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6R4M

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

Summary for 6R4M
Entry DOI10.2210/pdb6r4m/pdb
DescriptorPhosphatidylglycerol/phosphatidylinositol transfer protein, 2-acetamido-2-deoxy-beta-D-glucopyranose (2 entities in total)
Functional Keywordsvacuole, ergosterol, lipid transport
Biological sourceSaccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast)
Total number of polymer chains3
Total formula weight66104.53
Authors
Winkler, M.B.L.,Kidmose, R.T.,Pedersen, B.P. (deposition date: 2019-03-22, release date: 2019-09-25, Last modification date: 2024-10-23)
Primary citationWinkler, 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
Cited by
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
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2.8 Å)
Structure validation

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