Seipin forms a flexible cage at lipid droplet formation sites

Arlt, Henning; Sui, Xuewu; Folger, Brayden; Adams, Carson; Chen, Xiao; Remme, Roman; Hamprecht, Fred A.; DiMaio, Frank; Liao, Maofu; Goodman, Joel M.; Farese, Robert V.; Walther, Tobias C.

doi:10.1101/2021.08.05.455270

Cited by 3 publications

(3 citation statements)

References 56 publications

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“…The absence of seipin results in aggregated, small LDs and/or supersized LDs as well as Bernardinelli–Seip congenital lipodystrophy type 2 (BSCL2). Seipin forms an unusual ring-like structure that consists of 10–12 subunits depending on the species. − Each subunit has a highly conserved lumenal domain, flanked by two transmembrane (TM) segments and nonconserved variable cytosolic tails. Cell experiments indicate that the cytosolic tails are dispensable while other parts are critical for seipin function .…”

Section: Ld Formationmentioning

confidence: 99%

“…In contrast, yeast seipin does not have the HH and is not functional by itself. Removing the TM segments or replacing one of them with other ER protein FIT2 results in the LD phenotype of seipin knockout cells. , …”

Section: Ld Formationmentioning

confidence: 99%

“…Removing the TM segments or replacing one of them with other ER protein FIT2 results in the LD phenotype of seipin knockout cells. 4,71 Recent MD simulations have provided important insights into the molecular functioning of human seipin. 33,73,74 Seipin−lipid interactions were analyzed in the seipin-containing bilayer simulations.…”

Section: ■ Ld Formationmentioning

confidence: 99%

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Computational Studies of Lipid Droplets

2022

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Lipid droplets (LDs) are intracellular organelles whose primary function is energy storage. Known to emerge from the endoplasmic reticulum (ER) bilayer, LDs have a unique structure with a core consisting of neutral lipids, triacylglycerol (TG) or sterol esters (SE), surrounded by a phospholipid (PL) monolayer and decorated by proteins that come and go throughout their complex lifecycle. In this Feature Article, we review recent developments in computational studies of LDs, a rapidly growing area of research. We highlight how molecular dynamics (MD) simulations have provided valuable molecular-level insight into LD targeting and LD biogenesis. Additionally, we review the physical properties of TG from different force fields compared with experimental data. Possible future directions and challenges are discussed.

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Section: Ld Formationmentioning

confidence: 99%

Section: Ld Formationmentioning

confidence: 99%

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Computational Studies of Lipid Droplets

2022

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Identification of two pathways mediating protein targeting from ER to lipid droplets

Song

Mizrak

Lee

et al. 2021

Preprint

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Pathways localizing proteins to their sites of action within a cell are essential for eukaryotic cell organization and function. Although mechanisms of protein targeting to many organelles have been defined, little is known about how proteins, such as key metabolic enzymes, target from the ER to cellular lipid droplets (LDs). Here, we identify two distinct pathways for ER-to-LD (ERTOLD) protein targeting: early ERTOLD, occurring during LD formation, and late ERTOLD, targeting mature LDs after their formation. By using systematic, unbiased approaches, we identified specific membrane-fusion machinery, including regulators, a tether, and SNARE proteins, that are required for late ERTOLD targeting. Components of this fusion machinery localize to LD-ER interfaces and appear to be organized at ER exit sites (ERES) to generate ER-LD membrane bridges. We also identified multiple cargoes for early and late ERTOLD. Collectively, our data provide a new model for how proteins target LDs from the ER.

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Seipin transmembrane segments critically function in triglyceride nucleation and lipid droplet budding from the membrane

Kim

Chung

Arlt

et al. 2021

Preprint

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Lipid droplets (LDs) are organelles formed in the endoplasmic reticulum (ER) to store triacylglycerol (TG) and sterol esters. The ER protein seipin is key for LD biogenesis. Seipin forms a cage-like structure, with each seipin monomer containing a conserved hydrophobic helix (HH) and two transmembrane (TM) segments. How the different parts of seipin function in TG nucleation and LD budding is poorly understood. Here, we utilized molecular dynamics simulations of human seipin, along with cell-based experiments, to study seipin’s functions in protein-lipid interactions, lipid diffusion, and LD maturation. All-atom (AA) simulations indicate that most seipin TM segment residues located in the phospholipid (PL) tail region of the bilayer attract TG. We also find seipin TM segments control lipid diffusion and permeation into the protein complex. Simulating larger, growing LDs with coarse-grained (CG) models, we find that the seipin TM segments form a constricted neck structure to facilitate conversion of a flat oil lens into a budding LD. Using cell experiments and simulations, we also show that conserved, positively charged residues at the end of seipin’s TM segments affect LD maturation. We propose a model in which seipin TM segments critically function in TG nucleation and LD growth.

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Seipin forms a flexible cage at lipid droplet formation sites

Cited by 3 publications

References 56 publications

Computational Studies of Lipid Droplets

Computational Studies of Lipid Droplets

Identification of two pathways mediating protein targeting from ER to lipid droplets

Seipin transmembrane segments critically function in triglyceride nucleation and lipid droplet budding from the membrane

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