Cryo-EM structures of the mammalian endo-lysosomal TRPML1 channel elucidate the combined regulation mechanism.
Cryo-EM structures of the mammalian endo-lysosomal TRPML1 channel elucidate the combined regulation mechanism.
复制标题
哺乳动物内溶酶体 TRPML1 通道的冷冻电镜结构阐明了联合调节机制
DOI：
10.1007/s13238-017-0476-5
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发表时间：
2017-11
期刊：
影响因子：
21.1
通讯作者：
Yang M
中科院分区：
文献类型：
--
作者：
Zhang S;Li N;Zeng W;Gao N;Yang M
TRPML 1通道是一种非选择性的第二组瞬时受体电位（TRP）通道，具有Ca 2+渗透性。TRPML 1主要定位于所有哺乳动物细胞类型的晚期内体和溶酶体中，在内吞、膜运输和溶酶体生物合成过程中不可或缺。TRPML 1的突变会导致严重的溶酶体贮积症，称为IV型粘脂沉积症（MLIV）。在本研究中，我们确定了冷冻电镜（cryo-EM）结构ofMus musculusTRPML 1（mTRPML 1）在脂质纳米盘和Amphipols。Amphipols中mTRPML 1的两种不同状态被添加到关闭状态中，这可能代表激活和调节后的两种不同确认。多囊蛋白-粘磷脂结构域（PMD）可以感知腔/细胞外刺激，并在胞吞过程中进行“向上移动”运动，从而触发TRPML 1的整体构象变化。基于结构的比较，我们建议TRPML 1调节pH值，Ca 2+，和磷酸肌醇的组合方式，以适应动态的内吞过程。
TRPML1 channel is a non-selective group-2 transient receptor potential (TRP) channel with Ca2+permeability. Located mainly in late endosome and lysosome of all mammalian cell types, TRPML1 is indispensable in the processes of endocytosis, membrane trafficking, and lysosome biogenesis. Mutations of TRPML1 cause a severe lysosomal storage disorder called mucolipidosis type IV (MLIV). In the present study, we determined the cryo-electron microscopy (cryo-EM) structures ofMus musculusTRPML1 (mTRPML1) in lipid nanodiscs and Amphipols. Two distinct states of mTRPML1 in Amphipols are added to the closed state, on which could represent two different confirmations upon activation and regulation. The polycystin-mucolipin domain (PMD) may sense the luminal/extracellular stimuli and undergo a “move upward” motion during endocytosis, thus triggering the overall conformational change in TRPML1. Based on the structural comparisons, we propose TRPML1 is regulated by pH, Ca2+, and phosphoinositides in a combined manner so as to accommodate the dynamic endocytosis process.
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