Structure of mammalian endolysosomal TRPML1 channel in nanodiscs.
Structure of mammalian endolysosomal TRPML1 channel in nanodiscs.
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DOI：
10.1038/nature24035
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发表时间：
2017-10-19
期刊：
影响因子：
64.8
通讯作者：
Jiang Y
中科院分区：
文献类型：
--
作者：
Chen Q;She J;Zeng W;Guo J;Xu H;Bai XC;Jiang Y
瞬时受体电位粘脂蛋白1（TRPML 1）是一种在哺乳动物细胞中广泛表达的内/溶酶体阳离子通道，其功能丧失突变是IV型粘脂沉积症（MLIV）（一种常染色体隐性溶酶体贮积病）的直接原因。在这里，我们提出了单粒子冷冻电子显微镜（cryo-EM）结构的小鼠TRPML 1通道嵌入纳米盘。结合诱变，TRPML 1结构揭示了磷脂酰肌醇二磷酸（PIP 2）结合到通道的N-末端-远离孔-并且S2和S3之间的螺旋-转角-螺旋延伸可能将配体结合耦合到孔开口。紧密堆积的选择性过滤器包含多个离子结合位点，并且保守的酸性残基形成管腔Ca 2+阻断位点，其赋予管腔pH和Ca 2+调节通道电导。管腔连接结构域在通道顶部形成有孔的冠层，提供通向孔的多个管腔离子通道，并且还产生负静电陷阱-优选地用于管腔入口处的二价阳离子。该结构还揭示了封闭通道中两个均匀分布的S4-S5接头构象，为TRPML通道中S4-S5接头介导的PIP 2门控机制提供了结构暗示。
Transient receptor potential mucolipin 1 (TRPML1) is an endo/lysosomal cation channel ubiquitously expressed in mammalian cells and its loss-of-function mutations are the direct cause of Type IV mucolipidosis (MLIV), an autosomal recessive lysosomal storage disease. Here we present the single particle cryo-electron microscopy (cryo-EM) structure of the mouse TRPML1 channel embedded in nanodiscs. Combined with mutagenesis, the TRPML1 structure reveals that phosphatidylinositol bisphosphate (PIP2) binds to the N-terminus of the channel – distal from the pore – and the helix-turn-helix extension between S2 and S3 likely couples ligand binding to pore opening. The tightly packed selectivity filter contains multiple ion binding sites and the conserved acidic residues form the luminal Ca2+ blocking site that confers luminal pH and Ca2+ modulation on channel conductance. A luminal linker domain forms a fenestrated canopy atop the channel, providing multiple luminal ion passages to the pore and also creating a negative electrostatic trap – preferably for divalent cations at the luminal entrance. The structure also reveals two equally distributed S4-S5 linker conformations in the closed channel, providing structural implication for the S4-S5 linker-mediated PIP2 gating mechanism among TRPML channels.
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影响因子：
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作者：
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影响因子：
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发表时间：
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影响因子：
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