To Bud or Not to Bud: A Perspective on Molecular Simulations of Lipid Droplet Budding

Zoni, Valeria; Nieto, Vincent; Endter, Laura J; Risselada, Herre Jelger; Monticelli, Luca; Vanni, Stefano

doi:10.3389/fmolb.2019.00124

Cited by 30 publications

(31 citation statements)

References 32 publications

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“…The finite size of the seipin oligomer sets a threshold on the amount of TG molecules that the protein can accumulate via direct protein-TG interactions, but those molecules can act as a seed for further growth of the TG blister inside the seipin ring. However, the observation that even in the presence of excess amounts of TG, blister growth is arrested at relatively low amounts of TG molecules [at least in comparison with protein-free systems, where TG blisters can accumulate up to hundreds of TG molecules (44)] indicates that seipin is likely insufficient to promote extensive LD growth, per se, in the absence of partner proteins (15,17) or variations in membrane properties (45)(46)(47).…”

Section: Resultsmentioning

confidence: 99%

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

Zoni

Khaddaj

Lukmantara

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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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.

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Section: Resultsmentioning

confidence: 99%

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

Zoni

Khaddaj

Lukmantara

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…The ring structure formed by the protomer β-sandwiches is oriented parallel to the membrane, whereas the α-helices point toward the membrane. Recent in silico data indicates that these α-helices protrude into the membrane and bind TAG, likely to facilitate efficient packaging into LDs ( Zoni et al, 2019 ; Prasanna et al, 2021 ).…”

Section: Fa Metabolic Hubs At Ld-organelle Contact Sitesmentioning

confidence: 99%

Lipid Droplet-Organelle Contact Sites as Hubs for Fatty Acid Metabolism, Trafficking, and Metabolic Channeling

Renne

Hariri

2021

Front. Cell Dev. Biol.

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Cells prepare for fluctuations in nutrient availability by storing energy in the form of neutral lipids in organelles called Lipid Droplets (LDs). Upon starvation, fatty acids (FAs) released from LDs are trafficked to different cellular compartments to be utilized for membrane biogenesis or as a source of energy. Despite the biochemical pathways being known in detail, the spatio-temporal regulation of FA synthesis, storage, release, and breakdown is not completely understood. Recent studies suggest that FA trafficking and metabolism are facilitated by inter-organelle contact sites that form between LDs and other cellular compartments such as the Endoplasmic Reticulum (ER), mitochondria, peroxisomes, and lysosomes. LD-LD contact sites are also sites where FAs are transferred in a directional manner to support LD growth and expansion. As the storage site of neutral lipids, LDs play a central role in FA homeostasis. In this mini review, we highlight the role of LD contact sites with other organelles in FA trafficking, channeling, and metabolism and discuss the implications for these pathways on cellular lipid and energy homeostasis.

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“…The finite size of the seipin oligomer sets a threshold on the amount of TG molecules that the protein can accumulate via direct protein-TG interactions, but those molecules can act as a seed for further growth of the TG blister inside the seipin ring. However, the observation that even in the presence of excess amount of TG, blister growth is arrested at relatively low amounts of TG molecules (at least in comparison with protein-free systems, where TG blisters can accumulate up to hundreds of TG molecules(42)) indicates that seipin is likely insufficient to promote extensive LD growth per se, in the absence of partner proteins (15,17) or variations in membrane properties (43)(44)(45).…”

Section: Seipin Promotes the Accumulation Of Tg Molecules At Low Tg Cmentioning

confidence: 99%

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

Zoni

Shinoda

2020

Preprint

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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.

show abstract

To Bud or Not to Bud: A Perspective on Molecular Simulations of Lipid Droplet Budding

Cited by 30 publications

References 32 publications

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

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

Lipid Droplet-Organelle Contact Sites as Hubs for Fatty Acid Metabolism, Trafficking, and Metabolic Channeling

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

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