Structural Insights into the Niemann-Pick C1 (NPC1)-Mediated Cholesterol Transfer and Ebola Infection

被引：253

作者：

Gong, Xin ^{[1
,2
,3
]}

Qian, Hongwu ^{[1
,2
,3
]}

Zhou, Xinhui ^{[1
,2
,3
]}

Wu, Jianping ^{[1
,2
,3
]}

Wan, Tao ^{[4
]}

Cao, Pingping ^{[1
,2
,3
]}

Huang, Weiyun ^{[1
,2
,3
]}

Zhao, Xin ^{[1
,2
,3
]}

Wang, Xudong ^{[4
]}

Wang, Peiyi ^{[5
]}

Shi, Yi ^{[4
,6
]}

Gao, George F. ^{[4
,6
]}

Zhou, Qiang ^{[1
,2
,3
]}

Yan, Nieng ^{[1
,2
,3
]}

机构：

[1] Tsinghua Univ, Sch Life Sci, State Key Lab Membrane Biol, Beijing 100084, Peoples R China

[2] Tsinghua Univ, Sch Life Sci, Beijing Adv Innovat Ctr Struct Biol, Beijing 100084, Peoples R China

[3] Tsinghua Univ, Sch Life Sci, Tsinghua Peking Joint Ctr Life Sci, Beijing 100084, Peoples R China

[4] Chinese Acad Sci, Inst Microbiol, CAS Key Lab Pathogen Microbiol & Immunol CASPMI, Beijing 100101, Peoples R China

[5] Univ Leeds, Sch Biol Sci, Leeds LS2 9JT, W Yorkshire, England

[6] Univ Chinese Acad Sci, Savaid Med Sch, Beijing 100049, Peoples R China

来源：

CELL | 2016年 / 165卷 / 06期

基金：

中国国家自然科学基金;

关键词：

STEROL-SENSING DOMAIN; VIRUS ENTRY REQUIRES; COENZYME-A REDUCTASE; NPC1; PROTEIN; CRYSTAL-STRUCTURE; FILOVIRUS ENTRY; MEMBRANE; BINDING; REVEALS; GENE;

D O I：

10.1016/j.cell.2016.05.022

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Niemann-Pick disease type C (NPC) is associated with mutations in NPC1 and NPC2, whose gene products are key players in the endosomal/lysosomal egress of low-density lipoprotein-derived cholesterol. NPC1 is also the intracellular receptor for Ebola virus (EBOV). Here, we present a 4.4 angstrom structure of full-length human NPC1 and a low-resolution reconstruction of NPC1 in complex with the cleaved glycoprotein (GPcl) of EBOV, both determined by single-particle electron cryomicroscopy. NPC1 contains 13 transmembrane segments (TMs) and three distinct lumenal domains A (also designated NTD), C, and I. TMs 2-13 exhibit a typical resistance-nodulation-cell division fold, among which TMs 3-7 constitute the sterol-sensing domain conserved in several proteins involved in cholesterol metabolism and signaling. A trimeric EBOV-GPcl binds to one NPC1 monomer through the domain C. Our structural and biochemical characterizations provide an important framework for mechanistic understanding of NPC1-mediated intracellular cholesterol trafficking and Ebola virus infection.

引用

页码：1467 / 1478

页数：12

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