ArticleProceedings of the National Academy of Sciences of the United States of America2017
3.3 Å structure of Niemann-Pick C1 protein reveals insights into the function of the C-terminal luminal domain in cholesterol transport.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
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Who cites it
53 citing papers in PubMed.
- Clinical and molecular spectrum of Niemann-Pick disease type C patients in India.Frontiers in pediatrics · 2026Article
- From autophagy-lysosomal deficits to neurodegeneration in Niemann-Pick type C1 disease: implications for age-related neurodegenerative disorders.Frontiers in neuroscience · 2026Review
- NPC1 as a novel therapeutic target for induction of pyroptosis in cancers.Biomarker research · 2025Article
- Niemann Pick C1 mistargeting disrupts lysosomal cholesterol homeostasis contributing to neurodegeneration in a Batten disease model.Science advances · 2025Article
- Autophagy-NADFrontiers in molecular biosciences · 2025Review
- Flotillins in membrane trafficking and physiopathology.Biology of the cell · 2025Review
- The mycobacterium lipid transporter MmpL3 is dimeric in detergent solution, SMALPs and reconstituted nanodiscs.RSC chemical biology · 2024Article
- LipIDens: simulation assisted interpretation of lipid densities in cryo-EM structures of membrane proteins.Nature communications · 2023Article
- The energetics and ion coupling of cholesterol transport through Patched1.Science advances · 2023Article
- Understanding the phenotypic variability in Niemann-Pick disease type C (NPC): a need for precision medicine.NPJ genomic medicine · 2023Review
- The Energetics and Ion Coupling of Cholesterol Transport Through Patched1.bioRxiv : the preprint server for biology · 2023Article
- Genetics of vegetarianism: A genome-wide association study.PloS one · 2023Article
- Alterations in Cholesterol and Phosphoinositides Levels in the Intracellular Cholesterol Trafficking Disorder NPC.Advances in experimental medicine and biology · 2023Article
- Severe neurometabolic phenotype inFrontiers in molecular neuroscience · 2023Article
- Structural basis of Tom20 and Tom22 cytosolic domains as the human TOM complex receptors.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Article
- Evaluating cepharanthine analogues as natural drugs against SARS-CoV-2.FEBS open bio · 2022Article
- Structural insights into the mechanism of human NPC1L1-mediated cholesterol uptake.Science advances · 2021Article
- Structure, Assembly, and Function of Tripartite Efflux and Type 1 Secretion Systems in Gram-Negative Bacteria.Chemical reviews · 2021Review
- Structural and Functional Diversity of Resistance-Nodulation-Cell Division Transporters.Chemical reviews · 2021Review
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7 authors.
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Abstract
Niemann-Pick C1 (NPC1) and NPC2 proteins are indispensable for the export of LDL-derived cholesterol from late endosomes. Mutations in these proteins result in Niemann-Pick type C disease, a lysosomal storage disease. Despite recent reports of the NPC1 structure depicting its overall architecture, the function of its C-terminal luminal domain (CTD) remains poorly understood even though 45% of NPC disease-causing mutations are in this domain. Here, we report a crystal structure at 3.3 Å resolution of NPC1* (residues 314-1,278), which-in contrast to previous lower resolution structures-features the entire CTD well resolved. Notably, all eight cysteines of the CTD form four disulfide bonds, one of which (C909-C914) enforces a specific loop that in turn mediates an interaction with a loop of the N-terminal domain (NTD). Importantly, this loop and its interaction with the NTD were not observed in any previous structures due to the lower resolution. Our mutagenesis experiments highlight the physiological relevance of the CTD-NTD interaction, which might function to keep the NTD in the proper orientation for receiving cholesterol from NPC2. Additionally, this structure allows us to more precisely map all of the disease-causing mutations, allowing future molecular insights into the pathogenesis of NPC disease.
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