@article{168431,
  author = {Hongwu Qian and Xuelan Wu and Ximing Du and Xia Yao and Xin Zhao and Joyce Lee and Hongyuan Yang and Nieng Yan},
  title = {Structural Basis of Low-pH-Dependent Lysosomal Cholesterol Egress by NPC1 and NPC2},
  abstract = {<p>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\&nbsp;{\r A} and 3.0\&nbsp;{\r A}, 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\&nbsp;{\r A} resolution was obtained at pH 5.5, elucidating the molecular basis for cholesterol handoff from NPC2 to NPC1(NTD).</p>
},
  year = {2020},
  journal = {Cell},
  pages = {06/2020},
  issn = {1097-4172},
  doi = {10.1016/j.cell.2020.05.020},
  language = {eng},
}