Transmembrane Molecular Pump Activity of Niemann-Pick C1 Protein
- 22 December 2000
- journal article
- other
- Published by American Association for the Advancement of Science (AAAS) in Science
- Vol. 290 (5500) , 2295-2298
- https://doi.org/10.1126/science.290.5500.2295
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.Keywords
This publication has 17 references indexed in Scilit:
- Topological Analysis of Niemann-Pick C1 Protein Reveals That the Membrane Orientation of the Putative Sterol-sensing Domain Is Identical to Those of 3-Hydroxy-3-methylglutaryl-CoA Reductase and Sterol Regulatory Element Binding Protein Cleavage-activating ProteinJournal of Biological Chemistry, 2000
- Evidence for a Niemann–Pick C (NPC) Gene Family: Identification and Characterization of NPC1L1Genomics, 2000
- Niemann-Pick C1 Disease: The I1061T Substitution Is a Frequent Mutant Allele in Patients of Western European Descent and Correlates with a Classic Juvenile PhenotypeAmerican Journal of Human Genetics, 1999
- Gapped BLAST and PSI-BLAST: a new generation of protein database search programsNucleic Acids Research, 1997
- Niemann-Pick C1 Disease Gene: Homology to Mediators of Cholesterol HomeostasisScience, 1997
- The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehogNature, 1996
- Genes acrA and acrB encode a stress‐induced efflux system of Escherichia coliMolecular Microbiology, 1995
- CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choiceNucleic Acids Research, 1994
- The Niemann-Pick C lesion and its relationship to the intracellular distribution and utilization of LDL cholesterolBiochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1994
- Pharmacological inhibition of the intracellular transport of low-density lipoprotein-derived cholesterol in Chinese hamster ovary cellsBiochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism, 1990