Structural Basis for Dityrosine-Mediated Inhibition of α-Synuclein Fibrillization

Cagla Sahin; Eva Christina Østerlund; Nicklas Österlund; Joana Costeira-Paulo; Jannik Nedergaard Pedersen; Gunna Christiansen; Janni Nielsen; Anne Louise Grønnemose; Søren Kirk Amstrup; Manish K Tiwari; R Shyama Prasad Rao; Morten Jannik Bjerrum; Leopold L Ilag; Michael J Davies; Erik G Marklund; Jan Skov Pedersen; Michael Landreh; Ian Max Møller; Thomas J D Jørgensen; Daniel Erik Otzen

doi:10.1021/jacs.2c03607

Structural Basis for Dityrosine-Mediated Inhibition of α-Synuclein Fibrillization

Cagla Sahin, Eva Christina Østerlund, Nicklas Österlund, Joana Costeira-Paulo, Jannik Nedergaard Pedersen, Gunna Christiansen, Janni Nielsen, Anne Louise Grønnemose, Søren Kirk Amstrup, Manish K Tiwari, R Shyama Prasad Rao, Morten Jannik Bjerrum, Leopold L Ilag, Michael J Davies, Erik G Marklund, Jan Skov Pedersen, Michael Landreh, Ian Max Møller, Thomas J D Jørgensen, Daniel Erik Otzen

Research output: Contribution to journal › Journal article › Research › peer-review

10 Citations (Scopus)

41 Downloads (Pure)

Abstract

α-Synuclein (α-Syn) is an intrinsically disordered protein which self-assembles into highly organized β-sheet structures that accumulate in plaques in brains of Parkinson's disease patients. Oxidative stress influences α-Syn structure and self-assembly; however, the basis for this remains unclear. Here we characterize the chemical and physical effects of mild oxidation on monomeric α-Syn and its aggregation. Using a combination of biophysical methods, small-angle X-ray scattering, and native ion mobility mass spectrometry, we find that oxidation leads to formation of intramolecular dityrosine cross-linkages and a compaction of the α-Syn monomer by a factor of √2. Oxidation-induced compaction is shown to inhibit ordered self-assembly and amyloid formation by steric hindrance, suggesting an important role of mild oxidation in preventing amyloid formation.

Original language	English
Journal	Journal of the American Chemical Society
Volume	144
Issue number	27
Pages (from-to)	11949-11954
Number of pages	6
ISSN	0002-7863
DOIs	https://doi.org/10.1021/jacs.2c03607
Publication status	Published - 13 Jul 2022

Keywords

Amyloid/chemistry
Humans
Parkinson Disease/metabolism
Tyrosine/analogs & derivatives
alpha-Synuclein/chemistry

Access to Document

10.1021/jacs.2c03607Licence: CC BY 4.0

Open Access articleFinal published version, 2.47 MBLicence: CC BY 4.0

AUB Link

Search for the material in Aalborg University Library's search engine

Cite this

Sahin, C., Østerlund, E. C., Österlund, N., Costeira-Paulo, J., Pedersen, J. N., Christiansen, G., Nielsen, J., Grønnemose, A. L., Amstrup, S. K., Tiwari, M. K., Rao, R. S. P., Bjerrum, M. J., Ilag, L. L., Davies, M. J., Marklund, E. G., Pedersen, J. S., Landreh, M., Møller, I. M., Jørgensen, T. J. D., & Otzen, D. E. (2022). Structural Basis for Dityrosine-Mediated Inhibition of α-Synuclein Fibrillization. Journal of the American Chemical Society, 144(27), 11949-11954. https://doi.org/10.1021/jacs.2c03607

@article{c8625e556f7d4eab8adac4252c20279d,

title = "Structural Basis for Dityrosine-Mediated Inhibition of α-Synuclein Fibrillization",

abstract = "α-Synuclein (α-Syn) is an intrinsically disordered protein which self-assembles into highly organized β-sheet structures that accumulate in plaques in brains of Parkinson's disease patients. Oxidative stress influences α-Syn structure and self-assembly; however, the basis for this remains unclear. Here we characterize the chemical and physical effects of mild oxidation on monomeric α-Syn and its aggregation. Using a combination of biophysical methods, small-angle X-ray scattering, and native ion mobility mass spectrometry, we find that oxidation leads to formation of intramolecular dityrosine cross-linkages and a compaction of the α-Syn monomer by a factor of √2. Oxidation-induced compaction is shown to inhibit ordered self-assembly and amyloid formation by steric hindrance, suggesting an important role of mild oxidation in preventing amyloid formation.",

keywords = "Amyloid/chemistry, Humans, Parkinson Disease/metabolism, Tyrosine/analogs & derivatives, alpha-Synuclein/chemistry",

