Formation of covalent di-tyrosine dimers in recombinant α-synuclein

A van Maarschalkerweerd; MN Pedersen; H Peterson; M Nilsson; TTT Nguyen; T Skamris; K Rand; V Vetri; AE Langkilde; B Vestergaard

doi:10.1080/21690707.2015.1071302

Formation of covalent di-tyrosine dimers in recombinant α-synuclein

A van Maarschalkerweerd, MN Pedersen, H Peterson, M Nilsson, TTT Nguyen, T Skamris, K Rand, V Vetri, AE Langkilde, B Vestergaard

LUKKET: Institut for Lægemiddeldesign og Farmakologi

9 Citationer (Scopus)

Abstract

Parkinson's disease is associated with fibril deposition in the diseased brain. Misfolding events of the intrinsically disordered synaptic protein α-synuclein are suggested to lead to the formation of transient oligomeric and cytotoxic species. The etiology of Parkinson's disease is further associated with mitochondrial dysfunction and formation of reactive oxygen species. Oxidative stress causes chemical modification of native α-synuclein, plausibly further influencing misfolding events. Here, we present evidence for the spontaneous formation of covalent di-tyrosine α-synuclein dimers in standard recombinant protein preparations, induced without extrinsic oxidative or nitrative agents. The dimers exhibit no secondary structure but advanced SAXS studies reveal an increased structural definition, resulting in a more hydrophobic micro-environment than the highly disordered monomer. Accordingly, monomers and dimers follow distinct fibrillation pathways.

Originalsprog	Engelsk
Tidsskrift	Intrinsically Disordered Proteins
Vol/bind	3
Udgave nummer	1
Sider (fra-til)	1-12
Antal sider	12
ISSN	null
DOI	https://doi.org/10.1080/21690707.2015.1071302
Status	Udgivet - 19 okt. 2015

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10.1080/21690707.2015.1071302

Citationsformater

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title = "Formation of covalent di-tyrosine dimers in recombinant α-synuclein",

abstract = "Parkinson's disease is associated with fibril deposition in the diseased brain. Misfolding events of the intrinsically disordered synaptic protein α-synuclein are suggested to lead to the formation of transient oligomeric and cytotoxic species. The etiology of Parkinson's disease is further associated with mitochondrial dysfunction and formation of reactive oxygen species. Oxidative stress causes chemical modification of native α-synuclein, plausibly further influencing misfolding events. Here, we present evidence for the spontaneous formation of covalent di-tyrosine α-synuclein dimers in standard recombinant protein preparations, induced without extrinsic oxidative or nitrative agents. The dimers exhibit no secondary structure but advanced SAXS studies reveal an increased structural definition, resulting in a more hydrophobic micro-environment than the highly disordered monomer. Accordingly, monomers and dimers follow distinct fibrillation pathways.",

author = "{van Maarschalkerweerd}, A and MN Pedersen and H Peterson and M Nilsson and TTT Nguyen and T Skamris and K Rand and V Vetri and AE Langkilde and B Vestergaard",

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T1 - Formation of covalent di-tyrosine dimers in recombinant α-synuclein

AU - van Maarschalkerweerd, A

AU - Pedersen, MN

AU - Peterson, H

AU - Nilsson, M

AU - Nguyen, TTT

AU - Skamris, T

AU - Rand, K

AU - Vetri, V

AU - Langkilde, AE

AU - Vestergaard, B

N1 - doi: 10.1080/21690707.2015.1071302

PY - 2015/10/19

Y1 - 2015/10/19

N2 - Parkinson's disease is associated with fibril deposition in the diseased brain. Misfolding events of the intrinsically disordered synaptic protein α-synuclein are suggested to lead to the formation of transient oligomeric and cytotoxic species. The etiology of Parkinson's disease is further associated with mitochondrial dysfunction and formation of reactive oxygen species. Oxidative stress causes chemical modification of native α-synuclein, plausibly further influencing misfolding events. Here, we present evidence for the spontaneous formation of covalent di-tyrosine α-synuclein dimers in standard recombinant protein preparations, induced without extrinsic oxidative or nitrative agents. The dimers exhibit no secondary structure but advanced SAXS studies reveal an increased structural definition, resulting in a more hydrophobic micro-environment than the highly disordered monomer. Accordingly, monomers and dimers follow distinct fibrillation pathways.

AB - Parkinson's disease is associated with fibril deposition in the diseased brain. Misfolding events of the intrinsically disordered synaptic protein α-synuclein are suggested to lead to the formation of transient oligomeric and cytotoxic species. The etiology of Parkinson's disease is further associated with mitochondrial dysfunction and formation of reactive oxygen species. Oxidative stress causes chemical modification of native α-synuclein, plausibly further influencing misfolding events. Here, we present evidence for the spontaneous formation of covalent di-tyrosine α-synuclein dimers in standard recombinant protein preparations, induced without extrinsic oxidative or nitrative agents. The dimers exhibit no secondary structure but advanced SAXS studies reveal an increased structural definition, resulting in a more hydrophobic micro-environment than the highly disordered monomer. Accordingly, monomers and dimers follow distinct fibrillation pathways.

U2 - 10.1080/21690707.2015.1071302

DO - 10.1080/21690707.2015.1071302

M3 - Journal article

SN - null

VL - 3

SP - 1

EP - 12

JO - Intrinsically Disordered Proteins

JF - Intrinsically Disordered Proteins

IS - 1

ER -

Formation of covalent di-tyrosine dimers in recombinant α-synuclein

Abstract

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