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Structure of human Niemann-Pick C1 protein.

Publication ,  Journal Article
Li, X; Wang, J; Coutavas, E; Shi, H; Hao, Q; Blobel, G
Published in: Proc Natl Acad Sci U S A
July 19, 2016

Niemann-Pick C1 protein (NPC1) is a late-endosomal membrane protein involved in trafficking of LDL-derived cholesterol, Niemann-Pick disease type C, and Ebola virus infection. NPC1 contains 13 transmembrane segments (TMs), five of which are thought to represent a "sterol-sensing domain" (SSD). Although present also in other key regulatory proteins of cholesterol biosynthesis, uptake, and signaling, the structure and mechanism of action of the SSD are unknown. Here we report a crystal structure of a large fragment of human NPC1 at 3.6 Å resolution, which reveals internal twofold pseudosymmetry along TM 2-13 and two structurally homologous domains that protrude 60 Å into the endosomal lumen. Strikingly, NPC1's SSD forms a cavity that is accessible from both the luminal bilayer leaflet and the endosomal lumen; computational modeling suggests that this cavity is large enough to accommodate one cholesterol molecule. We propose a model for NPC1 function in cholesterol sensing and transport.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

July 19, 2016

Volume

113

Issue

29

Start / End Page

8212 / 8217

Location

United States

Related Subject Headings

  • Sequence Alignment
  • Protein Conformation
  • Niemann-Pick C1 Protein
  • Membrane Glycoproteins
  • Lysosomes
  • Intracellular Signaling Peptides and Proteins
  • Humans
  • DNA, Complementary
  • Cholesterol
  • Carrier Proteins
 

Citation

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Li, X., Wang, J., Coutavas, E., Shi, H., Hao, Q., & Blobel, G. (2016). Structure of human Niemann-Pick C1 protein. Proc Natl Acad Sci U S A, 113(29), 8212–8217. https://doi.org/10.1073/pnas.1607795113
Li, Xiaochun, Jiawei Wang, Elias Coutavas, Hang Shi, Qi Hao, and Günter Blobel. “Structure of human Niemann-Pick C1 protein.Proc Natl Acad Sci U S A 113, no. 29 (July 19, 2016): 8212–17. https://doi.org/10.1073/pnas.1607795113.
Li X, Wang J, Coutavas E, Shi H, Hao Q, Blobel G. Structure of human Niemann-Pick C1 protein. Proc Natl Acad Sci U S A. 2016 Jul 19;113(29):8212–7.
Li, Xiaochun, et al. “Structure of human Niemann-Pick C1 protein.Proc Natl Acad Sci U S A, vol. 113, no. 29, July 2016, pp. 8212–17. Pubmed, doi:10.1073/pnas.1607795113.
Li X, Wang J, Coutavas E, Shi H, Hao Q, Blobel G. Structure of human Niemann-Pick C1 protein. Proc Natl Acad Sci U S A. 2016 Jul 19;113(29):8212–8217.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

July 19, 2016

Volume

113

Issue

29

Start / End Page

8212 / 8217

Location

United States

Related Subject Headings

  • Sequence Alignment
  • Protein Conformation
  • Niemann-Pick C1 Protein
  • Membrane Glycoproteins
  • Lysosomes
  • Intracellular Signaling Peptides and Proteins
  • Humans
  • DNA, Complementary
  • Cholesterol
  • Carrier Proteins