Exceptional stability of a perilipin on lipid droplets depends on its polar residues, suggesting multimeric assembly

Numerous proteins target lipid droplets (LDs) through amphipathic helices (AHs). It is generally assumed that AHs insert bulky hydrophobic residues in packing defects at the LD surface. However, this model does not explain targeting of perilipins, most abundant and specific LDs, which are weakly hydrophobic. A striking example Plin4, whose gigantic repetitive AH lacks residues. Using a range complementary approaches, we show Plin4 forms remarkably immobile stable protein layer surface cellular or vitro generated oil droplets, decreases size. stability on LDs exquisitely sensitive to nature distribution its polar These results suggest arrangements adjacent via polar/electrostatic interactions, reminiscent organization apolipoproteins lipoprotein particles, thus pointing general mechanism stabilization lateral interactions.