6W5V

NPC1-NPC2 complex structure at pH 5.5

6W5V の概要

• エントリーDOI: 10.2210/pdb6w5v/pdb
• EMDBエントリー: 21545 21546 21547 21548 21549
• 分子名称: NPC intracellular cholesterol transporter 1, NPC intracellular cholesterol transporter 2, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• 機能のキーワード: cholesterol lysosome, transport protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 169672.48

構造登録者

Yan, N.,Qian, H.W.,Wu, X.L. (登録日: 2020-03-13, 公開日: 2020-06-17, 最終更新日: 2025-05-21)

主引用文献

Qian, H.,Wu, X.,Du, X.,Yao, X.,Zhao, X.,Lee, J.,Yang, H.,Yan, N.
Structural Basis of Low-pH-Dependent Lysosomal Cholesterol Egress by NPC1 and NPC2.
Cell, 182:98-111.e18, 2020

PubMed Abstract: Lysosomal cholesterol egress requires two proteins, NPC1 and NPC2, whose defects are responsible for Niemann-Pick disease type C (NPC). Here, we present systematic structural characterizations that reveal the molecular basis for low-pH-dependent cholesterol delivery from NPC2 to the transmembrane (TM) domain of NPC1. At pH 8.0, similar structures of NPC1 were obtained in nanodiscs and in detergent at resolutions of 3.6 Å and 3.0 Å, respectively. A tunnel connecting the N-terminal domain (NTD) and the transmembrane sterol-sensing domain (SSD) was unveiled. At pH 5.5, the NTD exhibits two conformations, suggesting the motion for cholesterol delivery to the tunnel. A putative cholesterol molecule is found at the membrane boundary of the tunnel, and TM2 moves toward formation of a surface pocket on the SSD. Finally, the structure of the NPC1-NPC2 complex at 4.0 Å resolution was obtained at pH 5.5, elucidating the molecular basis for cholesterol handoff from NPC2 to NPC1(NTD).

PubMed: 32544384
DOI: 10.1016/j.cell.2020.05.020

実験手法

ELECTRON MICROSCOPY (4 Å)