Seipin accumulates and traps diacylglycerols and triglycerides in its ring-like structure

Abstract

Lipid droplets (LDs) are intracellular organelles responsible for lipid storage, and they emerge from the endoplasmic reticulum (ER) upon the accumulation of neutral lipids, mostly triglycerides (TG), between the two leaflets of the ER membrane. LD biogenesis takes place at ER sites that are marked by the protein seipin, which subsequently recruits additional proteins to catalyze LD formation. Deletion of seipin, however, does not abolish LD biogenesis, and its precise role in controlling LD assembly remains unclear. Here, we use molecular dynamics simulations to investigate the molecular mechanism through which seipin promotes LD formation. We find that seipin clusters TG, as well as its precursor diacylglycerol, inside its unconventional ring-like oligomeric structure and that both its luminal and transmembrane regions contribute to this process. This mechanism is abolished upon mutations of polar residues involved in protein–TG interactions into hydrophobic residues. Our results suggest that seipin remodels the membrane of specific ER sites to prime them for LD biogenesis.

Retinyl esters form lipid droplets independently of triacylglycerol and seipin

“…Our data suggest that the role of seipin in LD formation is determined in part by the neutral lipids being stored in LDs. Seipin enhances TAG sequestering inside ringlike oligomeric structures ( Chung et al, 2019 ; Salo et al, 2019 ; Prasanna et al, 2021 ; Zoni et al, 2021 ). Seipin oligomers can trap TAGs in the ER bilayer via luminal hydrophobic helices and promote TAG clustering at low concentrations ( Prasanna et al, 2021 ).…”

“…Seipin has also been suggested to determine the site of LD biogenesis in the ER ( Chung et al, 2019 ; Salo et al, 2019 ), to regulate the flow of neutral lipids and proteins from the ER to nascent LDs at ER–LD contacts ( Grippa et al, 2015 ; Salo et al, 2019 ; Wang et al, 2014 ), and to regulate lipid metabolism at LD biogenesis sites ( Renne et al, 2020 ). Recently, seipin was shown to trap TAGs in the ER bilayer via luminal hydrophobic helices ( Prasanna et al, 2021 ; Zoni et al, 2021 ).…”

Fat inclusions strongly alter membrane mechanics

“…The assembly of triacylglycerol LDs is facilitated by membrane curvature, composition, and specific proteins (10,(13)(14)(15)(16)(17)(18) that decrease the critical nucleation concentration (10,(19)(20)(21). Accordingly, when the ER's curved structure is lost due to the dysfunction in the ER shaping proteins, triacylglycerols accumulate in the bilayer, unable to effectively condense into LDs (10,18).…”

Seipin forms a flexible cage at lipid droplet formation sites

“…This domain is reported to bind negatively charged phospholipids 16 . The lumenal domains form a ring of hydrophobic helices oriented toward the center of the toroid complex and are predicted to insert into the lumenal leaflet of the ER membrane 15,17,18 . In mammals, these helices are necessary for seipin’s interaction with the LDAC accessory protein LD assembly factor 1 (LDAF1) 19 , which may be an orthologue of yeast LD organization (Ldo) proteins 20,21 .…”