Characterization and function studies of Ncr1p: A yeast ortholog of mammalian niemann pick C1 protein (NPC1)

Abstract

Niemann-Pick disease type C (NPC) is a neurodegenerative lipids storage disorder and 95% cases attribute to NPC1 mutations. The purposes of this study were to confirm the localization, trafficking and molecular mechanism of Ncr1p, a yeast homolog of NPC1 on ergosterol transport. In our study, Ncr1p was localized on vacuole limiting membrane at steady phase. This protein is transported to its destination by vacuole protein sorting pathway. Ncr1p implicates a synergistic effect with other ergosterol metabolism and transport related proteins. Deletion of NCR1 gene partially eliminates unfolded protein response induced by excess ergosterol in ER. The most important finding is a 30 minutes delay of oleate incorporation into ergosterol in are2I?ncr1I? compared with are2I?. Under the same growth condition, about 50% more free ergosterol is accumulated in vacuole of are2I?ncr1I? compared with are2I?. Based on our results, a model of ergosterol transport in S. cerevisiae was proposed.