ArticleProceedings of the National Academy of Sciences of the United States of America2011
Niemann-Pick type C 1 function requires lumenal domain residues that mediate cholesterol-dependent NPC2 binding.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 94 papers.
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Who cites it
94 citing papers in PubMed, 157 citations in OpenAlex.
- Palmitoyltransferase DHHC13 controls lysosomal cholesterol egress through palmitoylating Niemann-Pick C1.Life metabolism · 2026Article
- Cholesterol at the Center of Alzheimer's Disease: A Unifying Hypothesis on the Pathogenic Mechanism.Molecules (Basel, Switzerland) · 2026Review
- Dysregulation of muscle cholesterol transport in amyotrophic lateral sclerosis.Brain : a journal of neurology · 2025Article
- Unifying biology of neurodegeneration in lysosomal storage diseases.Journal of inherited metabolic disease · 2025Review
- NPC Intracellular Cholesterol Transporter 1 Regulates Ovarian Maturation and Molting in FemaleInternational journal of molecular sciences · 2024Article
- Ebola Virus Glycoprotein Strongly Binds to Membranes in the Absence of Receptor Engagement.ACS infectious diseases · 2024Article
- The Genetic Basis, Lung Involvement, and Therapeutic Options in Niemann-Pick Disease: A Comprehensive Review.Biomolecules · 2024Review
- Imipramine Treatment Alters Sphingomyelin, Cholesterol, and Glycerophospholipid Metabolism in Isolated Macrophage Lysosomes.Biomolecules · 2023Article
- Insight Into the Dynamics of the Ixodes ricinus Nymphal Midgut Proteome.Molecular & cellular proteomics : MCP · 2023Article
- At a glance: the largest Niemann-Pick type C1 cohort with 602 patients diagnosed over 15 years.European journal of human genetics : EJHG · 2023Article
- The Cerebellum in Niemann-Pick C1 Disease: Mouse Versus Man.Cerebellum (London, England) · 2023Review
- Purification and structure of luminal domain C of human Niemann-Pick C1 protein.Acta crystallographica. Section F, Structural biology communications · 2023Article
- Alterations in Cholesterol and Phosphoinositides Levels in the Intracellular Cholesterol Trafficking Disorder NPC.Advances in experimental medicine and biology · 2023Article
- Kinetic modelling of sterol transport between plasma membrane and endo-lysosomes based on quantitative fluorescence and X-ray imaging data.Frontiers in cell and developmental biology · 2023Article
- Cholesterol sulfate alleviates ulcerative colitis by promoting cholesterol biosynthesis in colonic epithelial cells.Nature communications · 2022Article
- A lysosomal biogenesis map reveals the cargo spectrum of yeast vacuolar protein targeting pathways.The Journal of cell biology · 2022Article
- Pathways and Mechanisms of Cellular Cholesterol Efflux-Insight From Imaging.Frontiers in cell and developmental biology · 2022Review
- Inhibition of Histone Deacetylases 1, 2, and 3 Enhances Clearance of Cholesterol Accumulation in Niemann-Pick C1 Fibroblasts.ACS pharmacology & translational science · 2021Article
- Modeling Brain Pathology of Niemann-Pick Disease Type C Using Patient-Derived Neurons.Movement disorders : official journal of the Movement Disorder Society · 2021Article
- Molecular dynamics study with mutation shows that N-terminal domain structural re-orientation in Niemann-Pick type C1 is required for proper alignment of cholesterol transport.Journal of neurochemistry · 2021Article
34 more citing papers are in PubMed but not listed here.
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Authors and funding
2 authors at 2 institutions in 1 country.
Funding
Abstract
Niemann-Pick type C1 (NPC1) protein is needed for cellular utilization of low-density lipoprotein-derived cholesterol that has been delivered to lysosomes. The protein has 13 transmembrane domains, three large lumenal domains, and a cytoplasmic tail. NPC1's lumenally oriented, N-terminal domain binds cholesterol and has been proposed to receive cholesterol from NPC2 protein as part of the process by which cholesterol is exported from lysosomes into the cytosol. Using surface plasmon resonance and affinity chromatography, we show here that the second lumenal domain of NPC1 binds directly to NPC2 protein. For these experiments, a soluble NPC1 lumenal domain 2 was engineered by replacing adjacent transmembrane domains with antiparallel coiled-coil sequences. Interaction of NPC2 with NPC1 lumenal domain 2 is only detected at acidic pH, conditions that are optimal for cholesterol binding to NPC2 and transfer to NPC1; the pH is also appropriate for the acidic environment where binding would take place. Binding to NPC1 domain 2 requires the presence of cholesterol on NPC2 protein, a finding that supports directional transfer of cholesterol from NPC2 onto NPC1's N-terminal domain. Finally, human disease-causing mutations in NPC1 domain 2 decrease NPC2 binding, suggesting that NPC2 binding is necessary for NPC1 function in humans. These data support a model in which NPC1 domain 2 holds NPC2 in position to facilitate directional cholesterol transfer from NPC2 onto NPC1 protein for export from lysosomes.
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