Mechanism and Determinants of Amphipathic Helix-Containing Protein Targeting to Lipid Droplets

Dev Cell. 2018 Jan 8;44(1):73-86.e4. doi: 10.1016/j.devcel.2017.12.011. Epub 2018 Jan 8.


Cytosolic lipid droplets (LDs) are the main storage organelles for metabolic energy in most cells. They are unusual organelles that are bounded by a phospholipid monolayer and specific surface proteins, including key enzymes of lipid and energy metabolism. Proteins targeting LDs from the cytoplasm often contain amphipathic helices, but how they bind to LDs is not well understood. Combining computer simulations with experimental studies in vitro and in cells, we uncover a general mechanism for targeting of cytosolic proteins to LDs: large hydrophobic residues of amphipathic helices detect and bind to large, persistent membrane packing defects that are unique to the LD surface. Surprisingly, amphipathic helices with large hydrophobic residues from many different proteins are capable of binding to LDs. This suggests that LD protein composition is additionally determined by mechanisms that selectively prevent proteins from binding LDs, such as macromolecular crowding at the LD surface.

Keywords: all-atom molecular dynamics simulations; amphipathic helices; cell biology; lipid droplets; phospholipid bilayers; phospholipid monolayers; phospholipid packing defects; protein targeting; reconstitution assay.

Publication types

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

MeSH terms

  • Animals
  • Cells, Cultured
  • Drosophila Proteins / chemistry*
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / growth & development
  • Drosophila melanogaster / metabolism*
  • Hydrophobic and Hydrophilic Interactions
  • Lipid Droplets / chemistry*
  • Lipid Droplets / metabolism*
  • Male
  • Phospholipids / metabolism
  • Protein Conformation
  • Protein Transport


  • Drosophila Proteins
  • Phospholipids