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*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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.

Original languageEnglish
JournalCell
Volume179
Issue number2
Pages (from-to)485-497.e18
ISSN0092-8674
DOIs
Publication statusPublished - 3. Oct 2019

Fingerprint

Sterols
Protein C
Membranes
Tunnels
Protons
Cryoelectron Microscopy
Crystallography
Yeast
Electron microscopy
Saccharomyces cerevisiae
Membrane Proteins
Homeostasis
Mutation

Keywords

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

Cite this

Winkler, M. B. L., Kidmose, R. T., Szomek, M., Thaysen, K., Rawson, S., Muench, S. P., ... Pedersen, B. P. (2019). Structural Insight into Eukaryotic Sterol Transport through Niemann-Pick Type C Proteins. Cell, 179(2), 485-497.e18. https://doi.org/10.1016/j.cell.2019.08.038
Winkler, Mikael B.L. ; Kidmose, Rune T. ; Szomek, Maria ; Thaysen, Katja ; Rawson, Shaun ; Muench, Stephen P. ; Wüstner, Daniel ; Pedersen, Bjørn Panyella. / Structural Insight into Eukaryotic Sterol Transport through Niemann-Pick Type C Proteins. In: Cell. 2019 ; Vol. 179, No. 2. pp. 485-497.e18.
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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 {\AA} 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.",
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Winkler, MBL, Kidmose, RT, Szomek, M, Thaysen, K, Rawson, S, Muench, SP, Wüstner, D & Pedersen, BP 2019, 'Structural Insight into Eukaryotic Sterol Transport through Niemann-Pick Type C Proteins', Cell, vol. 179, no. 2, pp. 485-497.e18. https://doi.org/10.1016/j.cell.2019.08.038

Structural Insight into Eukaryotic Sterol Transport through Niemann-Pick Type C Proteins. / Winkler, Mikael B.L.; Kidmose, Rune T.; Szomek, Maria; Thaysen, Katja; Rawson, Shaun; Muench, Stephen P.; Wüstner, Daniel; Pedersen, Bjørn Panyella.

In: Cell, Vol. 179, No. 2, 03.10.2019, p. 485-497.e18.

Research output: Contribution to journalJournal articleResearchpeer-review

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AU - Winkler, Mikael B.L.

AU - Kidmose, Rune T.

AU - Szomek, Maria

AU - Thaysen, Katja

AU - Rawson, Shaun

AU - Muench, Stephen P.

AU - Wüstner, Daniel

AU - Pedersen, Bjørn Panyella

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N2 - 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.

AB - 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.

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KW - lipid trafficking

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KW - NPC2

KW - sterol homeostasis

KW - sterol membrane integration

KW - X-ray crystallography

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VL - 179

SP - 485-497.e18

JO - Cell

JF - Cell

SN - 0092-8674

IS - 2

ER -

Winkler MBL, Kidmose RT, Szomek M, Thaysen K, Rawson S, Muench SP et al. Structural Insight into Eukaryotic Sterol Transport through Niemann-Pick Type C Proteins. Cell. 2019 Oct 3;179(2):485-497.e18. https://doi.org/10.1016/j.cell.2019.08.038