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

Abstract

Lipid droplets (LD) 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 catalyse 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 molecules inside its unconventional ring-like oligomeric structure, and that both its luminal and transmembrane regions contribute to this process. Diacylglycerol, the precursor of TG, also clusters inside the seipin oligomer, in turn promoting TG accumulation. Our results suggest that seipin remodels the membrane of specific ER sites to prime them for LD biogenesis.

Pre-existing bilayer stresses modulate triglyceride accumulation in the ER versus lipid droplets

“…Recent experimental and computational results suggest that nucleation is largely driven by protein activity in vivo ( Zoni et al, 2020 Prasanna et al, 2021 ). On the other hand, it remains unclear whether variations in PL content could alter TG concentration in the ER.…”

Seipin—still a mysterious protein?

“…In line with this, a conserved, luminal region near the TMDs, called switch domain or locking helix, appears to be important to control TMD orientation and flexibility (Klug et al, 2021;Arlt et al, 2022). Indeed, simulations indicate that the TMDs and nearby residues are important for seipin function in both attracting TAGs in the ER bilayer (Zoni et al, 2021b) and facilitating the conversion of a flat TAG-lens into a budding LD (Kim et al, 2022a).…”

“…Seipin also contains hydrophobic helices (HHs) in the center of the ring, partially embedded in the ER bilayer. Molecular simulations supported by mutational analysis indicate that the HHs may induce nanoscale clustering of TAG molecules (Zoni et al, 2021b;Klug et al, 2021;Prasanna et al, 2021;Kim et al, 2022a;Renne et al, 2022) (Figure 1B). Importantly, seipin induces this TAG lensing at a lower concentration than TAG alone, providing a plausible explanation why LDs form at sites marked by seipin and ER TAG is increased in seipin KO (Gao et al, 2017;Choudhary et al, 2020).…”

A Unique Junctional Interface at Contact Sites Between the Endoplasmic Reticulum and Lipid Droplets

“…Furthermore, the seipin complex at the base of ER-LD junctions might create a selectivity barrier and thereby uncouples the lipid composition of these ER subdomains from the bulk of the ER. Based on molecular dynamic simulations, seipin has recently been proposed to directly interact with, and thereby enrich, TAG and DAG within its ring-shaped structure (Prasanna et al, 2020;Zoni et al, 2020). Hence, seipin might function as a lipid transporter and/or gatekeeper to locally regulate lipid levels at ER-LD junctions.…”