6W5R

NPC1 structure in Nanodisc

Summary for 6W5R

• Entry DOI: 10.2210/pdb6w5r/pdb
• EMDB information: 21545 21546 21547 21548 21549
• Descriptor: NPC intracellular cholesterol transporter 1, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, beta-D-mannopyranose-(1-3)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• Functional Keywords: cholesterol lysosome, transport protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 150483.10

Authors

Yan, N.,Qian, H.W.,Wu, X.L. (deposition date: 2020-03-13, release date: 2020-06-17, Last modification date: 2025-05-28)

Primary citation

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

Experimental method

ELECTRON MICROSCOPY (3.6 Å)