Yeast sterol transport system consisting of two proteins, NCR1 (YPL006w) and NPC2 (YDL046w), components of the Niemann-Pick Type C transporter. It drives sterol integration into the lysosomal membrane before redistributing them to other cellular membranes. Expression of yeast NP-C-related gene 1 (NCR1), the orthologue of the human NP-C gene 1 (NPC1) defective in the disease, in Chinese hamster ovary NPC1 mutant cells suppressed lipid accumulation (Malathi et al. 2004). Deletion of NCR1, encoding a transmembrane glycoprotein predominantly residing in the vacuole of normal yeast, gave no phenotype. However, a dominant mutation in the putative sterol-sensing domain of Ncr1p conferred temperature and polyene antibiotic sensitivity without changes in sterol metabolism. Instead, the mutant cells were resistant to inhibitors of sphingolipid biosynthesis and super sensitive to sphingosine and C2-ceramide. Plasma membrane sphingolipids accumulated and redistributed to the vacuole and other subcellular membranes of the mutant cells. Malathi et al. 2004 proposed that the primordial function of these proteins is to recycle sphingolipids, and that defects in this process in higher eukaryotes secondarily result in cholesterol accumulation. Winkler et al. 2019 presented a framework for sterol membrane integration. Sterols are transferred between hydrophobic pockets of vacuolar NPC2 and NCR1. NCR1 has its N-terminal domain (NTD) positioned to deliver a sterol to a tunnel connecting the 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. Winkler et al. 2019 proposed a model for sterol integration that clarifies the role of these NPC proteins.
|Protein Name:||Phosphatidylglycerol/phosphatidylinositol transfer protein|
|Species:||Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast)  |
|Number of TMSs:||1|
|Location1 / Topology2 / Orientation3:
1: MTHSLKALFA LLFLYTAAVN AGVIGIFNAL PPPNTKPING ESPLYQCDIL DKQLVEIKEV
61: NLDPNPPVRG ENLTISANGE VFETIEEGAY IDVEVRLGYI RLLSQTFDLC ETLEDNDIEG
121: LSCPIEPGEY NIKKIVEIPG EVPPGKYVVV ARAYTEKDDL ITCLTGEVIF PPR