Elevated concentrations cause upright alpha-synuclein conformation at lipid interfaces

Steven J Roeters; Kris Strunge; Kasper B Pedersen; Thaddeus W Golbek; Mikkel Bregnhøj; Yuge Zhang; Yin Wang; Mingdong Dong; Janni Nielsen; Daniel E Otzen; Birgit Schiøtt; Tobias Weidner

doi:10.1038/s41467-023-39843-1

Elevated concentrations cause upright alpha-synuclein conformation at lipid interfaces

Steven J Roeters^*, Kris Strunge, Kasper B Pedersen, Thaddeus W Golbek, Mikkel Bregnhøj, Yuge Zhang, Yin Wang, Mingdong Dong, Janni Nielsen, Daniel E Otzen, Birgit Schiøtt, Tobias Weidner^*

^*Corresponding author for this work

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

9 Citations (Scopus)

Abstract

The amyloid aggregation of α-synuclein (αS), related to Parkinson's disease, can be catalyzed by lipid membranes. Despite the importance of lipid surfaces, the 3D-structure and orientation of lipid-bound αS is still not known in detail. Here, we report interface-specific vibrational sum-frequency generation (VSFG) experiments that reveal how monomeric αS binds to an anionic lipid interface over a large range of αS-lipid ratios. To interpret the experimental data, we present a frame-selection method ("ViscaSelect") in which out-of-equilibrium molecular dynamics simulations are used to generate structural hypotheses that are compared to experimental amide-I spectra via excitonic spectral calculations. At low and physiological αS concentrations, we derive flat-lying helical structures as previously reported. However, at elevated and potentially disease-related concentrations, a transition to interface-protruding αS structures occurs. Such an upright conformation promotes lateral interactions between αS monomers and may explain how lipid membranes catalyze the formation of αS amyloids at elevated protein concentrations.

Original language	English
Article number	5731
Journal	Nature Communications
Volume	14
Issue	1
Number of pages	12
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-023-39843-1
Publication status	Published - Dec 2023

Keywords

Humans
alpha-Synuclein
Parkinson Disease
Amides
Amyloidogenic Proteins
Lipids

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title = "Elevated concentrations cause upright alpha-synuclein conformation at lipid interfaces",

abstract = "The amyloid aggregation of α-synuclein (αS), related to Parkinson's disease, can be catalyzed by lipid membranes. Despite the importance of lipid surfaces, the 3D-structure and orientation of lipid-bound αS is still not known in detail. Here, we report interface-specific vibrational sum-frequency generation (VSFG) experiments that reveal how monomeric αS binds to an anionic lipid interface over a large range of αS-lipid ratios. To interpret the experimental data, we present a frame-selection method ({"}ViscaSelect{"}) in which out-of-equilibrium molecular dynamics simulations are used to generate structural hypotheses that are compared to experimental amide-I spectra via excitonic spectral calculations. At low and physiological αS concentrations, we derive flat-lying helical structures as previously reported. However, at elevated and potentially disease-related concentrations, a transition to interface-protruding αS structures occurs. Such an upright conformation promotes lateral interactions between αS monomers and may explain how lipid membranes catalyze the formation of αS amyloids at elevated protein concentrations.",

keywords = "Humans, alpha-Synuclein, Parkinson Disease, Amides, Amyloidogenic Proteins, Lipids",

author = "Roeters, {Steven J} and Kris Strunge and Pedersen, {Kasper B} and Golbek, {Thaddeus W} and Mikkel Bregnh{\o}j and Yuge Zhang and Yin Wang and Mingdong Dong and Janni Nielsen and Otzen, {Daniel E} and Birgit Schi{\o}tt and Tobias Weidner",

year = "2023",

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doi = "10.1038/s41467-023-39843-1",

language = "English",

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AU - Roeters, Steven J

AU - Strunge, Kris

AU - Pedersen, Kasper B

AU - Golbek, Thaddeus W

AU - Bregnhøj, Mikkel

AU - Zhang, Yuge

AU - Wang, Yin

AU - Dong, Mingdong

AU - Nielsen, Janni

AU - Otzen, Daniel E

AU - Schiøtt, Birgit

AU - Weidner, Tobias

PY - 2023/12

Y1 - 2023/12

N2 - The amyloid aggregation of α-synuclein (αS), related to Parkinson's disease, can be catalyzed by lipid membranes. Despite the importance of lipid surfaces, the 3D-structure and orientation of lipid-bound αS is still not known in detail. Here, we report interface-specific vibrational sum-frequency generation (VSFG) experiments that reveal how monomeric αS binds to an anionic lipid interface over a large range of αS-lipid ratios. To interpret the experimental data, we present a frame-selection method ("ViscaSelect") in which out-of-equilibrium molecular dynamics simulations are used to generate structural hypotheses that are compared to experimental amide-I spectra via excitonic spectral calculations. At low and physiological αS concentrations, we derive flat-lying helical structures as previously reported. However, at elevated and potentially disease-related concentrations, a transition to interface-protruding αS structures occurs. Such an upright conformation promotes lateral interactions between αS monomers and may explain how lipid membranes catalyze the formation of αS amyloids at elevated protein concentrations.

AB - The amyloid aggregation of α-synuclein (αS), related to Parkinson's disease, can be catalyzed by lipid membranes. Despite the importance of lipid surfaces, the 3D-structure and orientation of lipid-bound αS is still not known in detail. Here, we report interface-specific vibrational sum-frequency generation (VSFG) experiments that reveal how monomeric αS binds to an anionic lipid interface over a large range of αS-lipid ratios. To interpret the experimental data, we present a frame-selection method ("ViscaSelect") in which out-of-equilibrium molecular dynamics simulations are used to generate structural hypotheses that are compared to experimental amide-I spectra via excitonic spectral calculations. At low and physiological αS concentrations, we derive flat-lying helical structures as previously reported. However, at elevated and potentially disease-related concentrations, a transition to interface-protruding αS structures occurs. Such an upright conformation promotes lateral interactions between αS monomers and may explain how lipid membranes catalyze the formation of αS amyloids at elevated protein concentrations.

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KW - alpha-Synuclein

KW - Parkinson Disease

KW - Amides

KW - Amyloidogenic Proteins

KW - Lipids

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DO - 10.1038/s41467-023-39843-1

M3 - Journal article

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VL - 14

JO - Nature Communications

JF - Nature Communications

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ER -

Elevated concentrations cause upright alpha-synuclein conformation at lipid interfaces

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