Dr. Yoel Klug-Sucking up the fat: mechanism of lipid droplet formation
12/12/2022 13:00
Dr. Yoel Klug


All cells have evolved the means to store energy and thereby minimize the effects of fluctuations in nutrient availability. Cells store energy in the form of neutral lipids, such as triacylglycerol, in specialized organelles called lipid droplets (LDs). Besides storage of metabolic energy, LDs play important roles in lipid and protein homeostasis and their deregulation is observed in a wide range of pathologies from obesity and atherosclerosis to diabetes. Despite their central roles in cellular metabolism, the mechanisms of LD biogenesis remained largely unknown. LD biogenesis occurs at the endoplasmic reticulum and is coordinated by the evolutionary conserved membrane protein Seipin, which is mutated in lipodystrophy. Despite the clear link between Seipin and LD formation, how Seipin promoted and influenced LD formation remained unclear.

We addressed this major open question in the field. Using structural, biochemical and molecular dynamics simulation approaches we revealed the mechanism of LD formation by the yeast Seipin Sei1 and its membrane partner Ldb16. We showed that Sei1 luminal domain assembles a homooligomeric ring, which, in contrast to other Seipins, is unable to concentrate triacylglycerol. Instead, Sei1 positions Ldb16, which concentrates triacylglycerol within the Sei1 ring through critical hydroxyl residues. Triacylglycerol recruitment to the complex is further promoted by Sei1 transmembrane segments, which also control Ldb16 stability. In vivo studies using chimeras between yeast and human Seipin indicate that triacylglycerol-binding activity by Seipin is conserved across eukaryotes, thus defining a unifying mechanism for Seipin mediated LD formation and lipid storage