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

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

Author information

1
Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02124, USA.
2
Department of Chemistry, James Franck Institute, and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA.
3
Department of Chemistry, James Franck Institute, and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA. Electronic address: gavoth@uchicago.edu.
4
Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02124, USA. Electronic address: robert@hsph.harvard.edu.
5
Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02124, USA; Howard Hughes Medical Institute, Boston, MA 02115, USA. Electronic address: twalther@hsph.harvard.edu.

Abstract

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

PMID:
29316443
PMCID:
PMC5764114
DOI:
10.1016/j.devcel.2017.12.011
[Indexed for MEDLINE]
Free PMC Article

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