Structural insights from lipid-bilayer nanodiscs link α-Synuclein membrane-binding modes to amyloid fibril formation

Thibault Viennet; Michael M. Wördehoff; Boran Uluca; Chetan Poojari; Hamed Shaykhalishahi; Dieter Willbold; Birgit Strodel; Henrike Heise; Alexander K. Buell; Wolfgang Hoyer; Manuel Etzkorn

doi:10.1038/s42003-018-0049-z

Structural insights from lipid-bilayer nanodiscs link α-Synuclein membrane-binding modes to amyloid fibril formation

Thibault Viennet, Michael M. Wördehoff, Boran Uluca, Chetan Poojari, Hamed Shaykhalishahi, Dieter Willbold, Birgit Strodel, Henrike Heise, Alexander K. Buell, Wolfgang Hoyer, Manuel Etzkorn^*

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

84 Citations (Scopus)

Abstract

The protein α-Synuclein (αS) is linked to Parkinson’s disease through its abnormal aggregation, which is thought to involve cytosolic and membrane-bound forms of αS. Following previous studies using micelles and vesicles, we present a comprehensive study of αS interaction with phospholipid bilayer nanodiscs. Using a combination of NMR-spectroscopic, biophysical, and computational methods, we structurally and kinetically characterize αS interaction with different membrane discs in a quantitative and site-resolved way. We obtain global and residue-specific αS membrane affinities, and determine modulations of αS membrane binding due to αS acetylation, membrane plasticity, lipid charge density, and accessible membrane surface area, as well as the consequences of the different binding modes for αS amyloid fibril formation. Our results establish a structural and kinetic link between the observed dissimilar binding modes and either aggregation-inhibiting properties, largely unperturbed aggregation, or accelerated aggregation due to membrane-assisted fibril nucleation.

Original language	English
Article number	44
Journal	Communications Biology
Volume	1
Issue	44
Number of pages	12
DOIs	https://doi.org/10.1038/s42003-018-0049-z
Publication status	Published - 1 Dec 2018
Externally published	Yes

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title = "Structural insights from lipid-bilayer nanodiscs link α-Synuclein membrane-binding modes to amyloid fibril formation",

abstract = "The protein α-Synuclein (αS) is linked to Parkinson{\textquoteright}s disease through its abnormal aggregation, which is thought to involve cytosolic and membrane-bound forms of αS. Following previous studies using micelles and vesicles, we present a comprehensive study of αS interaction with phospholipid bilayer nanodiscs. Using a combination of NMR-spectroscopic, biophysical, and computational methods, we structurally and kinetically characterize αS interaction with different membrane discs in a quantitative and site-resolved way. We obtain global and residue-specific αS membrane affinities, and determine modulations of αS membrane binding due to αS acetylation, membrane plasticity, lipid charge density, and accessible membrane surface area, as well as the consequences of the different binding modes for αS amyloid fibril formation. Our results establish a structural and kinetic link between the observed dissimilar binding modes and either aggregation-inhibiting properties, largely unperturbed aggregation, or accelerated aggregation due to membrane-assisted fibril nucleation.",

author = "Thibault Viennet and W{\"o}rdehoff, {Michael M.} and Boran Uluca and Chetan Poojari and Hamed Shaykhalishahi and Dieter Willbold and Birgit Strodel and Henrike Heise and Buell, {Alexander K.} and Wolfgang Hoyer and Manuel Etzkorn",

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year = "2018",

month = dec,

day = "1",

doi = "10.1038/s42003-018-0049-z",

language = "English",

volume = "1",

journal = "Communications Biology",

issn = "2399-3642",

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Structural insights from lipid-bilayer nanodiscs link α-Synuclein membrane-binding modes to amyloid fibril formation. / Viennet, Thibault; Wördehoff, Michael M.; Uluca, Boran et al.
In: Communications Biology, Vol. 1, No. 44, 44, 01.12.2018.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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T1 - Structural insights from lipid-bilayer nanodiscs link α-Synuclein membrane-binding modes to amyloid fibril formation

AU - Viennet, Thibault

AU - Wördehoff, Michael M.

AU - Uluca, Boran

AU - Poojari, Chetan

AU - Shaykhalishahi, Hamed

AU - Willbold, Dieter

AU - Strodel, Birgit

AU - Heise, Henrike

AU - Buell, Alexander K.

AU - Hoyer, Wolfgang

AU - Etzkorn, Manuel

PY - 2018/12/1

Y1 - 2018/12/1

N2 - The protein α-Synuclein (αS) is linked to Parkinson’s disease through its abnormal aggregation, which is thought to involve cytosolic and membrane-bound forms of αS. Following previous studies using micelles and vesicles, we present a comprehensive study of αS interaction with phospholipid bilayer nanodiscs. Using a combination of NMR-spectroscopic, biophysical, and computational methods, we structurally and kinetically characterize αS interaction with different membrane discs in a quantitative and site-resolved way. We obtain global and residue-specific αS membrane affinities, and determine modulations of αS membrane binding due to αS acetylation, membrane plasticity, lipid charge density, and accessible membrane surface area, as well as the consequences of the different binding modes for αS amyloid fibril formation. Our results establish a structural and kinetic link between the observed dissimilar binding modes and either aggregation-inhibiting properties, largely unperturbed aggregation, or accelerated aggregation due to membrane-assisted fibril nucleation.

AB - The protein α-Synuclein (αS) is linked to Parkinson’s disease through its abnormal aggregation, which is thought to involve cytosolic and membrane-bound forms of αS. Following previous studies using micelles and vesicles, we present a comprehensive study of αS interaction with phospholipid bilayer nanodiscs. Using a combination of NMR-spectroscopic, biophysical, and computational methods, we structurally and kinetically characterize αS interaction with different membrane discs in a quantitative and site-resolved way. We obtain global and residue-specific αS membrane affinities, and determine modulations of αS membrane binding due to αS acetylation, membrane plasticity, lipid charge density, and accessible membrane surface area, as well as the consequences of the different binding modes for αS amyloid fibril formation. Our results establish a structural and kinetic link between the observed dissimilar binding modes and either aggregation-inhibiting properties, largely unperturbed aggregation, or accelerated aggregation due to membrane-assisted fibril nucleation.

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Structural insights from lipid-bilayer nanodiscs link α-Synuclein membrane-binding modes to amyloid fibril formation

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