Role of Hydrophobic Amino-Acid Side-Chains in the Narrow Selectivity Filter of the CFTR Chloride Channel Pore in Conductance and Selectivity.

IF 2.3 4区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Journal of Membrane Biology Pub Date : 2023-12-01 Epub Date: 2023-10-12 DOI:10.1007/s00232-023-00294-w
Paul Linsdell
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引用次数: 0

Abstract

Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. Structural analysis of CFTR has identified a narrow, hydrophobic region close to the extracellular end of the open channel pore that may function as a selectivity filter. The present study combines comprehensive mutagenesis of hydrophobic amino-acid side-chains within the selectivity filter with functional evaluation of channel Cl- conductance and anion selectivity. Among these hydrophobic amino-acids, one (F337) appears to play a dominant role in determining both conductance and selectivity. Anion selectivity appears to depend on both side-chain size and hydrophobicity at this position. In contrast, conductance is disrupted by all F337 mutations, suggesting that unique interactions between permeating Cl- ions and the native phenylalanine side-chain are important for conductance. Surprisingly, a positively charged lysine side-chain can be substituted for several hydrophobic residues within the selectivity filter (including F337) with only minor changes in pore function, arguing against a crucial role for overall hydrophobicity. These results suggest that localized interactions between permeating anions and amino-acid side-chains within the selectivity filter may be more important in determining pore functional properties than are global features such as overall hydrophobicity.

Abstract Image

疏水性氨基酸侧链在CFTR氯化物通道孔的窄选择性过滤器中的导电性和选择性作用。
囊性纤维化是由囊性纤维化跨膜电导调节因子(CFTR)阴离子通道的突变引起的。CFTR的结构分析已经确定了一个靠近开放通道孔细胞外端的狭窄疏水区域,该区域可能起到选择性过滤器的作用。本研究将选择性过滤器内疏水性氨基酸侧链的综合诱变与通道氯电导和阴离子选择性的功能评估相结合。在这些疏水性氨基酸中,一种(F337)似乎在决定电导和选择性方面发挥着主导作用。阴离子选择性似乎取决于该位置的侧链大小和疏水性。相反,电导被所有F337突变破坏,这表明渗透的Cl-离子和天然苯丙氨酸侧链之间的独特相互作用对电导很重要。令人惊讶的是,带正电的赖氨酸侧链可以取代选择性过滤器(包括F337)内的几个疏水残基,孔功能只有微小的变化,这与整体疏水性的关键作用相反。这些结果表明,在确定孔功能性质方面,选择性过滤器内渗透阴离子和氨基酸侧链之间的局部相互作用可能比整体特征(如整体疏水性)更重要。
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
Journal of Membrane Biology
Journal of Membrane Biology 生物-生化与分子生物学
CiteScore
4.80
自引率
4.20%
发文量
63
审稿时长
6-12 weeks
期刊介绍: The Journal of Membrane Biology is dedicated to publishing high-quality science related to membrane biology, biochemistry and biophysics. In particular, we welcome work that uses modern experimental or computational methods including but not limited to those with microscopy, diffraction, NMR, computer simulations, or biochemistry aimed at membrane associated or membrane embedded proteins or model membrane systems. These methods might be applied to study topics like membrane protein structure and function, membrane mediated or controlled signaling mechanisms, cell-cell communication via gap junctions, the behavior of proteins and lipids based on monolayer or bilayer systems, or genetic and regulatory mechanisms controlling membrane function. Research articles, short communications and reviews are all welcome. We also encourage authors to consider publishing ''negative'' results where experiments or simulations were well performed, but resulted in unusual or unexpected outcomes without obvious explanations. While we welcome connections to clinical studies, submissions that are primarily clinical in nature or that fail to make connections to the basic science issues of membrane structure, chemistry and function, are not appropriate for the journal. In a similar way, studies that are primarily descriptive and narratives of assays in a clinical or population study are best published in other journals. If you are not certain, it is entirely appropriate to write to us to inquire if your study is a good fit for the journal.
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