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题名: pH-dependent channel gating in connexin26 hemichannels involves conformational changes in N-terminus
作者: Wang, Xia1, 2;  Xu, Xue1, 2;  Ma, Ming1, 2;  Zhou, Wei1, 2;  Wang, Yonghua1, 2;  Yang, Ling3
关键词: Molecular dynamic simulation ;  Connexin26 ;  pH ;  Channel gating
刊名: BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
发表日期: 2012-05-01
DOI: 10.1016/j.bbamem.2011.12.027
卷: 1818, 期:5, 页:1148-1157
收录类别: SCI
文章类型: Article
类目[WOS]: Biochemistry & Molecular Biology ;  Biophysics
研究领域[WOS]: Biochemistry & Molecular Biology ;  Biophysics
英文摘要: Connexin (Cx) hemichannels controlling an exchange of ions and metabolites between the cytoplasm and extracellular milieu can be modulated by the variation of intracellular pH during physiological and pathological conditions. To address the mechanism by which the pH exerts its effect on hemichannels, we have performed two 100-ns molecular dynamics simulations of the Cx26 channel in both acidic and neutral states. The results show that: 1) transmembrane domains undergo clockwise motions around the pore axis under both acidic and neutral conditions, while extracellular segments keep stable. 2) Under neutral condition, Cx26 has a tightly closed configuration that occurs through the assembly of N-terminal helix (NTH) region. This shows a constriction formed by the interhelical interactions of Asp2 and Met1 from neighboring NTH, which shapes the narrowest segment (pore radius<2 angstrom) of the pore, preventing the passage of ions from the extracellular side. This indicates that Asp2 may act as a channel gate. 3) Under the acidic condition, the constriction is relieved by the protonation of Asp2 causing interruption of interhelical interactions, Cx26 has a flexibly opening pore (pore radius > 4.5 angstrom) around NTH region, allowing the passage of chloride ions unimpeded by the side-chain Asp2. While in the extracellular part two chloride ions interact with the side-chain Lys41 from three subunits. Finally, we provide a plausible mechanism of pH-dependent gating of hemichannel that involves protonation of the aspartic residues, suggesting that the pH sensitivity of hemichannel permeability is a sophisticated mechanism for cell regulating ion permeation. (C) 2011 Elsevier B.V. All rights reserved.
关键词[WOS]: MOLECULAR-DYNAMICS SIMULATIONS ;  GAP-JUNCTION CHANNELS ;  3-DIMENSIONAL STRUCTURE ;  PROTEIN CONNEXIN43 ;  STRUCTURAL MODELS ;  AMINO-TERMINUS ;  PERMEABILITY ;  TAURINE ;  PORE ;  AMINOSULFONATES
语种: 英语
WOS记录号: WOS:000302971100004
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/142864
Appears in Collections:中国科学院大连化学物理研究所_期刊论文

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作者单位: 1.NW A&F Univ, Ctr Bioinformat, Yangling 712100, Shaanxi, Peoples R China
2.NW A&F Univ, Coll Life Sci, Yangling 712100, Shaanxi, Peoples R China
3.Chinese Acad Sci, Dalian Inst Chem Phys, Lab Pharmaceut Resource Discovery, Dalian 116023, Liaoning, Peoples R China

Recommended Citation:
Wang, Xia,Xu, Xue,Ma, Ming,et al. pH-dependent channel gating in connexin26 hemichannels involves conformational changes in N-terminus[J]. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES,2012,1818(5):1148-1157.
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