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Seipin traps triacylglycerols to facilitate their nanoscale clustering in the endoplasmic reticulum membrane
Authors:Xavier Prasanna  Veijo T Salo  Shiqian Li  Katharina Ven  Helena Vihinen  Eija Jokitalo  Ilpo Vattulainen  Elina Ikonen
Institution:1. Department of Physics, University of Helsinki, Helsinki, Finland;2. Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki, Finland;3. Minerva Foundation Institute for Medical Research, Helsinki, Finland;4. Institute of Biotechnology, University of Helsinki, Helsinki, Finland;Universitat zu Koln, GERMANY
Abstract:Seipin is a disk-like oligomeric endoplasmic reticulum (ER) protein important for lipid droplet (LD) biogenesis and triacylglycerol (TAG) delivery to growing LDs. Here we show through biomolecular simulations bridged to experiments that seipin can trap TAGs in the ER bilayer via the luminal hydrophobic helices of the protomers delineating the inner opening of the seipin disk. This promotes the nanoscale sequestration of TAGs at a concentration that by itself is insufficient to induce TAG clustering in a lipid membrane. We identify Ser166 in the α3 helix as a favored TAG occupancy site and show that mutating it compromises the ability of seipin complexes to sequester TAG in silico and to promote TAG transfer to LDs in cells. While the S166D-seipin mutant colocalizes poorly with promethin, the association of nascent wild-type seipin complexes with promethin is promoted by TAGs. Together, these results suggest that seipin traps TAGs via its luminal hydrophobic helices, serving as a catalyst for seeding the TAG cluster from dissolved monomers inside the seipin ring, thereby generating a favorable promethin binding interface.

A combination of biomolecular simulations and experiments reveals that the disc-like oligomeric lipodystrophy protein seipin interacts with and traps triglycerides in the endoplasmic reticulum, thus facilitating the formation and growth of lipid droplets.
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