Relative contribution of different transmembrane segments to the CFTR chloride channel pore

被引:30
|
作者
Wang, Wuyang [1 ]
El Hiani, Yassine [1 ]
Rubaiy, Hussein N. [1 ]
Linsdell, Paul [1 ]
机构
[1] Dalhousie Univ, Dept Physiol & Biophys, Halifax, NS B3H 4R2, Canada
来源
PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY | 2014年 / 466卷 / 03期
基金
加拿大健康研究院;
关键词
Chloride channel; Cystic fibrosis transmembrane conductance regulator; Ion channel pore; Permeation; Site-directed mutagenesis; Substituted cysteine accessibility; CONDUCTANCE REGULATOR; ANION SELECTIVITY; POSITIVE CHARGES; MOLECULAR DETERMINANTS; CONFORMATIONAL-CHANGES; OUTER MOUTH; BINDING; PERMEATION; DOMAIN; IDENTIFICATION;
D O I
10.1007/s00424-013-1317-x
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
The membrane-spanning part of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel comprises 12 transmembrane (TM) alpha-helices, arranged in 2 symmetrical groups of 6. However, those TMs that line the channel pore are not completely defined. We used patch clamp recording to compare the accessibility of cysteine-reactive reagents to cysteines introduced into different TMs. Several residues in TM11 were accessible to extracellular and/or intracellular cysteine reactive reagents; however, no reactive cysteines were identified in TMs 5 or 11. Two accessible residues in TM11 (T1115C and S1118C) were found to be more readily modified from the extracellular solution in closed channels, but more readily modified from the intracellular solution in open channels, as previously reported for T338C in TM6. However, the effects of mutagenesis at S1118 (TM11) on a range of pore functional properties were relatively minor compared to the large effects of mutagenesis at T338 (TM6). Our results suggest that the CFTR pore is lined by TM11 but not by TM5 or TM7. Comparison with previous works therefore suggests that the pore is lined by TMs 1, 6, 11, and 12, suggesting that the structure of the open channel pore is asymmetric in terms of the contributions of different TMs. Although TMs 6 and 11 appear to undergo similar conformational changes during channel opening and closing, the influence of these two TMs on the functional properties of the narrowest region of the pore is clearly unequal.
引用
收藏
页码:477 / 490
页数:14
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