Journal
CELL
Volume 182, Issue 1, Pages 98-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2020.05.020
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Funding
- Princeton Center for Complex Materials
- National Science Foundation (NSF)-MRSEC program [DMR-1420541]
- Ara Parseghian Medical Research Foundation
- New Jersey Council for Cancer Research
- National Health and Medical Research Council, Australia [1141939]
- Innovation Fund for New Ideas in the Natural Sciences, SEAS Innovation Research Grant
- Shirley M. Tilghman endowed professorship from Princeton University
- National Health and Medical Research Council of Australia [1141939] Funding Source: NHMRC
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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 angstrom and 3.0 angstrom, 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 angstrom resolution was obtained at pH 5.5, elucidating the molecular basis for cholesterol handoff from NPC2 to NPC1(NTD).
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