Out-of-the-groove transport of lipids by TMEM16 and GPCR scramblases Academic Article uri icon


MeSH Major

  • Fungal Proteins
  • Hypocreales
  • Ion Channels
  • Phospholipid Transfer Proteins


  • Phospholipid scramblases externalize phosphatidylserine to facilitate numerous physiological processes. Several members of the structurally unrelated TMEM16 and G protein-coupled receptor (GPCR) protein families mediate phospholipid scrambling. The structure of a TMEM16 scramblase shows a membrane-exposed hydrophilic cavity, suggesting that scrambling occurs via the ‟credit-card" mechanism where lipid headgroups permeate through the cavity while their tails remain associated with the membrane core. Here we show that afTMEM16 and opsin, representatives of the TMEM16 and GCPR scramblase families, transport phospholipids with polyethylene glycol headgroups whose globular dimensions are much larger than the width of the cavity. This suggests that transport of these large headgroups occurs outside rather than within the cavity. These large lipids are scrambled at rates comparable to those of normal phospholipids and their presence in the reconstituted vesicles promotes scrambling of normal phospholipids. This suggests that both large and small phospholipids can move outside the cavity. We propose that the conformational rearrangements underlying TMEM16- and GPCR-mediated credit-card scrambling locally deform the membrane to allow transbilayer lipid translocation outside the cavity and that both mechanisms underlie transport of normal phospholipids.

publication date

  • July 24, 2018



  • Academic Article



  • eng

PubMed Central ID

  • PMC6065010

Digital Object Identifier (DOI)

  • 10.1073/pnas.1806721115

PubMed ID

  • 29925604

Additional Document Info

start page

  • E7033

end page

  • E7042


  • 115


  • 30