title: Transmembrane molecular pump activity of Niemann-Pick C1 protein.
abstract: Niemann-Pick C1 (NPC1) disease is characterized by cholesterol accumulation in lysosomes and aberrant feedback regulation of cellular cholesterol homeostasis. We provide evidence that the NPC1 protein has homology with the resistance-nodulation-division (RND) family of prokaryotic permeases and may normally function as a transmembrane efflux pump. Studies of acriflavine loading in normal and NPC1 fibroblasts indicated that NPC1 uses a proton motive force to remove accumulated acriflavine from the endosomal/lysosomal system. Expression of NPC1 in Escherichia coli (i) facilitated the transport of acriflavine across the plasma membrane, causing cytosolic accumulation, and (ii) resulted in transport of oleic acid but not cholesterol or cholesterol-oleate across the plasma membrane. These studies establish NPC1 as a eukaryotic member of the RND permease family.
authors: Department of Human Genetics, Box 1498, The Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA.
authors: J P
authors: JP
authors: Davies
authors: F W
authors: FW
authors: Chen
authors: Y A
authors: YA
authors: Ioannou
mesh_terms: D000167:Acriflavine / Q000378:metabolism; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001692:Biological Transport; D002352:Carrier Proteins; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D002788:Cholesterol Esters / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts; D005453:Fluorescence; D005456:Fluorescent Dyes / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008247:Lysosomes / Q000378:metabolism; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000737:chemistry; D026901:Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D000077296:Niemann-Pick C1 Protein; D009542:Niemann-Pick Diseases / Q000235:genetics / Q000378:metabolism*; D019301:Oleic Acid / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D018892:Proton-Motive Force; D011994:Recombinant Proteins / Q000378:metabolism; D016415:Sequence Alignment
chemical_list: D002352:Carrier Proteins; D002788:Cholesterol Esters; D005456:Fluorescent Dyes; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C121980:MexD protein, Pseudomonas aeruginosa; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein; D011506:Proteins; D011994:Recombinant Proteins; D000167:Acriflavine; D019301:Oleic Acid; D002784:Cholesterol