Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA.
FEBS J. 2018 Jan;285(2):233-243. doi: 10.1111/febs.14154. Epub 2017 Jul 25.
In eukaryotes, two-pore channels (TPC1-3) comprise a family of ion channels that regulate the conductance of Na and Ca ions across cellular membranes. TPC1-3 form endolysosomal channels, but TPC3 can also function in the plasma membrane. TPC1/3 are voltage-gated channels, but TPC2 opens in response to binding endolysosome-specific lipid phosphatidylinositol-3,5-diphosphate (PI(3,5)P ). Filoviruses, such as Ebola, exploit TPC-mediated ion release as a means of escape from the endolysosome during infection. Antagonists that block TPC1/2 channel conductance abrogate filoviral infections. TPC1/2 form complexes with the mechanistic target of rapamycin complex 1 (mTORC1) at the endolysosomal surface that couple cellular metabolic state and cytosolic nutrient concentrations to the control of membrane potential and pH. We determined the X-ray structure of TPC1 from Arabidopsis thaliana (AtTPC1) to 2.87Å resolution-one of the two first reports of a TPC channel structure. Here, we summarize these findings and the implications that the structure may have for understanding endolysosomal control mechanisms and their role in human health.
在真核生物中，双孔通道（TPC1-3）构成了一类离子通道家族，它们调节跨细胞膜的 Na 和 Ca 离子的电导率。TPC1-3 形成内体溶酶体通道，但 TPC3 也可以在质膜中发挥作用。TPC1/3 是电压门控通道，但 TPC2 响应结合内体溶酶体特异性脂质磷脂酰肌醇-3,5-二磷酸（PI(3,5)P ）而打开。丝状病毒，如埃博拉病毒，利用 TPC 介导的离子释放作为在感染过程中从内体溶酶体逃逸的一种手段。阻断 TPC1/2 通道电导的拮抗剂可消除丝状病毒感染。TPC1/2 在内体溶酶体表面与雷帕霉素靶蛋白复合物 1（mTORC1）形成复合物，将细胞代谢状态和细胞质营养浓度与膜电位和 pH 的控制联系起来。我们以 2.87Å 的分辨率确定了来自拟南芥的 TPC1（AtTPC1）的 X 射线结构——这是首次报道的两种 TPC 通道结构之一。在这里，我们总结了这些发现及其对理解内体溶酶体控制机制及其在人类健康中的作用的意义。
