α-Synuclein Senses Lipid Packing Defects and Induces Lateral Expansion of Lipids Leading to Membrane Remodeling

Ouberaï, Myriam; Wang, Juan; Swann, Marcus J.; Galvagnion, Céline; Guilliams, Tim; Dobson, Christopher M.; Welland, Mark E.

doi:10.1074/jbc.m113.478297

Cited by 184 publications

(168 citation statements)

References 64 publications

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“…The basis for curvature sensing by aSyn may include defects in highly curved membranes that have been proposed to provide preferred binding sites for amphipathic helices, including those adopted by aSyn in its membrane-bound conformation (54,57,63,82). At the same time, the charge distribution of the amphipathic N-terminal helix of aSyn may also play a key role in curvature sensing (54,58).…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, it has been shown that curvature selectivity by aSyn cannot be comprehensively characterized through measurements of affinity alone (54), and further studies will be required to evaluate more directly the curvature selectivity of Ac-aSyn. In addition, it is now generally accepted that aSyn can influence membrane properties, specifically curvature, in addition to sensing them (57,58,60,62,63,66,75,83), and the influence of N-terminal acetylation on this activity of the protein remains to be explored.…”

Section: Discussionmentioning

confidence: 99%

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N-terminal Acetylation Stabilizes N-terminal Helicity in Lipid- and Micelle-bound α-Synuclein and Increases Its Affinity for Physiological Membranes

Dikiy

Eliezer

2014

Journal of Biological Chemistry

166

153

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Background:The functional effects of normal N-terminal acetylation of the Parkinson disease protein ␣-synuclein are unknown. Results: N-Acetylation stabilizes helical structure at the N terminus of membrane-bound forms of synuclein, including a novel partly helical state. Conclusion: Stabilization of helicity increases affinity for membranes similar to synaptic vesicles. Significance: In vivo N-acetylation of ␣-synuclein likely affects its physiological function and dysfunction.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

N-terminal Acetylation Stabilizes N-terminal Helicity in Lipid- and Micelle-bound α-Synuclein and Increases Its Affinity for Physiological Membranes

Dikiy

Eliezer

2014

Journal of Biological Chemistry

166

153

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“…33 and 34 and Discussion for a divergent view). Membrane binding by α-synuclein is likely physiologically important because in in vitro experiments, α-synuclein remodels membranes (35,36), influences lipid packing (37,38), and induces vesicle clustering (39). Moreover, membranes were found to be important for the neuropathological effects of α-synuclein (40)(41)(42)(43)(44).…”

mentioning

confidence: 99%

α-Synuclein assembles into higher-order multimers upon membrane binding to promote SNARE complex formation

Burré¹,

Sharma²,

Südhof

2014

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

389

445

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Physiologically, α-synuclein chaperones soluble NSF attachment protein receptor (SNARE) complex assembly and may also perform other functions; pathologically, in contrast, α-synuclein misfolds into neurotoxic aggregates that mediate neurodegeneration and propagate between neurons. In neurons, α-synuclein exists in an equilibrium between cytosolic and membrane-bound states. Cytosolic α-synuclein appears to be natively unfolded, whereas membrane-bound α-synuclein adopts an α-helical conformation. Although the majority of studies showed that cytosolic α-synuclein is monomeric, it is unknown whether membrane-bound α-synuclein is also monomeric, and whether chaperoning of SNARE complex assembly by α-synuclein involves its cytosolic or membrane-bound state. Here, we show using chemical cross-linking and fluorescence resonance energy transfer (FRET) that α-synuclein multimerizes into large homomeric complexes upon membrane binding. The FRET experiments indicated that the multimers of membrane-bound α-synuclein exhibit defined intermolecular contacts, suggesting an ordered array. Moreover, we demonstrate that α-synuclein promotes SNARE complex assembly at the presynaptic plasma membrane in its multimeric membrane-bound state, but not in its monomeric cytosolic state. Our data delineate a folding pathway for α-synuclein that ranges from a monomeric, natively unfolded form in cytosol to a physiologically functional, multimeric form upon membrane binding, and show that only the latter but not the former acts as a SNARE complex chaperone at the presynaptic terminal, and may protect against neurodegeneration.Parkinson's disease | synapse | SNARE proteins | membrane fusion α -Synuclein is an abundant presynaptic protein that physiologically acts to promote soluble NSF attachment protein receptor (SNARE) complex assembly in vitro and in vivo (1-3). Point mutations in α-synuclein (A30P, E46K, H50Q, G51D, and A53T) as well as α-synuclein gene duplications and triplications produce early-onset Parkinson's disease (PD) (4-10). Moreover, α-synuclein is a major component of intracellular protein aggregates called Lewy bodies, which are pathological hallmarks of neurodegenerative disorders such as PD, Lewy body dementia, and multiple system atrophy (11-14). Strikingly, neurotoxic α-synuclein aggregates propagate between neurons during neurodegeneration, suggesting that such α-synuclein aggregates are not only intrinsically neurotoxic but also nucleate additional fibrillization (15-18).α-Synuclein is highly concentrated in presynaptic terminals where α-synuclein exists in an equilibrium between a soluble and a membrane-bound state, and is associated with synaptic vesicles (19)(20)(21)(22). The labile association of α-synuclein with membranes (23, 24) suggests that binding of α-synuclein to synaptic vesicles, and its dissociation from these vesicles, may regulate its physiological function. Membrane-bound α-synuclein assumes an α-helical conformation (25-32), whereas cytosolic α-synuclein is natively unfolded and monomeric (refs. 25, 2...

