Structural Insight into Eukaryotic Sterol Transport through Niemann-Pick Type C Proteins

Cell. 2019 Oct 3;179(2):485-497.e18. doi: 10.1016/j.cell.2019.08.038. Epub 2019 Sep 19.


Niemann-Pick type C (NPC) proteins are essential for sterol homeostasis, believed to drive sterol integration into the lysosomal membrane before redistribution to other cellular membranes. Here, using a combination of crystallography, cryo-electron microscopy, and biochemical and in vivo studies on the Saccharomyces cerevisiae NPC system (NCR1 and NPC2), we present a framework for sterol membrane integration. Sterols are transferred between hydrophobic pockets of vacuolar NPC2 and membrane-protein NCR1. NCR1 has its N-terminal domain (NTD) positioned to deliver a sterol to a tunnel connecting NTD to the luminal membrane leaflet 50 Å away. A sterol is caught inside this tunnel during transport, and a proton-relay network of charged residues in the transmembrane region is linked to this tunnel supporting a proton-driven transport mechanism. We propose a model for sterol integration that clarifies the role of NPC proteins in this essential eukaryotic pathway and that rationalizes mutations in patients with Niemann-Pick disease type C.

Keywords: NCR1; NPC1; NPC2; Niemann-Pick type C proteins; X-ray crystallography; cryo-EM; lipid trafficking; sterol homeostasis; sterol membrane integration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biological Transport
  • Carrier Proteins / chemistry*
  • Cryoelectron Microscopy
  • Crystallography
  • Intracellular Membranes / metabolism
  • Lysosomes / metabolism
  • Protein Domains
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / chemistry*
  • Sterols / metabolism*
  • Vacuoles / metabolism
  • Vesicular Transport Proteins / chemistry*


  • Carrier Proteins
  • NCR1 protein, S cerevisiae
  • Npc2 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Sterols
  • Vesicular Transport Proteins