ArticlePLoS computational biology2020
Cholesterol binding to the sterol-sensing region of Niemann Pick C1 protein confines dynamics of its N-terminal domain.
Article in PLoS computational biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 24 citations in OpenAlex.
- Article
- Clinical and molecular spectrum of Niemann-Pick disease type C patients in India.Frontiers in pediatrics · 2026Article
- Physics-based evolution of transmembrane helices reveals mechanisms of cholesterol attraction.Nature communications · 2025Article
- The SLC-ome of membrane transport: From molecular discovery to physiology and clinical applications.Physiological reviews · 2025Review
- NPC1 as a novel therapeutic target for induction of pyroptosis in cancers.Biomarker research · 2025Article
- Mechanistic insights into Alpha-Synuclein binding to P2RX7: A molecular dynamic and docking study.PloS one · 2025Article
- Loss of Sc5d results in micrognathia due to a failure in osteoblast differentiation.Journal of advanced research · 2024Article
- The expanding boundaries of sphingolipid lysosomal storage diseases; insights from Niemann-Pick disease type C.Biochemical Society transactions · 2023Review
- Lipid Transporters Beam Signals from Cell Membranes.Membranes · 2021Review
- An Intracellular Pathway Controlled by the N-terminus of the Pump Subunit Inhibits the Bacterial KdpFABC Ion Pump in High KJournal of molecular biology · 2021Article
- Long chain sphingomyelin depletes cholesterol from the cytoplasmic leaflet in asymmetric lipid membranes.RSC advances · 2021Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Lysosomal accumulation of cholesterol is a hallmark of Niemann Pick type C (NPC) disease caused by mutations primarily in the lysosomal membrane protein NPC1. NPC1 contains a transmembrane sterol-sensing domain (SSD), which is supposed to regulate protein activity upon cholesterol binding, but the mechanisms underlying this process are poorly understood. Using atomistic simulations, we show that in the absence of cholesterol in the SSD, the luminal domains of NPC1 are highly dynamic, resulting in the disengagement of the NTD from the rest of the protein. The disengaged NPC1 adopts a flexed conformation that approaches the lipid bilayer, and could represent a conformational state primed to receive a sterol molecule from the soluble lysosomal cholesterol carrier NPC2. The binding of cholesterol to the SSD of NPC1 allosterically suppresses the conformational dynamics of the luminal domains resulting in an upright NTD conformation. The presence of an additional 20% cholesterol in the membrane has negligible impact on this process. The additional presence of an NTD-bound cholesterol suppresses the flexing of the NTD. We propose that cholesterol acts as an allosteric effector, and the modulation of NTD dynamics by the SSD-bound cholesterol constitutes an allosteric feedback mechanism in NPC1 that controls cholesterol abundance in the lysosomal membrane.
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