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

Mikael B L Winkler, Rune T Kidmose, Maria Szomek, Katja Thaysen, Shaun Rawson, Stephen P Muench, Daniel Wüstner, Bjørn Panyella Pedersen

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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
Pages (from-to)485-497
Publication statusPublished - Oct 2019


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


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