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 language | English |
|---|---|
| Journal | Cell |
| Volume | 179 |
| Issue number | 2 |
| Pages (from-to) | 485-497.e18 |
| ISSN | 0092-8674 |
| DOIs | |
| Publication status | Published - 3. Oct 2019 |
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Keywords
- cryo-EM
- lipid trafficking
- NCR1
- Niemann-Pick type C proteins
- NPC1
- NPC2
- sterol homeostasis
- sterol membrane integration
- X-ray crystallography
Cite this
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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, 03.10.2019, p. 485-497.e18.Research output: Contribution to journal › Journal article › Research › peer-review
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
PY - 2019/10/3
Y1 - 2019/10/3
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.
KW - cryo-EM
KW - lipid trafficking
KW - NCR1
KW - Niemann-Pick type C proteins
KW - NPC1
KW - NPC2
KW - sterol homeostasis
KW - sterol membrane integration
KW - X-ray crystallography
U2 - 10.1016/j.cell.2019.08.038
DO - 10.1016/j.cell.2019.08.038
M3 - Journal article
C2 - 31543266
AN - SCOPUS:85072735334
VL - 179
SP - 485-497.e18
JO - Cell
JF - Cell
SN - 0092-8674
IS - 2
ER -