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Structural Basis of Low-pH-Dependent Lysosomal Cholesterol Egress by NPC1 and NPC2

Qian, Hongwu, Wu, Xuelan, Du, Ximing, Yao, Xia, Zhao, Xin, Lee, Joyce, Yang, Hongyuan, Yan, Nieng·2020·Cell
DOI 10.1016/j.cell.2020.05.020
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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).

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Metadata

Authors
Qian, H., Wu, X., Du, X., Yao, X., Zhao, X., Lee, J., Yang, H., & Yan, N.
Venue
Cell
Publisher
Elsevier BV
Published
2020-07
Volume
182
Issue
1
Pages
98-111.e18
ISSN
0092-8674
DOI
10.1016/j.cell.2020.05.020
Cited by
185
References
4
Language
en
Licence
Funders
  • Ara Parseghian Medical Research Foundation
  • National Health and Medical Research Council
  • Princeton University
  • National Science Foundation

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