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

TitleStructural Basis of Low-pH-Dependent Lysosomal Cholesterol Egress by NPC1 and NPC2.
Publication TypeJournal Article
Year of Publication2020
AuthorsQian, H, Wu, X, Du, X, Yao, X, Zhao, X, Lee, J, Yang, H, Yan, N
Date Published2020 Jul 09
KeywordsAmino Acid Sequence, Animals, Cell Line, Cholesterol, Green Fluorescent Proteins, Humans, Hydrogen-Ion Concentration, Intracellular Signaling Peptides and Proteins, Lysosomes, Models, Molecular, Nanoparticles, Niemann-Pick C1 Protein, Protein Domains, Structural Homology, Protein, Structure-Activity Relationship, Vesicular Transport Proteins

<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 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).</p>

Alternate JournalCell
PubMed ID32544384