6C96

Cryo-EM structure of mouse TPC1 channel in the apo state

6C96 の概要

• エントリーDOI: 10.2210/pdb6c96/pdb
• EMDBエントリー: 7434
• 分子名称: Two pore calcium channel protein 1, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (4 entities in total)
• 機能のキーワード: ion channel, membrane protein
• 由来する生物種: Mus musculus (Mouse)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 192166.71

構造登録者

She, J.,Guo, J.,Chen, Q.,Bai, X.,Jiang, Y. (登録日: 2018-01-25, 公開日: 2018-04-04, 最終更新日: 2024-11-06)

主引用文献

She, J.,Guo, J.,Chen, Q.,Zeng, W.,Jiang, Y.,Bai, X.C.
Structural insights into the voltage and phospholipid activation of the mammalian TPC1 channel.
Nature, 556:130-134, 2018

PubMed 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 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.

PubMed: 29562233
DOI: 10.1038/nature26139

実験手法

ELECTRON MICROSCOPY (3.4 Å)