| The N-terminal domain of NPC1L1 binds cholesterol and plays essential roles in cholesterol uptake. | |
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MedLine Citation:
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PMID: 21602275 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Niemann-Pick C1 Like 1 (NPC1L1) is a multi-transmembrane protein playing a crucial role in dietary and biliary cholesterol absorption. Cholesterol promotes the formation and endocytosis of NPC1L1-flotillin-cholesterol membrane microdomains, which is an early step in cholesterol uptake. How cholesterol is sensed in this step is unknown. Here, we find that the N-terminal domain (NTD) of NPC1L1 binds cholesterol. Mutation of residue L216 in NPC1L1-NTD eliminates cholesterol binding, decreases the formation of NPC1L1-flotillin-cholesterol membrane microdomains, and prevents NPC1L1-mediated cholesterol uptake in culture cells and mice livers. NPC1L1-NTD specifically binds cholesterol but not plant sterols, which may account for the selective cholesterol absorption in intestine. Furthermore, 25- or 27-hydroxycholesterol competes with cholesterol to bind NPC1L1-NTD and inhibits the cholesterol induced endocytosis of NPC1L1. Together, these results demonstrate that plasma membrane-localized NPC1L1 binds exogenous cholesterol via its NTD, and facilitates the formation of NPC1L1-flotillin-cholesterol membrane microdomains that are then internalized into cells through clathrin-AP2 pathway. Our study uncovers the mechanism of cholesterol sensing by NPC1L1 and proposes a mechanism for selective cholesterol absorption. |
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Authors:
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Jin-Hui Zhang; Liang Ge; Wei Qi; Liqing Zhang; Hong-Hua Miao; Bo-Liang Li; Maojun Yang; Bao-Liang Song |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-5-20 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: - ISSN: 1083-351X ISO Abbreviation: - Publication Date: 2011 May |
Date Detail:
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Created Date: 2011-5-23 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Shanghai Institutes for Biological Sciences, CAS, China; |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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