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“…6 It has been shown that non-specific interactions with the NPs can alter SLB structure and elasticity. 5 NPs can adhere to the lipid bilayer and cause changes in the lipid phase, 7 induce formation of lipid domains [8][9] or pores and extract lipids 10 inducing lipid bilayer disruption. [11][12] Physical chemical properties of NPs, 5,13 such as size, 4,11,[14][15] charge 12,16 and surface chemistry [17][18][19][20] are the main factors modulating NP-membrane interactions.…”

Section: Introductionmentioning

confidence: 99%

The effect of the protein corona on the interaction between nanoparticles and lipid bilayers

Silvio

Maccarini

Parker

et al. 2017

Journal of Colloid and Interface Science

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2 HypothesisIt is known that nanoparticles (NPs) in a biological fluid are immediately coated by a protein corona (PC), composed of a hard (strongly bounded) and a soft (loosely associated) layers, which represents the real nano-interface interacting with the cellular membrane in vivo. In this regard, supported lipid bilayers (SLB) have extensively been used as relevant model systems for elucidating the interaction between biomembranes and NPs. Herein we show how the presence of a PC on the NP surface changes the interaction between NPs and lipid bilayers with particular care on the effects induced by the NPs on the bilayer structure. ExperimentsIn the present work we combined Quartz Crystal Microbalance with Dissipation Monitoring (QCM-D) and Neutron Reflectometry (NR) experimental techniques to elucidate how the NPmembrane interaction is modulated by the presence of proteins in the environment and their effect on the lipid bilayer. FindingsOur study showed that the NP-membrane interaction is significantly affected by the presence of proteins and in particular we observed an important role of the soft corona in this phenomenon. KEYWORDSsupported lipid bilayer, protein corona nanoparticles, quartz crystal microbalance, neutron reflectometry, soft corona, hard corona. ABBREVIATIONNPs nanoparticles; SLB supported lipid bilayer; PC protein corona; QCM-D quartz crystal microbalance with dissipation; NR neutron reflectometry; PS polystyrene; PBS phosphate buffered saline; FBS fetal bovine serum; HC hard corona; SC soft corona; DOPC 1,2-Dioleoylsn-glycero-3-phosphocholine; SLD scattering length density; APM area per molecule; 4MW 4 matching water; SMW silicon matching water; LUV large unilamellar vesicle; GUV giant unilamellar vesicle; DPPC Dipalmitoyl-phosphatidyl-choline.3

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α-Synuclein Senses Lipid Packing Defects and Induces Lateral Expansion of Lipids Leading to Membrane Remodeling

Cited by 184 publications

References 64 publications

N-terminal Acetylation Stabilizes N-terminal Helicity in Lipid- and Micelle-bound α-Synuclein and Increases Its Affinity for Physiological Membranes

N-terminal Acetylation Stabilizes N-terminal Helicity in Lipid- and Micelle-bound α-Synuclein and Increases Its Affinity for Physiological Membranes

α-Synuclein assembles into higher-order multimers upon membrane binding to promote SNARE complex formation

The effect of the protein corona on the interaction between nanoparticles and lipid bilayers

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