Structure of human Niemann-Pick C1 protein.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Li, X; Wang, J; Coutavas, E; Shi, H; Hao, Q; Blobel, G

Published Date

  • July 19, 2016

Published In

Volume / Issue

  • 113 / 29

Start / End Page

  • 8212 - 8217

PubMed ID

  • 27307437

Pubmed Central ID

  • PMC4961162

Electronic International Standard Serial Number (EISSN)

  • 1091-6490

Digital Object Identifier (DOI)

  • 10.1073/pnas.1607795113


  • eng

Conference Location

  • United States