Determinants of Endoplasmic Reticulum-to-Lipid Droplet Protein Targeting

Olarte, Maria-Jesus; Kim, Siyoung; Sharp, Morris E.; Swanson, Jessica M. J.; Farese, Robert V.; Walther, Tobias C.

doi:10.1016/j.devcel.2020.07.001

Cited by 57 publications

(80 citation statements)

References 95 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In our case, this might be particularly important pertaining to the observation that seipin interacts with TG molecules via multiple polar residues. However, a specific role of the polar moiety of TG in establishing interactions with proteins is supported by recent experimental observations (57) and could be the subject of future validation by atomistic simulations.…”

Section: Discussionmentioning

confidence: 69%

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.

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 69%

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.

View full text Add to dashboard Cite

show abstract

“…While studies indicate that LD proteins may interact with TGs contained within the LD interior (Olarte et al, 2020), (Santinho et al, 2021), it is unknown whether smectic lipid phase transitions influence LD protein targeting. Therefore, we imaged the canonical LD protein Erg6 tagged with mNeonGreen (Erg6-mNg) over time in AGR conditions.…”

Section: Resultsmentioning

confidence: 99%

“…However, neutral lipids clearly impact the composition of the LD surface proteome; for example, in yeast, some proteins preferentially decorate TG-rich LDs (Gao et al, 2017). Molecular studies also indicate that protein insertion into the LD neutral lipid core enables proteins to fold with lower free energy, and polar residues within hydrophobic regions can even interact with TG, further anchoring them to the LD (Olarte et al, 2020). However, how neutral lipid pools ultimately influence the composition and dynamics of the LD proteome is relatively unexplored, yet central to our understanding of LD organization and functional diversity.…”

Section: Introductionmentioning

confidence: 99%

Liquid-crystalline lipid phase transitions in lipid droplets selectively remodel the LD proteome

Rogers

Gui

Kovalenko

et al. 2021

Preprint

View full text Add to dashboard Cite

Lipid droplets (LDs) are reservoirs for triglycerides (TGs) and sterol-esters (SEs). How lipids are organized within LDs and influence the LD proteome remains unclear. Using in situ cryo-electron tomography, we show that glucose restriction triggers lipid phase transitions within LDs generating liquid-crystalline lattices inside them. Mechanistically, this requires TG lipolysis, which alters LD neutral lipid composition and promotes SE transition to a liquid-crystalline phase. Fluorescence imaging and proteomics further reveal that LD liquid-crystalline lattices selectively remodel the LD proteome. Some canonical LD proteins including Erg6 re-localize to the ER network, whereas others remain on LDs. Model peptide LiveDrop also redistributes from LDs to the ER, suggesting liquid-crystalline-phases influence ER-LD inter-organelle transport. Proteomics also indicates glucose restriction elevates peroxisome lipid oxidation, suggesting TG mobilization provides fatty acids for cellular energetics. This suggests glucose restriction drives TG mobilization, which alters the phase properties of LD lipids and selectively remodels the LD proteome.

show abstract

“…[16][17][18][19] The more common (and easier) approach is to create a new TG topology by replacing the head group of a PL with one of its tails without creating a new parameter set. This approach has been used in all-atom (AA) MD [20][21][22][23] and coarse-grained (CG) MD simulations, the latter run with the MARTINI CG force field. [24][25][26][27] Recent 10 µs-long AA simulations of LDs report surface-oriented TG (called SURF-TG in this work), 22 which was also implicated in NMR experiments.…”

Section: Introductionmentioning

confidence: 99%

Physical Characterization of Triolein and Implications for Its Role in Lipid Droplet Biogenesis

Kim

Voth

2021

Preprint

Self Cite

View full text Add to dashboard Cite

Lipid droplets (LDs) are neutral lipid storing organelles surrounded by a phospholipid (PL) monolayer. At present, how LDs are formed in the endoplasmic reticulum (ER) bilayer is poorly understood. In this study, we present a revised triolein (TG) model, the main constituent of the LD core, and characterize its properties in a bilayer membrane to demonstrate the implications of its behavior in LD biogenesis. In all-atom (AA) bilayer simulations, TG resides at the surface, adopting PL-like conformations (denoted in this work as SURF-TG). Free energy sampling simulation results estimate the barrier for TG relocating from the bilayer surface to the bilayer center to be ~2 kcal/mol in the absence of an oil lens. Conical SURF-TG is able to modulate membrane properties by increasing PL ordering, decreasing bending modulus, and creating local negative curvature. The other conical lipid, dioleoyl-glycerol (DAG), also reduces the membrane bending modulus and populates the negative curvature regions. A phenomenological coarse-grained (CG) model is also developed to observe larger scale SURF-TG-mediated membrane deformation. The CG simulations confirm that TG nucleates between the bilayer leaflets at a critical concentration when SURF-TG is evenly distributed. However, when one monolayer contains more SURF-TG, the membrane bends toward the other leaflet. The central conclusion of this study is that SURF-TG is a negative curvature inducer, as well as a membrane modulator. To this end, a model has proposed in which the accumulation of SURF-TG in the luminal leaflet bends the ER bilayer toward the cytosolic side, followed by TG nucleation.

show abstract

Determinants of Endoplasmic Reticulum-to-Lipid Droplet Protein Targeting

Abstract: Highlights d Specific membrane-embedded ER proteins target and accumulate on LDs d Minimal targeting motifs use Trp and positive-charged residues for LD accumulation d Distribution of these residues within motifs correlates with LD accumulation

Cited by 57 publications

References 95 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

Liquid-crystalline lipid phase transitions in lipid droplets selectively remodel the LD proteome

Physical Characterization of Triolein and Implications for Its Role in Lipid Droplet Biogenesis

Contact Info

Product

Resources

About