Tegin Şahin, Ulrich Zachariae
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引用次数: 0

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 timescale of ion conduction and investigated the conformational changes induced by the presence or absence of bound PI(3,5)P2. Our findings reveal that hTPC2 adopts distinct conformations depending on the presence of PI(3,5)P2 and elucidate the allosteric transition pathways between these structures. Additionally, we examined the permeation mechanism, solvation states, and binding sites of ions during ion permeation through the pore. The results of our simulations explain the experimental observation that hTPC2 is more selective for Na+ over Ca2+ ions in the presence of PI(3,5)P2via a multilayer selectivity mechanism. Importantly, mutations in the selectivity filter region of hTPC2 maintain cation conduction but change the ion selectivity of hTPC2 drastically.

人TPC2阳离子通道的门控和选择性机制的硅表征。
双孔通道(Two-pore channels, TPCs)是双对称的内溶酶体阳离子通道,是重要的药物靶点,尤其是抗病毒药物。它们被钙、配体结合和膜电压激活,并且迄今为止,它们是唯一显示根据结合配体的类型改变离子选择性的离子通道。然而,尽管它们很重要,但TPCs的配体活化及其离子选择性的分子机制仍然知之甚少。在这里,我们着手阐明人类TPC2 (hTPC2)离子选择性的机制基础和配体诱导的脂质PI(3,5)P2激活通道的分子机制。我们进行了全原子硅电生理模拟,研究了Na+和Ca2+在离子传导时间尺度上通过全长hTPC2的渗透,并研究了存在或不存在结合PI(3,5)P2所引起的构象变化。我们的研究结果表明,hTPC2采用不同的构象取决于PI(3,5)P2的存在,并阐明了这些结构之间的变构转变途径。此外,我们还研究了离子通过孔渗透时的渗透机制、溶剂化状态和离子的结合位点。我们的模拟结果解释了hTPC2在PI(3,5) p2存在下通过多层选择性机制对Na+比Ca2+离子更具选择性的实验观察。重要的是,hTPC2选择性过滤区域的突变维持了阳离子传导,但急剧改变了hTPC2的离子选择性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
6.00
自引率
10.50%
发文量
88
审稿时长
6-12 weeks
期刊介绍: General physiology is the study of biological mechanisms through analytical investigations, which decipher the molecular and cellular mechanisms underlying biological function at all levels of organization. The mission of Journal of General Physiology (JGP) is to publish mechanistic and quantitative molecular and cellular physiology of the highest quality, to provide a best-in-class author experience, and to nurture future generations of independent researchers. The major emphasis is on physiological problems at the cellular and molecular level.
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