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Structural insight into eukaryotic sterol transport through Niemann-Pick Type C proteins

DOI: 10.1016/j.cell.2019.08.038 DOI Help

Authors: Mikael B. L. Winkler (Aarhus University) , Rune T. Kidmose (Aarhus University) , Maria Szomek (University of Southern Denmark) , Katja Thaysen (University of Southern Denmark) , Shaun Rawson (University of Leeds) , Stephen P. Muench (University of Leeds) , Daniel Wüstner (University of Southern Denmark) , Bjorn Panyella Pedersen (Aarhus University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Cell

State: Published (Approved)
Published: October 2019
Diamond Proposal Number(s): 13062 , 17844 , 21288 , 21404

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.

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

Subject Areas: Biology and Bio-materials

Diamond Offline Facilities: Electron Bio-Imaging Centre (eBIC)
Instruments: I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography , Krios I-Titan Krios I at Diamond , Krios II-Titan Krios II at Diamond

Other Facilities: EM Microscopes at Aarhus university and Leeds university; SLS; DESY; MaxIV; ESRF