Determinants of Endoplasmic Reticulum-to-Lipid Droplet Protein Targeting

Dev Cell. 2020 Aug 24;54(4):471-487.e7. doi: 10.1016/j.devcel.2020.07.001. Epub 2020 Jul 29.


Lipid droplet (LD) formation from the endoplasmic reticulum (ER) is accompanied by the targeting and accumulation of specific hydrophobic, membrane-embedded proteins on LDs. The determinants of this process are unknown. Here, we study the hydrophobic membrane motifs of two Drosophila melanogaster proteins, GPAT4 and ALG14, that utilize this pathway, and we identify crucial sequence features that mediate LD accumulation. Molecular dynamics simulations and studies in cells reveal that LD targeting of these motifs requires deeply inserted tryptophans that have lower free energy in the LD oil phase and positively charged residues near predicted hairpin hinges that become less constrained in the LD environment. Analyzing hydrophobic motifs from similar LD-targeting proteins, it appears that the distribution of tryptophan and positively charged residues distinguishes them from non-LD-targeting membrane motifs. Our studies identify specific sequence features and principles of hydrophobic membrane motifs that mediate their accumulation on LDs.

Keywords: LiveDrop; UDP-N-acetylglucosaminyltransferase subunit; endoplasmic reticulum; glycerol-3-phosphate acyltransferase 4; lipid droplets; protein targeting.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Motifs / genetics
  • Animals
  • Cell Membrane / genetics
  • Cell Membrane / metabolism
  • Drosophila Proteins / genetics*
  • Drosophila melanogaster / genetics
  • Endoplasmic Reticulum / genetics*
  • Endoplasmic Reticulum / metabolism
  • Energy Metabolism / genetics
  • Glycerol-3-Phosphate O-Acyltransferase / genetics*
  • Hydrophobic and Hydrophilic Interactions
  • Lipid Droplets / metabolism*
  • N-Acetylglucosaminyltransferases / genetics*
  • Tryptophan / metabolism


  • Drosophila Proteins
  • Tryptophan
  • Glycerol-3-Phosphate O-Acyltransferase
  • gpat4 protein, Drosophila
  • N-Acetylglucosaminyltransferases