ArticleProceedings of the National Academy of Sciences of the United States of America2004
Binding between the Niemann-Pick C1 protein and a photoactivatable cholesterol analog requires a functional sterol-sensing domain.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 87 papers, 1 of them a synthesis that pooled it.
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Who cites it
87 citing papers in PubMed, 1 synthesis or guideline pooled it, 203 citations in OpenAlex.
- Cholesterol and Its Derivatives: Multifaceted Players in Breast Cancer Progression.Frontiers in oncology · 2022Pooled it
- Alterations in Cholesterol and Phosphoinositides Levels in the Intracellular Cholesterol Trafficking Disorder NPC.Advances in experimental medicine and biology · 2023Article
- PI(4,5)PAdvances in experimental medicine and biology · 2023Article
- Profile of Ta-Yuan Chang.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Article
- Annexin A6 and NPC1 regulate LDL-inducible cell migration and distribution of focal adhesions.Scientific reports · 2022Article
- 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
- Cholesterol binding to the sterol-sensing region of Niemann Pick C1 protein confines dynamics of its N-terminal domain.PLoS computational biology · 2020Article
- Cryo-EM structures of NPC1L1 reveal mechanisms of cholesterol transport and ezetimibe inhibition.Science advances · 2020Article
- Article
- Cholesterol Transport in Wild-Type NPC1 and P691S: Molecular Dynamics Simulations Reveal Changes in Dynamical Behavior.International journal of molecular sciences · 2020Article
- Structural basis for itraconazole-mediated NPC1 inhibition.Nature communications · 2020Article
- Image-based screen capturing misfolding status of Niemann-Pick type C1 identifies potential candidates for chaperone drugs.PloS one · 2020Article
- Quantitating the epigenetic transformation contributing to cholesterol homeostasis using Gaussian process.Nature communications · 2019Article
- Synthesis and characterization of diazirine alkyne probes for the study of intracellular cholesterol trafficking.Journal of lipid research · 2019Article
- Cholesterol increases protein levels of the E3 ligase MARCH6 and thereby stimulates protein degradation.The Journal of biological chemistry · 2019Article
- Lipid⁻Protein Interactions in Niemann⁻Pick Type C Disease: Insights from Molecular Modeling.International journal of molecular sciences · 2019Article
- NPC intracellular cholesterol transporter 1 (NPC1)-mediated cholesterol export from lysosomes.The Journal of biological chemistry · 2019Review
- Mass spectrometry imaging of lipids: untargeted consensus spectra reveal spatial distributions in Niemann-Pick disease type C1.Journal of lipid research · 2018Article
- Current advances of carbene-mediated photoaffinity labeling in medicinal chemistry.RSC advances · 2018Review
27 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Niemann-Pick type C (NPC) 1 protein plays important roles in moving cholesterol and other lipids out of late endosomes by means of vesicular trafficking, but it is not known whether NPC1 directly interacts with cholesterol. We performed photoaffinity labeling of intact cells expressing fluorescent protein (FP)-tagged NPC1 by using [(3)H]7,7-azocholestanol ([(3)H]AC). After immunoprecipitation, (3)H-labeled NPC1-GFP appeared as a single band. Including excess unlabeled sterol to the labeling reaction significantly diminished the labeling. Altering the NPC1 sterol-sensing domain (SSD) with loss-of-function mutations (P692S and Y635C) severely reduced the extent of labeling. To further demonstrate the specificity of labeling, we show that NPC2, a late endosomal/lysosomal protein that binds to cholesterol with high affinity, is labeled, whereas mutant NPC2 proteins inactive in binding cholesterol are not. Vamp7, an abundant late endosomal membrane protein without an SSD but with one transmembrane domain, cannot be labeled. Binding between [(3)H]AC and NPC1 does not require NPC2. Treating cells with either U-18666A, a compound that creates an NPC-like phenotype, or with bafilomycin A1, a compound that raises late endosomal pH, has no effect on labeling of NPC1-YFP, suggesting that both drugs affect processes other than NPC1 binding to cholesterol. We also developed a procedure to label the NPC1-YFP by [(3)H]AC in vitro and showed that cholesterol is more effective in protection against labeling than its analogs epicholesterol or 5-alpha-cholestan. Overall, the results demonstrate that there is direct binding between NPC1 and azocholestanol; the binding does not require NPC2 but requires a functional SSD within NPC1.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.