Megadalton-sized Dityrosine Aggregates of α-Synuclein Retain High Degrees of Structural Disorder and Internal Dynamics

Verzini, Silvia; Shah, Maulik; Theillet, François‐Xavier; Belsom, Adam; Bieschke, Jan; Wanker, Erich E.; Rappsilber, Juri; Binolfi, Andrés; Selenko, Philipp

doi:10.1016/j.jmb.2020.10.023

Cited by 7 publications

(8 citation statements)

References 63 publications

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“…Biophysical techniques including circular dichroism (CD), light scattering, small angle neutron scattering (SANS), small angle X-ray scattering (SAXS), X-ray crystallography, NMR spectroscopy, and electron microscopy can provide useful information on protein structure. These methods are sensitive to modified structures, supplying valuable information on changes on morphology (i.e., mass, size and shape), secondary structure and solubility [ 45 , 196 , 197 ]. Some of these can also yield data on increased electron density between residues, thus supporting the presence of both intra- and intermolecular crosslinked species.…”

Section: Detection Of Crosslinks Including Advantages and Disadvantages Of Different Methodsmentioning

confidence: 99%

Oxidative Crosslinking of Peptides and Proteins: Mechanisms of Formation, Detection, Characterization and Quantification

et al. 2021

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Covalent crosslinks within or between proteins play a key role in determining the structure and function of proteins. Some of these are formed intentionally by either enzymatic or molecular reactions and are critical to normal physiological function. Others are generated as a consequence of exposure to oxidants (radicals, excited states or two-electron species) and other endogenous or external stimuli, or as a result of the actions of a number of enzymes (e.g., oxidases and peroxidases). Increasing evidence indicates that the accumulation of unwanted crosslinks, as is seen in ageing and multiple pathologies, has adverse effects on biological function. In this article, we review the spectrum of crosslinks, both reducible and non-reducible, currently known to be formed on proteins; the mechanisms of their formation; and experimental approaches to the detection, identification and characterization of these species.

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Section: Detection Of Crosslinks Including Advantages and Disadvantages Of Different Methodsmentioning

confidence: 99%

Oxidative Crosslinking of Peptides and Proteins: Mechanisms of Formation, Detection, Characterization and Quantification

et al. 2021

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show abstract

“…Biophysical techniques including circular dichroism (CD), light scattering, small angle neutron scattering (SANS), small angle X-ray scattering (SAXS), X-ray crystallography, NMR spectroscopy, and electron microscopy can provide useful information on protein structure. These methods are sensitive to modified structures, supplying valuable information on changes on morphology (i.e., mass, size and shape), secondary structure and solubility [45,196,197]. Some of these can also yield data on increased electron density between residues, thus supporting the presence of both intra-and intermolecular crosslinked species.…”

Section: Detection and Characterization Of Crosslinked Proteins Using...mentioning

confidence: 99%

Biomimetic Radical Chemistry and Applications 2021

2022

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“…The aggregation of α-synuclein has also been shown to be associated with increased oxidative or nitrosative stress [ 143 , 144 ]. Nitrated α-synuclein has an increased tendency to form dimers and oligomers by making cross-links between two tyrosine residues [ 145 , 146 ]. The latest findings point to the fact that this oxidative α-synuclein aggregation scavenges cytochrome c activity, thereby inhibiting the activity of this pro-apoptopic messenger and thus delaying the onset of programmed cell death [ 145 , 147 ].…”

Section: α-Synuclein and Mitochondrial Membranes: A Fatal Relationmentioning

confidence: 99%

Keeping α-Synuclein at Bay: A More Active Role of Molecular Chaperones in Preventing Mitochondrial Interactions and Transition to Pathological States?

Aspholm

Matečko-Burmann

Burmann

2020

Life

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The property of molecular chaperones to dissolve protein aggregates of Parkinson-related α-synuclein has been known for some time. Recent findings point to an even more active role of molecular chaperones preventing the transformation of α-synuclein into pathological states subsequently leading to the formation of Lewy bodies, intracellular inclusions containing protein aggregates as well as broken organelles found in the brains of Parkinson’s patients. In parallel, a short motif around Tyr39 was identified as being crucial for the aggregation of α-synuclein. Interestingly, this region is also one of the main segments in contact with a diverse pool of molecular chaperones. Further, it could be shown that the inhibition of the chaperone:α-synuclein interaction leads to a binding of α-synuclein to mitochondria, which could also be shown to lead to mitochondrial membrane disruption as well as the possible proteolytic processing of α-synuclein by mitochondrial proteases. Here, we will review the current knowledge on the role of molecular chaperones in the regulation of physiological functions as well as the direct consequences of impairing these interactions—i.e., leading to enhanced mitochondrial interaction and consequential mitochondrial breakage, which might mark the initial stages of the structural transition of α-synuclein towards its pathological states.

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Megadalton-sized Dityrosine Aggregates of α-Synuclein Retain High Degrees of Structural Disorder and Internal Dynamics

Cited by 7 publications

References 63 publications

Oxidative Crosslinking of Peptides and Proteins: Mechanisms of Formation, Detection, Characterization and Quantification

Oxidative Crosslinking of Peptides and Proteins: Mechanisms of Formation, Detection, Characterization and Quantification

Biomimetic Radical Chemistry and Applications 2021

Keeping α-Synuclein at Bay: A More Active Role of Molecular Chaperones in Preventing Mitochondrial Interactions and Transition to Pathological States?

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