Winkler, MBL, Kidmose, RT, Szomek, M et al. (5 more authors) (2019) Structural Insight into Eukaryotic Sterol Transport through Niemann-Pick Type C Proteins. Cell, 179 (2). 485-497.e18. ISSN 0092-8674
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.
Metadata
Item Type: | Article |
---|---|
Authors/Creators: |
|
Copyright, Publisher and Additional Information: | © 2019 Elsevier Inc. This is an author produced version of a article published in Cell. Uploaded in accordance with the publisher's self-archiving policy. |
Dates: |
|
Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Biomedical Sciences (Leeds) The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > Cryo EM, Image Processing (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 06 Sep 2019 10:56 |
Last Modified: | 20 Oct 2020 18:02 |
Status: | Published |
Publisher: | Elsevier |
Identification Number: | 10.1016/j.cell.2019.08.038 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:150541 |
Download
Filename: final_merged_accepted_manuscript_for_open_access_12mo_embargo_with_licence.pdf
Licence: CC-BY-NC-ND 4.0