Structures and gating mechanisms of human bestrophin anion channels.
Structures and gating mechanisms of human bestrophin anion channels.
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DOI：
10.1038/s41467-022-31437-7
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发表时间：
2022-07-04
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
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Bestrophin-1（Best 1）和Bestrophin-2（Best 2）是钙（Ca 2+）激活氯（Cl-）通道的Bestrophin家族的两个成员，在眼部生理学中发挥重要作用，并具有直接的病理相关性。在这里，我们报告了野生型人类Best 1和Best 2在不同状态下的冷冻电镜结构，分辨率高达1.8 μ m。钙离子结合的Best 1结构说明部分开放的构象在两个Ca 2+依赖的门的通道，在观察到的完全开放的构象在钙离子结合的Best 2，这是在雅阁与Best 1进行的电生理记录中的电流显着较小。闭合和开放状态的比较揭示了C-末端自动抑制段（AS），其通过以原聚体间方式围绕通道外周缠绕而同心地收缩通道，并且必须被释放以允许通道开放。我们的研究结果表明，从Best 1和Best 2中去除AS会导致具有相似活性的截短突变体，而在Best 1和Best 2之间交换AS会导致具有交换活性的嵌合突变体，这是AS在确定雌激素之间的特异性中的关键作用。Bestrophin通道对于眼睛的生理学是至关重要的。在这里，作者报告cryo-EM结构的人类雌激素在各种状态下，在高达1.8 μ m的分辨率，揭示旁系特异性的功能，渗透的分子机制的基础。
Bestrophin-1 (Best1) and bestrophin-2 (Best2) are two members of the bestrophin family of calcium (Ca2+)-activated chloride (Cl−) channels with critical involvement in ocular physiology and direct pathological relevance. Here, we report cryo-EM structures of wild-type human Best1 and Best2 in various states at up to 1.8 Å resolution. Ca2+-bound Best1 structures illustrate partially open conformations at the two Ca2+-dependent gates of the channels, in contrast to the fully open conformations observed in Ca2+-bound Best2, which is in accord with the significantly smaller currents conducted by Best1 in electrophysiological recordings. Comparison of the closed and open states reveals a C-terminal auto-inhibitory segment (AS), which constricts the channel concentrically by wrapping around the channel periphery in an inter-protomer manner and must be released to allow channel opening. Our results demonstrate that removing the AS from Best1 and Best2 results in truncation mutants with similar activities, while swapping the AS between Best1 and Best2 results in chimeric mutants with swapped activities, underlying a key role of the AS in determining paralog specificity among bestrophins. Bestrophin channels are critical for physiology of the eye. Here, authors report cryo-EM structures of human bestrophins in various states at up to 1.8 Å resolution, revealing paralog-specific features that underlie molecular mechanisms of permeation.
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影响因子：
48
作者：
Barad BA;Echols N;Wang RY;Cheng Y;DiMaio F;Adams PD;Fraser JS
通讯作者：
Fraser JS
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
4.4
作者：
Bakall, Benjamin;McLaughlin, Precious;Marmorstein, Alan D.
通讯作者：
Marmorstein, Alan D.
人 Bestropin1 中的双 Ca2 依赖性门是功能获得性突变致病机制的基础
影响因子：
5.9
作者：
Ji, Changyi;Kittredge, Alec;Yang, Tingting
通讯作者：
Yang, Tingting
DOI：
10.1107/s2059798318006551
发表时间：
2018-06-01
期刊：
Acta crystallographica. Section D, Structural biology
影响因子：
--
作者：
Afonine PV;Poon BK;Read RJ;Sobolev OV;Terwilliger TC;Urzhumtsev A;Adams PD
通讯作者：
Adams PD