4.8 Article

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


Volume 165, Issue 6, Pages 1467-1478


DOI: 10.1016/j.cell.2016.05.022




  1. Ministry of Science and Technology of China [2015CB9101012014, ZX09507003006]
  2. National Natural Science Foundation of China [31321062, 81590761]
  3. special project of Ebola virus research from the President Foundation of Chinese Academy of Sciences
  4. Strategic Priority Research Program of the Chinese Academy of Sciences [XDB08020100]
  5. International Early Career Scientist grant from the Howard Hughes Medical Institute
  6. endowed professorship from Bayer Healthcare

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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.


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