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

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Mikael B L Winkler
  • Rune T Kidmose
  • Maria Szomek, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, 5230 Odense M (Denmark).
  • ,
  • Katja Thaysen, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, 5230 Odense M (Denmark).
  • ,
  • Shaun Rawson, School of Biomedical Sciences and The Astbury Centre for Structural and Molecular Biology, University of Leeds, Leeds LS2 9JT, UK.
  • ,
  • Stephen P Muench, School of Biomedical Sciences and The Astbury Centre for Structural and Molecular Biology, University of Leeds, Leeds LS2 9JT, UK.
  • ,
  • Daniel Wüstner, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, 5230 Odense M (Denmark).
  • ,
  • Bjørn Panyella Pedersen

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.

Original languageEnglish
Article numbere18
JournalCell
Volume179
Issue2
Pages (from-to)485-497
ISSN0092-8674
DOIs
Publication statusPublished - Oct 2019

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