author = "Cagla Sahin and {\O}sterlund, {Eva Christina} and Nicklas {\"O}sterlund and Joana Costeira-Paulo and Pedersen, {Jannik Nedergaard} and Gunna Christiansen and Janni Nielsen and Gr{\o}nnemose, {Anne Louise} and Amstrup, {S{\o}ren Kirk} and Tiwari, {Manish K} and Rao, {R Shyama Prasad} and Bjerrum, {Morten Jannik} and Ilag, {Leopold L} and Davies, {Michael J} and Marklund, {Erik G} and Pedersen, {Jan Skov} and Michael Landreh and M{\o}ller, {Ian Max} and J{\o}rgensen, {Thomas J D} and Otzen, {Daniel Erik}",

year = "2022",

month = jul,

day = "13",

doi = "10.1021/jacs.2c03607",

language = "English",

volume = "144",

pages = "11949--11954",

journal = "Journal of the American Chemical Society",

issn = "0002-7863",

publisher = "American Chemical Society",

number = "27",

}

Sahin, C, Østerlund, EC, Österlund, N, Costeira-Paulo, J, Pedersen, JN, Christiansen, G, Nielsen, J, Grønnemose, AL, Amstrup, SK, Tiwari, MK, Rao, RSP, Bjerrum, MJ, Ilag, LL, Davies, MJ, Marklund, EG, Pedersen, JS, Landreh, M, Møller, IM, Jørgensen, TJD & Otzen, DE 2022, 'Structural Basis for Dityrosine-Mediated Inhibition of α-Synuclein Fibrillization', Journal of the American Chemical Society, vol. 144, no. 27, pp. 11949-11954. https://doi.org/10.1021/jacs.2c03607

TY - JOUR

T1 - Structural Basis for Dityrosine-Mediated Inhibition of α-Synuclein Fibrillization

AU - Sahin, Cagla

AU - Østerlund, Eva Christina

AU - Österlund, Nicklas

AU - Costeira-Paulo, Joana

AU - Pedersen, Jannik Nedergaard

AU - Christiansen, Gunna

AU - Nielsen, Janni

AU - Grønnemose, Anne Louise

AU - Amstrup, Søren Kirk

AU - Tiwari, Manish K

AU - Rao, R Shyama Prasad

AU - Bjerrum, Morten Jannik

AU - Ilag, Leopold L

AU - Davies, Michael J

AU - Marklund, Erik G

AU - Pedersen, Jan Skov

AU - Landreh, Michael

AU - Møller, Ian Max

AU - Jørgensen, Thomas J D

AU - Otzen, Daniel Erik

PY - 2022/7/13

Y1 - 2022/7/13

N2 - α-Synuclein (α-Syn) is an intrinsically disordered protein which self-assembles into highly organized β-sheet structures that accumulate in plaques in brains of Parkinson's disease patients. Oxidative stress influences α-Syn structure and self-assembly; however, the basis for this remains unclear. Here we characterize the chemical and physical effects of mild oxidation on monomeric α-Syn and its aggregation. Using a combination of biophysical methods, small-angle X-ray scattering, and native ion mobility mass spectrometry, we find that oxidation leads to formation of intramolecular dityrosine cross-linkages and a compaction of the α-Syn monomer by a factor of √2. Oxidation-induced compaction is shown to inhibit ordered self-assembly and amyloid formation by steric hindrance, suggesting an important role of mild oxidation in preventing amyloid formation.

AB - α-Synuclein (α-Syn) is an intrinsically disordered protein which self-assembles into highly organized β-sheet structures that accumulate in plaques in brains of Parkinson's disease patients. Oxidative stress influences α-Syn structure and self-assembly; however, the basis for this remains unclear. Here we characterize the chemical and physical effects of mild oxidation on monomeric α-Syn and its aggregation. Using a combination of biophysical methods, small-angle X-ray scattering, and native ion mobility mass spectrometry, we find that oxidation leads to formation of intramolecular dityrosine cross-linkages and a compaction of the α-Syn monomer by a factor of √2. Oxidation-induced compaction is shown to inhibit ordered self-assembly and amyloid formation by steric hindrance, suggesting an important role of mild oxidation in preventing amyloid formation.

KW - Amyloid/chemistry

KW - Humans

KW - Parkinson Disease/metabolism

KW - Tyrosine/analogs & derivatives

KW - alpha-Synuclein/chemistry

UR - http://www.scopus.com/inward/record.url?scp=85134426743&partnerID=8YFLogxK

U2 - 10.1021/jacs.2c03607

DO - 10.1021/jacs.2c03607

M3 - Journal article

C2 - 35749730

SN - 0002-7863

VL - 144

SP - 11949

EP - 11954

JO - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

IS - 27

ER -

Structural Basis for Dityrosine-Mediated Inhibition of α-Synuclein Fibrillization

Abstract

Keywords

Access to Document

AUB Link

Other files and links

Fingerprint

Cite this