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

  • Cell. 2016 Jun 2;165(6):1467-1478. doi: 10.1016/j.cell.2016.05.022.
Xin Gong  1 ,  Hongwu Qian  1 ,  Xinhui Zhou  1 ,  Jianping Wu  1 ,  Tao Wan  2 ,  Pingping Cao  1 ,  Weiyun Huang  1 ,  Xin Zhao  1 ,  Xudong Wang  2 ,  Peiyi Wang  3 ,  Yi Shi  4 ,  George F Gao  4 ,  Qiang Zhou  5 ,  Nieng Yan  6
Affiliations
  • 1. State Key Laboratory of Membrane Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China; Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.
  • 2. CAS Key Laboratory of Pathogenic Microbiology and Immunology (CASPMI), Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
  • 3. Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
  • 4. CAS Key Laboratory of Pathogenic Microbiology and Immunology (CASPMI), Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Savaid Medical School, University of Chinese Academy of Sciences, Beijing 100049, China.
  • 5. State Key Laboratory of Membrane Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China; Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China. Electronic address: [email protected].
  • 6. State Key Laboratory of Membrane Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China; Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China. Electronic address: [email protected].
PMID: 27238017 DOI: 10.1016/j.cell.2016.05.022
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 Å 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.