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Cell. 2019 Oct 3;179(2):485-497.e18. doi: 10.1016/j.cell.2019.08.038. Epub 2019 Sep 19.

Structural Insight into Eukaryotic Sterol Transport through Niemann-Pick Type C Proteins.

Author information

1
Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10, Aarhus C 8000, Denmark.
2
Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, Odense M 5230, Denmark.
3
School of Biomedical Sciences and The Astbury Centre for Structural and Molecular Biology, University of Leeds, Leeds LS2 9JT, UK.
4
Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10, Aarhus C 8000, Denmark; Aarhus Institute of Advanced Studies, Aarhus University, Høegh-Guldbergs Gade 6B, Aarhus C 8000, Denmark. Electronic address: bpp@mbg.au.dk.

Abstract

Niemann-Pick type C (NPC) proteins are essential for sterol homeostasis, believed to drive sterol integration into the lysosomal membrane before redistribution to other cellular membranes. Here, using a combination of crystallography, cryo-electron microscopy, and biochemical and in vivo studies on the Saccharomyces cerevisiae NPC system (NCR1 and NPC2), we present a framework for sterol membrane integration. Sterols are transferred between hydrophobic pockets of vacuolar NPC2 and membrane-protein NCR1. NCR1 has its N-terminal domain (NTD) positioned to deliver a sterol to a tunnel connecting NTD to the luminal membrane leaflet 50 Å away. A sterol is caught inside this tunnel during transport, and a proton-relay network of charged residues in the transmembrane region is linked to this tunnel supporting a proton-driven transport mechanism. We propose a model for sterol integration that clarifies the role of NPC proteins in this essential eukaryotic pathway and that rationalizes mutations in patients with Niemann-Pick disease type C.

KEYWORDS:

NCR1; NPC1; NPC2; Niemann-Pick type C proteins; X-ray crystallography; cryo-EM; lipid trafficking; sterol homeostasis; sterol membrane integration

PMID:
31543266
DOI:
10.1016/j.cell.2019.08.038

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