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Mikael Winkler

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

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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, e18, 10.2019, p. 485-497.

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

Harvard

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, e18, pp. 485-497. https://doi.org/10.1016/j.cell.2019.08.038

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Vancouver

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;179(2):485-497. e18. https://doi.org/10.1016/j.cell.2019.08.038

Author

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.

Bibtex

@article{06e758d97f0043b185bb2ea033cc05e9,
title = "Structural Insight into Eukaryotic Sterol Transport through Niemann-Pick Type C Proteins",
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.",
author = "Winkler, {Mikael B L} and Kidmose, {Rune T} and Maria Szomek and Katja Thaysen and Shaun Rawson and Muench, {Stephen P} and Daniel W{\"u}stner and Pedersen, {Bj{\o}rn Panyella}",
note = "Copyright {\circledC} 2019 Elsevier Inc. All rights reserved.",
year = "2019",
month = "10",
doi = "10.1016/j.cell.2019.08.038",
language = "English",
volume = "179",
pages = "485--497",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "2",

}

RIS

TY - JOUR

T1 - Structural Insight into Eukaryotic Sterol Transport through Niemann-Pick Type C Proteins

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

N1 - Copyright © 2019 Elsevier Inc. All rights reserved.

PY - 2019/10

Y1 - 2019/10

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.

U2 - 10.1016/j.cell.2019.08.038

DO - 10.1016/j.cell.2019.08.038

M3 - Journal article

C2 - 31543266

VL - 179

SP - 485

EP - 497

JO - Cell

JF - Cell

SN - 0092-8674

IS - 2

M1 - e18

ER -