Single-molecule nanopore dielectrophoretic trapping of α-synuclein with lipid membranes
Single-molecule nanopore dielectrophoretic trapping of α-synuclein with lipid membranes
The lipid-α-Synuclein (α-Syn) interaction plays a crucial role in the pathogenesis of Parkinson's disease. Here, we investigate the lipid-binding and -unbinding kinetics of α-Syn in an α-hemolysin (αHL) single nanopore. Under an applied voltage, an engineered α-Syn sequence can be trapped at the nanopore due to the dielectrophoretic force. The conformational switch events of α-Syn can be observed at the pore-membrane junction through the interpretation of blockade current amplitudes and dwell time. This allows further analysis of α-Syn conformational dynamics. We study how disease-associated metal ions (Cu
2+, Zn
2+) modulate the dynamics of α-Syn at the interface of the membranes and pore and how α-helical peptidomimetics stabilize the helical conformation of α-Syn in a lipidic environment. These studies aid our understanding of the complexity of the interaction of α-Syn, lipid membranes, and metal ions, and in using peptidomimetics, a new strategy against α-Syn toxicity and aggregation is advanced.
lipid bilayer, nanopore, neurodegeneration, Parkinson's disease, metal ions, trapping., peptidomimetic, α-Synuclein
Wu, Jinming
2c85f85a-450d-42d8-a65b-c321318854b7
Yamashita, Tohru
1fb50b71-f393-48b4-8707-27cbb7a22958
Hamilton, Andrew D.
048a6c75-91bf-4555-ab12-ce885eee65dd
Thompson, Sam
99b7e34e-fe24-401c-b7b0-64e56cbbbcb1
Luo, Jinghui
d9dcd354-dcbb-4153-903f-3694c522374c
15 February 2023
Wu, Jinming
2c85f85a-450d-42d8-a65b-c321318854b7
Yamashita, Tohru
1fb50b71-f393-48b4-8707-27cbb7a22958
Hamilton, Andrew D.
048a6c75-91bf-4555-ab12-ce885eee65dd
Thompson, Sam
99b7e34e-fe24-401c-b7b0-64e56cbbbcb1
Luo, Jinghui
d9dcd354-dcbb-4153-903f-3694c522374c
Wu, Jinming, Yamashita, Tohru, Hamilton, Andrew D., Thompson, Sam and Luo, Jinghui
(2023)
Single-molecule nanopore dielectrophoretic trapping of α-synuclein with lipid membranes.
Cell Reports Physical Science, 4 (2), [101243].
(doi:10.1016/j.xcrp.2022.101243).
Abstract
The lipid-α-Synuclein (α-Syn) interaction plays a crucial role in the pathogenesis of Parkinson's disease. Here, we investigate the lipid-binding and -unbinding kinetics of α-Syn in an α-hemolysin (αHL) single nanopore. Under an applied voltage, an engineered α-Syn sequence can be trapped at the nanopore due to the dielectrophoretic force. The conformational switch events of α-Syn can be observed at the pore-membrane junction through the interpretation of blockade current amplitudes and dwell time. This allows further analysis of α-Syn conformational dynamics. We study how disease-associated metal ions (Cu
2+, Zn
2+) modulate the dynamics of α-Syn at the interface of the membranes and pore and how α-helical peptidomimetics stabilize the helical conformation of α-Syn in a lipidic environment. These studies aid our understanding of the complexity of the interaction of α-Syn, lipid membranes, and metal ions, and in using peptidomimetics, a new strategy against α-Syn toxicity and aggregation is advanced.
Text
23-01-16 ViewPageProof_XCRP_101243
- Accepted Manuscript
Text
1-s2.0-S2666386422005690-main
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More information
Accepted/In Press date: 22 December 2022
e-pub ahead of print date: 18 January 2023
Published date: 15 February 2023
Additional Information:
Funding Information:
We acknowledge financial support from The Universities of Oxford and Southampton, the Paul Scherrer Institute , the EPSRC ( EP/S028722/1 to S.T.), the Swiss National Scientific Foundation ( 310030_197626 to J.L.), the BrightFocus Foundation ( A20201759S to J.L.), and Takeda Pharmaceutical Company Limited for their generosity in providing financial and logistical support during a sabbatical position for T.Y. as a visiting scientist at the University of Oxford .
Publisher Copyright:
© 2022 The Author(s)
Keywords:
lipid bilayer, nanopore, neurodegeneration, Parkinson's disease, metal ions, trapping., peptidomimetic, α-Synuclein
Identifiers
Local EPrints ID: 476083
URI: http://eprints.soton.ac.uk/id/eprint/476083
ISSN: 2666-3864
PURE UUID: b90733a9-9557-4f86-81d3-46ae42df5392
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Date deposited: 12 Apr 2023 11:45
Last modified: 28 Aug 2024 01:49
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Contributors
Author:
Jinming Wu
Author:
Tohru Yamashita
Author:
Andrew D. Hamilton
Author:
Jinghui Luo
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