Quantitative insights into the mechanism of proton conduction and selectivity for the human voltage- gated proton channel Hv1

• 成果类型: Article
• 署名作者: Liu, Yu; Li, Chenghan; Freites, Alfredo; Tobias, Douglas J.; Voth, Gregory A.
• 署名单位: University of Chicago; University of Chicago; University of California System; University of California Irvine
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14148
• DOI: 10.1073/pnas.2407479121
• 发表日期: 2024-09-17
• 关键词: alveolar epithelial-cells; molecular-dynamics; permeation; currents; simulation; aspartate; transport; gromacs; models; kcsa

摘要

Human voltage- gated proton (hHv1) channels are crucial for regulating essential biological processes such as immune cell respiratory burst, sperm capacitation, and cancer cell migration. Despite the significant concentration difference between protons and other ions in physiological conditions, hHv1 demonstrates remarkable proton selectivity. Our calculations of single- proton, cation, and anion permeation free energy profiles quantitatively demonstrate that the proton selectivity of the wild- type channel originates from its strong proton affinity via the titration of the key residues D112 and D174, although the channel imposes similar kinetic blocking effects for protons compared to other ions. A two- proton knock- on model is proposed to mathematically explain the electrophysiological measurements of the pH- dependent proton conductance in the conductive state. Moreover, it is shown that the anion selectivity of the D112N mutant channel is tied to impaired proton transport and substantial anion leakage.