{"database":"biostudies-literature","file_versions":[],"scores":{"citationCount":0,"reanalysisCount":0,"viewCount":52,"searchCount":0},"additional":{"submitter":["Saha P"],"funding":["Ara Parseghian Medical Research Foundation","Chan Zuckerberg BioHub","National Institutes of Health"],"pagination":["e57089"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC7228765"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["9"],"pubmed_abstract":["Transport of LDL-derived cholesterol from lysosomes into the cytoplasm requires NPC1 protein; NPC1L1 mediates uptake of dietary cholesterol. We introduced single disulfide bonds into NPC1 and NPC1L1 to explore the importance of inter-domain dynamics in cholesterol transport. Using a sensitive method to monitor lysosomal cholesterol efflux, we found that NPC1's N-terminal domain need not release from the rest of the protein for efficient cholesterol export. Either introducing single disulfide bonds to constrain lumenal/extracellular domains or shortening a cytoplasmic loop abolishes transport activity by both NPC1 and NPC1L1. The widely prescribed cholesterol uptake inhibitor, ezetimibe, blocks NPC1L1; we show that residues that lie at the interface between NPC1L1's three extracellular domains comprise the drug's binding site. These data support a model in which cholesterol passes through the cores of NPC1/NPC1L1 proteins; concerted movement of various domains is needed for transfer and ezetimibe blocks transport by binding to multiple domains simultaneously."],"journal":["eLife"],"pubmed_title":["Inter-domain dynamics drive cholesterol transport by NPC1 and NPC1L1 proteins."],"pmcid":["PMC7228765"],"funding_grant_id":["5R01HL134991-04"],"pubmed_authors":["Pfeffer SR","Shumate JL","Elghobashi-Meinhardt N","Zhang L","Caldwell JG","Elias JE","Saha P","Lu A","Olsson NE"],"view_count":["52"],"additional_accession":[]},"is_claimable":false,"name":"Inter-domain dynamics drive cholesterol transport by NPC1 and NPC1L1 proteins.","description":"Transport of LDL-derived cholesterol from lysosomes into the cytoplasm requires NPC1 protein; NPC1L1 mediates uptake of dietary cholesterol. We introduced single disulfide bonds into NPC1 and NPC1L1 to explore the importance of inter-domain dynamics in cholesterol transport. Using a sensitive method to monitor lysosomal cholesterol efflux, we found that NPC1's N-terminal domain need not release from the rest of the protein for efficient cholesterol export. Either introducing single disulfide bonds to constrain lumenal/extracellular domains or shortening a cytoplasmic loop abolishes transport activity by both NPC1 and NPC1L1. The widely prescribed cholesterol uptake inhibitor, ezetimibe, blocks NPC1L1; we show that residues that lie at the interface between NPC1L1's three extracellular domains comprise the drug's binding site. These data support a model in which cholesterol passes through the cores of NPC1/NPC1L1 proteins; concerted movement of various domains is needed for transfer and ezetimibe blocks transport by binding to multiple domains simultaneously.","dates":{"release":"2020-01-01T00:00:00Z","publication":"2020 May","modification":"2024-11-20T08:14:44.936Z","creation":"2020-05-23T07:12:56Z"},"accession":"S-EPMC7228765","cross_references":{"pubmed":["32410728"],"doi":["10.7554/eLife.57089"]}}