6R4N

Crystal structure of S. cerevisia Niemann-Pick type C protein NPC2 with ergosterol bound

Summary for 6R4N

• Entry DOI: 10.2210/pdb6r4n/pdb
• Related: 6R4M
• Descriptor: Phosphatidylglycerol/phosphatidylinositol transfer protein, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• Functional Keywords: vacuole, ergosterol, lipid transport
• Biological source: Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast)
• Total number of polymer chains: 9
• Total formula weight: 202037.03

Authors

Winkler, M.B.L.,Kidmose, R.T.,Pedersen, B.P. (deposition date: 2019-03-22, release date: 2019-09-25, Last modification date: 2024-11-06)

Primary citation

Winkler, M.B.L.,Kidmose, R.T.,Szomek, M.,Thaysen, K.,Rawson, S.,Muench, S.P.,Wustner, D.,Pedersen, B.P.
Structural Insight into Eukaryotic Sterol Transport through Niemann-Pick Type C Proteins.
Cell, 179:485-497.e18, 2019

PubMed 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.

PubMed: 31543266
DOI: 10.1016/j.cell.2019.08.038

Experimental method

X-RAY DIFFRACTION (2.9 Å)