The N-terminal Domain of NPC1L1 Protein Binds Cholesterol and Plays Essential Roles in Cholesterol Uptake

	The N-terminal Domain of NPC1L1 Protein Binds Cholesterol and Plays Essential Roles in Cholesterol Uptake
	Zhang, JH; Ge, L; Qi, W; Zhang, LQ; Miao, HH; Li, BL; Yang, MJ; Song, BL
刊名	JOURNAL OF BIOLOGICAL CHEMISTRY
	2011
卷号	286 期号:28 页码:25088-25097
通讯作者	Song, BL (reprint author), 320 Yue Yang Rd, Shanghai 200031, Peoples R China.,blsong@sibs.ac.cn
英文摘要	Niemann-Pick C1-like 1 (NPC1L1) is a multitransmembrane 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 Leu-216 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 the clathrin-AP2 pathway. Our study uncovers the mechanism of cholesterol sensing by NPC1L1 and proposes a mechanism for selective cholesterol absorption.
学科主题	Biochemistry & Molecular Biology
类目[WOS]	Biochemistry & Molecular Biology
关键词[WOS]	PICK C1 PROTEIN ; REGULATED TRANSLOCATION ; STEROL BINDING ; CELL-SURFACE ; C2 DISEASE ; METABOLISM ; ABSORPTION ; EZETIMIBE ; REVEALS ; IDENTIFICATION
收录类别	SCI
语种	英语
WOS记录号	WOS:000292547900057
内容类型	期刊论文
版本	出版稿
源URL	[http://202.127.25.143/handle/331003/885]
专题	上海生化细胞研究所_上海生科院生化细胞研究所
推荐引用方式 GB/T 7714	Zhang, JH,Ge, L,Qi, W,et al. The N-terminal Domain of NPC1L1 Protein Binds Cholesterol and Plays Essential Roles in Cholesterol Uptake[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2011,286(28):25088-25097.
APA	Zhang, JH.,Ge, L.,Qi, W.,Zhang, LQ.,Miao, HH.,...&Song, BL.(2011).The N-terminal Domain of NPC1L1 Protein Binds Cholesterol and Plays Essential Roles in Cholesterol Uptake.JOURNAL OF BIOLOGICAL CHEMISTRY,286(28),25088-25097.
MLA	Zhang, JH,et al."The N-terminal Domain of NPC1L1 Protein Binds Cholesterol and Plays Essential Roles in Cholesterol Uptake".JOURNAL OF BIOLOGICAL CHEMISTRY 286.28(2011):25088-25097.