Structure of human Niemann-Pick C1 protein

Xiaochun Li, Jiawei Wang, Elias Coutavas, Hang Shi, Qi Hao, Günter Blobel

Research output: Contribution to journalArticle

65 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)8212-8217
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number29
DOIs
StatePublished - Jul 19 2016

Keywords

  • Allostery
  • Cholesterol traffic
  • Crystal structure
  • Endosomal membrane
  • Sterol-sensing domain

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Structure of human Niemann-Pick C1 protein'. Together they form a unique fingerprint.

  • Cite this