Structural insights into the voltage and phospholipid activation of the mammalian TPC1 channel

She Ji; Guo Jiangtao; Chen Qingfeng; Zeng Weizhong; Jiang Youxing; Bai Xiao-chen

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Structural insights into the voltage and phospholipid activation of the mammalian TPC1 channel

机译：对哺乳动物TPC1通道的电压和磷脂激活的结构见解

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The organellar two-pore channel (TPC) functions as a homodimer, in which each subunit contains two homologous Shaker-like six-transmembrane (6-TM)-domain repeats(1). TPCs belong to the voltage-gated ion channel superfamily(2) and are ubiquitously expressed in animals and plants(3,4). Mammalian TPC1 and TPC2 are localized at the endolysosomal membrane, and have critical roles in regulating the physiological functions of these acidic organelles(5-7). Here we present electron cryo-microscopy structures of mouse TPC1 (MmTPC1)-a voltage-dependent, phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5) P-2)-activated Na+-selective channelin both the apo closed state and ligand-bound open state. Combined with functional analysis, these structures provide comprehensive structural insights into the selectivity and gating mechanisms of mammalian TPC channels. The channel has a coin-slot-shaped ion pathway in the filter that defines the selectivity of mammalian TPCs. Only the voltage-sensing domain from the second 6-TM domain confers voltage dependence on MmTPC1. Endolysosome-specific PtdIns(3,5) P2 binds to the first 6-TM domain and activates the channel under conditions of depolarizing membrane potential. Structural comparisons between the apo and PtdIns(3,5) P-2-bound structures show the interplay between voltage and ligand in channel activation. These MmTPC1 structures reveal lipid binding and regulation in a 6-TM voltage-gated channel, which is of interest in light of the emerging recognition of the importance of phosphoinositide regulation of ion channels.

机译：细胞器双孔通道（TPC）充当同源二聚体，其中每个亚基包含两个同源的Shaker样六跨膜（6-TM）结构域重复序列（1）。 TPC属于电压门控离子通道超家族（2），在动物和植物中普遍存在（3,4）。哺乳动物TPC1和TPC2定位在溶酶体膜上，在调节这些酸性细胞器的生理功能中起关键作用（5-7）。在这里我们介绍了小鼠TPC1（MmTPC1）-电压依赖性磷脂酰肌醇3,5-二磷酸（PtdIns（3,5）P-2）激活的Na +选择性通道在apo闭合状态和配体中的电子冷冻显微镜结构绑定打开状态。结合功能分析，这些结构为哺乳动物TPC通道的选择性和门控机制提供了全面的结构见解。该通道在过滤器中具有一个硬币槽形的离子通道，该通道定义了哺乳动物TPC的选择性。仅来自第二个6-TM域的电压感测域赋予MmTPC1电压依赖性。内溶酶体特异性PtdIns（3,5）P2与第一个6-TM结构域结合并在去极化膜电位的条件下激活通道。 apo和PtdIns（3,5）P-2-结合结构之间的结构比较表明，通道激活中电压和配体之间存在相互作用。这些MmTPC1结构揭示了6-TM电压门控通道中的脂质结合和调节，鉴于人们逐渐认识到磷酸肌醇调节离子通道的重要性，这是令人感兴趣的。

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《Nature》 |2018年第7699期|130-134|共5页
作者
She Ji; Guo Jiangtao; Chen Qingfeng; Zeng Weizhong; Jiang Youxing; Bai Xiao-chen;
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作者单位

Univ Texas Southwestern Med Ctr Dallas, Dept Physiol, Dallas, TX 75390 USA;

Zhejiang Univ, Sch Med, Dept Biophys, Hangzhou 310058, Zhejiang, Peoples R China;

Univ Texas Southwestern Med Ctr Dallas, Dept Physiol, Dallas, TX 75390 USA;

Univ Texas Southwestern Med Ctr Dallas, Dept Physiol, Dallas, TX 75390 USA;

Univ Texas Southwestern Med Ctr Dallas, Dept Physiol, Dallas, TX 75390 USA;

Univ Texas Southwestern Med Ctr Dallas, Dept Biophys, Dallas, TX 75390 USA;

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收录信息美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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5. Modulation of voltage-gated potassium and sodium channels by halogenated general anesthetics: Structural and biophysical insights into the mechanisms of action. [D] . Barber, Annika F. 2013

机译：卤代全身麻醉药对电压门控钾离子和钠离子通道的调节：作用机理的结构和生物物理见解。
6. Structural insights into the voltage and phospholipid activation of mammalian TPC1 channel [O] . Ji She, Jiangtao Guo, Qingfeng Chen, -1

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7. Faculty Opinions recommendation of Structural insights into the voltage and phospholipid activation of the mammalian TPC1 channel. [O] . Bettina Böttcher, Jan-Hagen Krohn 2018

机译：教师意见建议结构见解对哺乳动物TPC1通道的电压和磷脂激活。

Structural insights into the voltage and phospholipid activation of the mammalian TPC1 channel

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