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FEBS J. 2018 Jan;285(2):233-243. doi: 10.1111/febs.14154. Epub 2017 Jul 25.

On the structure and mechanism of two-pore channels.

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Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA.


In eukaryotes, two-pore channels (TPC1-3) comprise a family of ion channels that regulate the conductance of Na+ and Ca2+ 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)P2 ). 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.


ion channels; lysosome; membrane protein; structure; transport

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