Structure of the ancient TRPY1 channel from Saccharomyces cerevisiae reveals mechanisms of modulation by lipids and calcium.
Structure of the ancient TRPY1 channel from Saccharomyces cerevisiae reveals mechanisms of modulation by lipids and calcium.
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DOI：
10.1016/j.str.2021.08.003
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发表时间：
2022-01-06
期刊：
影响因子：
--
通讯作者：
Moiseenkova-Bell VY
中科院分区：
文献类型：
--
作者：
Ahmed T;Nisler CR;Fluck EC 3rd;Walujkar S;Sotomayor M;Moiseenkova-Bell VY
瞬时受体电位（TRP）通道在真菌中作为机械敏感的渗透调节剂出现。酿酒酵母（Saccharomyces cerevisiae）液泡TRP酵母1 （TRPY1）是真菌中研究最多的TRP通道，但通道调节的结构和细节尚不清楚。在这里，我们描述了3.1 Å分辨率下TRPY1在封闭状态下的全长低温电镜结构。与其他真核TRP通道相比，尽管该结构包含一个进化上保守的典型跨膜结构域，但其胞质N端和c端显示出独特的结构褶皱。我们确定了一个抑制性磷脂酰肌醇3-磷酸（PI(3)P）脂结合位点，以及两个Ca2+结合位点：一个细胞质位点，与通道激活有关，一个空泡腔位点，与抑制有关。这些发现，加上来自微秒级分子动力学模拟和TRPY1开放状态模型的数据，为脂质和Ca2+调制TRPY1通道的基础以及TRP通道的分子进化提供了见解。Ahmed等人描述了封闭状态下酿酒酵母野生型TRPY1通道的高分辨率结构。作者在一个抑制PI(3)P脂质和两个钙离子存在的情况下捕获了该结构，一个参与抑制，另一个参与激活通道。
Transient Receptor Potential (TRP) channels emerged in fungi as mechanosensitive osmoregulators. The Saccharomyces cerevisiae vacuolar TRP yeast 1 (TRPY1) is the most studied TRP channel from fungi, but the structure and details of channel modulation remain elusive. Here, we describe the full-length cryo-electron microscopy structure of TRPY1 at 3.1 Å resolution in a closed state. The structure, despite containing an evolutionarily conserved and archetypical transmembrane domain, reveals distinctive structural folds for the cytosolic N- and C-termini, compared to other eukaryotic TRP channels. We identify an inhibitory phosphatidylinositol 3-phosphate (PI(3)P) lipid-binding site, along with two Ca2+-binding sites: a cytosolic site, implicated in channel activation and a vacuolar lumen site, implicated in inhibition. These findings, together with data from microsecond-long molecular dynamics simulations and a model of a TRPY1 open state, provide insights into the basis of TRPY1 channel modulation by lipids and Ca2+, and the molecular evolution of TRP channels. Ahmed et al. describes a high-resolution structure of wild-type TRPY1 channel from Saccharomyces cerevisiae in a closed state. The authors captured the structure in the presence of one inhibitory PI(3)P lipid and two calcium ions, one involved in inhibition and the other in activation of the channel.
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影响因子：
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作者：
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DOI：
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发表时间：
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