Send to

Choose Destination
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

Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10, Aarhus C 8000, Denmark.
Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, Odense M 5230, Denmark.
School of Biomedical Sciences and The Astbury Centre for Structural and Molecular Biology, University of Leeds, Leeds LS2 9JT, UK.
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:


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.


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


Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center