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TitleStructural Insights into the Niemann-Pick C1 (NPC1)-Mediated Cholesterol Transfer and Ebola Infection.
Journal, issue, pagesCell, Vol. 165, Issue 6, Page 1467-1478, Year 2016
Publish dateJun 2, 2016
AuthorsXin Gong / Hongwu Qian / Xinhui Zhou / Jianping Wu / Tao Wan / Pingping Cao / Weiyun Huang / Xin Zhao / Xudong Wang / Peiyi Wang / Yi Shi / George F Gao / Qiang Zhou / Nieng Yan /
PubMed AbstractNiemann-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. ...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.
External linksCell / PubMed:27238017 / PubMed Central
MethodsEM (single particle)
Resolution4.43 - 6.7 Å
Structure data

EMDB-6640: cryo-EM map of the full-length human NPC1 at 4.4 angstrom
PDB-3jd8: cryo-EM structure of the full-length human NPC1 at 4.4 angstrom
Method: EM (single particle) / Resolution: 4.43 Å

EMDB-6641:
cryo-EM map of the full-length human NPC1 at 6.7 angstrom
Method: EM (single particle) / Resolution: 6.7 Å

EMDB-8169: cryo-EM map of the full-length human NPC1 in complex with the cleaved glycoprotein of Ebola virus
PDB-5jnx: The 6.6 A cryo-EM structure of the full-length human NPC1 in complex with the cleaved glycoprotein of Ebola virus
Method: EM (single particle) / Resolution: 6.56 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-CLR:
CHOLESTEROL / Cholesterol

Source
  • homo sapiens (human)
  • ebola virus - zaire (1995)
KeywordsMEMBRANE PROTEIN / protein complex

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