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Title: Structure of human Niemann–Pick C1 protein

Journal Article · · Proceedings of the National Academy of Sciences of the United States of America
 [1];  [2];  [1];  [1];  [1];  [1]
  1. Rockefeller Univ., New York, NY (United States)
  2. Tsinghua Univ., Beijing (China)

Niemann–Pick C1 protein (NPC1) is a late-endosomal membrane protein involved in trafficking of LDL-derived cholesterol, Niemann–Pick disease type C, and Ebola virus infection. NPC1 contains 13 transmembrane segments (TMs), five of which are thought to represent a “sterol-sensing domain” (SSD). Although present also in other key regulatory proteins of cholesterol biosynthesis, uptake, and signaling, the structure and mechanism of action of the SSD are unknown. Here we report a crystal structure of a large fragment of human NPC1 at 3.6 Å resolution, which reveals internal twofold pseudosymmetry along TM 2–13 and two structurally homologous domains that protrude 60 Å into the endosomal lumen. Strikingly, NPC1's SSD forms a cavity that is accessible from both the luminal bilayer leaflet and the endosomal lumen; computational modeling suggests that this cavity is large enough to accommodate one cholesterol molecule. In conclusion, we propose a model for NPC1 function in cholesterol sensing and transport.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
Rockefeller Univ.; Howard Hughes Medical Inst.
OSTI ID:
1274750
Journal Information:
Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, Issue 29; ISSN 0027-8424
Publisher:
National Academy of SciencesCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 113 works
Citation information provided by
Web of Science

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Structural basis for itraconazole-mediated NPC1 inhibition journal January 2020
Coordinate regulation of mutant NPC1 degradation by selective ER autophagy and MARCH6-dependent ERAD journal September 2018
Different Niemann-Pick C1 Genotypes Generate Protein Phenotypes that Vary in their Intracellular Processing, Trafficking and Localization journal March 2019
Inhibition of tetrameric Patched1 by Sonic Hedgehog through an asymmetric paradigm journal November 2018
Lysosomal cholesterol export reconstituted from fragments of Niemann-Pick C1 journal July 2018
3.3 Å structure of Niemann–Pick C1 protein reveals insights into the function of the C-terminal luminal domain in cholesterol transport journal August 2017
NPC intracellular cholesterol transporter 1 (NPC1)-mediated cholesterol export from lysosomes journal February 2019
Plasmodium falciparum Niemann-Pick Type C1-Related Protein is a Druggable Target Required for Parasite Membrane Homeostasis posted_content July 2018
Quantitating the epigenetic transformation contributing to cholesterol homeostasis using Gaussian process journal November 2019
Two Patched molecules engage distinct sites on Hedgehog yielding a signaling-competent complex journal August 2018
Recent neuroimaging, neurophysiological, and neuropathological advances for the understanding of NPC journal January 2018
Astemizole Inhibits mTOR Signaling and Angiogenesis by Blocking Cholesterol Trafficking journal January 2018
Characterization of cholesterol homeostasis in sphingosine-1-phosphate lyase-deficient fibroblasts reveals a Niemann-Pick disease type C-like phenotype with enhanced lysosomal Ca2+ storage journal March 2017
Clues to the mechanism of cholesterol transfer from the structure of NPC1 middle lumenal domain bound to NPC2 journal August 2016
Transcription controls growth, cell kinetics and cholesterol supply to sustain ACTH responses journal October 2017
Concerted regulation of npc2 binding to endosomal/lysosomal membranes by bis(monoacylglycero)phosphate and sphingomyelin journal October 2017
EhNPC1 and EhNPC2 Proteins Participate in Trafficking of Exogenous Cholesterol in Entamoeba histolytica Trophozoites: Relevance for Phagocytosis journal December 2016
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Niemann–Pick type C disease: cellular pathology and pharmacotherapy journal November 2019
The lifecycle of the Ebola virus in host cells journal June 2017
Structural basis for human sterol isomerase in cholesterol biosynthesis and multidrug recognition journal June 2019
Structures of human Patched and its complex with native palmitoylated sonic hedgehog journal July 2018
Prospective Turkish Cohort Study to Investigate the Frequency of Niemann-Pick Disease Type C Mutations in Consanguineous Families with at Least One Homozygous Family Member journal August 2017
Plasmodium Niemann-Pick type C1-related protein is a druggable target required for parasite membrane homeostasis journal March 2019
Modeling Niemann-Pick disease type C1 in zebrafish: a robust platform for in vivo screening of candidate therapeutic compounds journal August 2018
Comparative study of the effect of disease causing and benign mutations in position Q92 on cholesterol binding by the NPC1 n-terminal domain journal October 2018
Identifying the structure-activity relationship of leelamine necessary for inhibiting intracellular cholesterol transport journal March 2017