Structural basis of low-pH-dependent lysosomal cholesterol egress by NPC1 and NPC2

H Qian, X Wu, X Du, X Yao, X Zhao, J Lee, H Yang… - Cell, 2020 - cell.com
H Qian, X Wu, X Du, X Yao, X Zhao, J Lee, H Yang, N Yan
Cell, 2020cell.com
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 …
Summary
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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