Movement of accessible plasma membrane cholesterol by the GRAMD1 lipid transfer protein complex

Elife. 2019 Nov 14;8:e51401. doi: 10.7554/eLife.51401.


Cholesterol is a major structural component of the plasma membrane (PM). The majority of PM cholesterol forms complexes with other PM lipids, making it inaccessible for intracellular transport. Transition of PM cholesterol between accessible and inaccessible pools maintains cellular homeostasis, but how cells monitor the accessibility of PM cholesterol remains unclear. We show that endoplasmic reticulum (ER)-anchored lipid transfer proteins, the GRAMD1s, sense and transport accessible PM cholesterol to the ER. GRAMD1s bind to one another and populate ER-PM contacts by sensing a transient expansion of the accessible pool of PM cholesterol via their GRAM domains. They then facilitate the transport of this cholesterol via their StART-like domains. Cells that lack all three GRAMD1s exhibit striking expansion of the accessible pool of PM cholesterol as a result of less efficient PM to ER transport of accessible cholesterol. Thus, GRAMD1s facilitate the movement of accessible PM cholesterol to the ER in order to counteract an acute increase of PM cholesterol, thereby activating non-vesicular cholesterol transport.

Keywords: GRAM domain; StART-like domain; biochemistry; cell biology; chemical biology; cholesterol; human; membrane contact sites; non-vesicular lipid transport; plasma membrane.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Biological Transport / drug effects
  • COS Cells
  • Carrier Proteins / chemistry
  • Carrier Proteins / metabolism*
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism*
  • Chlorocebus aethiops
  • Cholesterol / metabolism*
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism
  • HeLa Cells
  • Humans
  • Multiprotein Complexes / metabolism*
  • Mutant Proteins / metabolism
  • Protein Binding / drug effects
  • Protein Domains
  • Sirolimus / pharmacology
  • Sphingomyelins / metabolism


  • Carrier Proteins
  • Multiprotein Complexes
  • Mutant Proteins
  • Sphingomyelins
  • lipid transfer protein
  • Cholesterol
  • Sirolimus

Associated data

  • PDB/6GQF