@article{96b50075d7264a729dd3add99113158e,
title = "Structural insights into the Niemann-Pick C1 (NPC1)-mediated cholesterol transfer and ebola infection",
abstract = "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 {\AA} 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.",
author = "Xin Gong and Hongwu Qian and Xinhui Zhou and Jianping Wu and Tao Wan and Pingping Cao and Weiyun Huang and Xin Zhao and Xudong Wang and Peiyi Wang and Yi Shi and Gao, {George F.} and Qiang Zhou and Nieng Yan",
note = "Funding Information: We thank Jianlin Lei, Yanji Xu, and Xiaomei Li for technical support. We thank Xueming Li and Mingxu Hu for critical discussions. We thank the Tsinghua University Branch of China National Center for Protein Sciences (Beijing) for providing the facility support. The computation was completed on the {"}Explorer 100{"} cluster system of Tsinghua National Laboratory for Information Science and Technology. This work was supported by funds from the Ministry of Science and Technology of China (2015CB9101012014, ZX09507003006), National Natural Science Foundation of China (project 31321062 and 81590761), the special project of Ebola virus research from the President Foundation of Chinese Academy of Sciences, and Strategic Priority Research Program of the Chinese Academy of Sciences (XDB08020100). The research of Nieng Yan was supported in part by an International Early Career Scientist grant from the Howard Hughes Medical Institute and an endowed professorship from Bayer Healthcare. Funding Information: We thank Jianlin Lei, Yanji Xu, and Xiaomei Li for technical support. We thank Xueming Li and Mingxu Hu for critical discussions. We thank the Tsinghua University Branch of China National Center for Protein Sciences (Beijing) for providing the facility support. The computation was completed on the “Explorer 100” cluster system of Tsinghua National Laboratory for Information Science and Technology. This work was supported by funds from the Ministry of Science and Technology of China (2015CB9101012014, ZX09507003006), National Natural Science Foundation of China (project 31321062 and 81590761), the special project of Ebola virus research from the President Foundation of Chinese Academy of Sciences, and Strategic Priority Research Program of the Chinese Academy of Sciences (XDB08020100). The research of Nieng Yan was supported in part by an International Early Career Scientist grant from the Howard Hughes Medical Institute and an endowed professorship from Bayer Healthcare. Publisher Copyright: {\textcopyright} 2016 Elsevier Inc. All rights reserved.",
year = "2016",
month = jun,
day = "2",
doi = "10.1016/j.cell.2016.05.022",
language = "English (US)",
volume = "165",
pages = "1467--1478",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "6",
}