- EMDB-7434: Cryo-EM structure of mouse TPC1 channel in the apo state -
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Basic information
Entry
Database: EMDB / ID: EMD-7434
Title
Cryo-EM structure of mouse TPC1 channel in the apo state
Map data
TPC1 channel in the apo state
Sample
Organelle or cellular component: Apo mouse TPC1
Protein or peptide: Two pore calcium channel protein 1
Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Ligand: SODIUM ION
Function / homology
Function and homology information
endolysosome / intracellularly phosphatidylinositol-3,5-bisphosphate-gated monatomic cation channel activity / ligand-gated sodium channel activity / NAADP-sensitive calcium-release channel activity / voltage-gated monoatomic ion channel activity / Stimuli-sensing channels / regulation of monoatomic ion transmembrane transport / phosphatidylinositol-3,5-bisphosphate binding / syntaxin binding / voltage-gated sodium channel activity ...endolysosome / intracellularly phosphatidylinositol-3,5-bisphosphate-gated monatomic cation channel activity / ligand-gated sodium channel activity / NAADP-sensitive calcium-release channel activity / voltage-gated monoatomic ion channel activity / Stimuli-sensing channels / regulation of monoatomic ion transmembrane transport / phosphatidylinositol-3,5-bisphosphate binding / syntaxin binding / voltage-gated sodium channel activity / sodium ion transmembrane transport / positive regulation of autophagy / endocytosis involved in viral entry into host cell / recycling endosome membrane / early endosome membrane / endosome membrane / lysosomal membrane / protein homodimerization activity / identical protein binding / membrane Similarity search - Function
Two pore channel protein 1 / Voltage-dependent channel domain superfamily / Ion transport domain / Ion transport protein Similarity search - Domain/homology
National Institutes of Health/National Center for Research Resources (NIH/NCRR)
GM079179
United States
Howard Hughes Medical Institute (HHMI)
United States
Welch Foundation
I-1578
United States
Virginia Murchison Linthicum Scholar in Medical Research fund
United States
Cancer Prevention and Research Institute of Texas (CPRIT)
United States
Citation
Journal: Nature / Year: 2018 Title: Structural insights into the voltage and phospholipid activation of the mammalian TPC1 channel. Authors: Ji She / Jiangtao Guo / Qingfeng Chen / Weizhong Zeng / Youxing Jiang / Xiao-Chen Bai / Abstract: 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. TPCs belong to the voltage-gated ion ...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. TPCs belong to the voltage-gated ion channel superfamily and are ubiquitously expressed in animals and plants. Mammalian TPC1 and TPC2 are localized at the endolysosomal membrane, and have critical roles in regulating the physiological functions of these acidic organelles. Here we present electron cryo-microscopy structures of mouse TPC1 (MmTPC1)-a voltage-dependent, phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P)-activated Na-selective channel-in 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)P 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-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.
History
Deposition
Jan 25, 2018
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Header (metadata) release
Apr 4, 2018
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Map release
Apr 4, 2018
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Update
Jul 29, 2020
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Current status
Jul 29, 2020
Processing site: RCSB / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
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