| Membrane topology of human NPC1L1, a key protein in enterohepatic cholesterol absorption. | |
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MedLine Citation:
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PMID: 19325169 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The Niemann-Pick C1 Like 1 (NPC1L1) is a predicted polytopic membrane protein that is critical for cholesterol absorption. NPC1L1 takes up free cholesterol into cells through vesicular endocytosis. Ezetimibe, a clinically used cholesterol absorption inhibitor, blocks the endocytosis of NPC1L1 thereby inhibiting cholesterol uptake. Human NPC1L1 is a 1,332-amino acid protein with a putative sterol-sensing domain (SSD) that shows sequence homo-logy to HMG-CoA reductase (HMGCR), Niemann-Pick C1 (NPC1), and SREBP cleavage-activating protein (SCAP). Here, we use protease protection and immunofluorescence in selectively permeabilized cells to study the topology of human NPC1L1. Our data indicate that NPC1L1 contains 13 transmembrane helices. The NH2-terminus of NPC1L1 is in the lumen while the COOH-terminus projects to the cytosol. human NPC1L1 contains seven small cytoplasmic loops--four small and three large luminal loops--one of which has been reported to bind ezetimibe. Ezetimibe-glucuronide, the major metabolite of ezetimibe in vivo, can block the internalization of NPC1L1 and cholesterol. The membrane topology of NPC1L1 is similar to that of NPC1, and the putative SSD of NPC1L1 is oriented in the same manner as those of HMGCR, NPC1, and SCAP. The defined topology of NPC1L1 provides necessary information for further dissecting the functions of the different domains of NPC1L1. |
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Authors:
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Jiang Wang; Bei-Bei Chu; Liang Ge; Bo-Liang Li; Yan Yan; Bao-Liang Song |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-03-26 |
Journal Detail:
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Title: Journal of lipid research Volume: 50 ISSN: 0022-2275 ISO Abbreviation: J. Lipid Res. Publication Date: 2009 Aug |
Date Detail:
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Created Date: 2009-07-15 Completed Date: 2009-09-01 Revised Date: 2010-09-23 |
Medline Journal Info:
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Nlm Unique ID: 0376606 Medline TA: J Lipid Res Country: United States |
Other Details:
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Languages: eng Pagination: 1653-62 Citation Subset: IM |
Affiliation:
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The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Motifs Amino Acid Sequence Animals Anticholesteremic Agents / pharmacology Azetidines / pharmacology Biological Transport / drug effects Cell Line, Tumor Cell Membrane / chemistry* Cholesterol / metabolism* Conserved Sequence Epitopes Glucuronides / pharmacology Humans Membrane Proteins / antagonists & inhibitors, chemistry*, metabolism* Models, Biological Molecular Sequence Data Protein Structure, Secondary Protein Structure, Tertiary Protein Transport / drug effects Rats Recombinant Fusion Proteins / chemistry, metabolism Transfection |
| Chemical | |
Reg. No./Substance:
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0/Anticholesteremic Agents; 0/Azetidines; 0/Epitopes; 0/Glucuronides; 0/Membrane Proteins; 0/NPC1L1 protein, human; 0/Recombinant Fusion Proteins; 0/ezetimibe glucuronide; 57-88-5/Cholesterol |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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