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 |
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Journal | Cell |
Volume | 179 |
Issue number | 2 |
Pages (from-to) | 485-497.e18 |
ISSN | 0092-8674 |
DOIs | |
Publication status | Published - 3. Oct 2019 |
Keywords
- cryo-EM
- lipid trafficking
- NCR1
- Niemann-Pick type C proteins
- NPC1
- NPC2
- sterol homeostasis
- sterol membrane integration
- X-ray crystallography