Copper Induced Radical Dimerization of α-Synuclein Requires Histidine

Abeyawardhane, Dinendra L; Fernández, Ricardo D.; Heitger, Denver R.; Crozier, Madeleine K; Wolver, Julia C; Lucas, Heather R.

doi:10.1021/jacs.8b08947

Cited by 29 publications

(38 citation statements)

References 60 publications

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“…Finally, a recent study demonstrated that Cu(I) binding to the AcAS variant activates O 2 resulting in both intermolecular Y39‐Y39 dityrosine crosslinking within the fibrillar core, as well as intramolecular crosslinking within the C‐terminal region (Abeyawardhane et al ) (Fig. b).…”

Section: Linking Post‐translational Modifications and Metal‐binding Imentioning

confidence: 95%

“…Since copper ions are predominantly found in their Cu(I) state in the reducing environment of living cells, characterization of the physiologically relevant Cu(I) complexes became particularly important (Binolfi et al 2011;Miotto et al 2015;Miotto et al 2017;Gentile et al 2018;Abeyawardhane et al 2018b). These studies revealed that Cu(I) binding to the high-affinity Met1-X3-Met5 site is influenced by acetylation at the N-terminus (Fig.…”

Section: Sumoylation Of A-synucleinmentioning

confidence: 99%

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Effects of alpha‐synuclein post‐translational modifications on metal binding

González

Arcos-López

König

et al. 2019

Journal of Neurochemistry

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Parkinson’s disease is the second most common neurodegenerative disorder worldwide. Neurodegeneration in this pathology is characterized by the loss of dopaminergic neurons in the substantia nigra, coupled with cytoplasmic inclusions known as Lewy bodies containing α‐synuclein. The brain is an organ that concentrates metal ions, and there is emerging evidence that a break‐down in metal homeostasis may be a critical factor in a variety of neurodegenerative diseases. α‐synuclein has emerged as an important metal‐binding protein in the brain, whereas these interactions play an important role in its aggregation and might represent a link between protein aggregation, oxidative damage, and neuronal cell loss. Additionally, α‐synuclein undergoes several post‐translational modifications that regulate its structure and physiological function, and may be linked to the aggregation and/or oligomer formation. This review is focused on the interaction of this protein with physiologically relevant metal ions, highlighting the cases where metal‐AS interactions profile as key modulators for its structural, aggregation, and membrane‐binding properties. The impact of α‐synuclein phosphorylation and N‐terminal acetylation in the metal‐binding properties of the protein are also discussed, underscoring a potential interplay between PTMs and metal ion binding in regulating α‐synuclein physiological functions and its role in pathology. This article is part of the Special Issue “Synuclein”.

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Section: Linking Post‐translational Modifications and Metal‐binding Imentioning

confidence: 95%

Section: Sumoylation Of A-synucleinmentioning

confidence: 99%

Effects of alpha‐synuclein post‐translational modifications on metal binding

González

Arcos-López

König

et al. 2019

Journal of Neurochemistry

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“…Metal dyshomeostasis has long been linked to PD [18][19][20], and victims of PD present with increased cerebral iron levels and diminished levels of copper in affected regions of the brain. Although the precise roles of brain metals on the function of NAc αSyn have yet to be elucidated, we [10,[21][22][23] and others [9,24,25] have demonstrated how prevalent brain biometals modulate the structural outcome of NAc αSyn self-assembly pathways and influence both the potential and the extent of its aggregation.…”

Section: Introductionmentioning

confidence: 90%

“…In this article, we employ systematic tyrosine-to-phenylalanine NAc αSyn mutations to examine the impact of iron binding on the global protein dynamics of NAc αSyn. In our previous studies [10,21], dityrosine formation was cataloged after an extended aggregation process under fibrillation conditions, while in these studies the immediate impact of iron binding was monitored, so our data herein depict preferential interactions in an unrestricted dynamic system. Previous reports from our group that utilized the PICUP method examined the influence of metals on the wild type protein [23]; through the work described herein, we will be able to map the involvement of specific tyrosine residues in the crosslinking process.…”

Section: Introductionmentioning

confidence: 99%

Mapping of Photochemically-Derived Dityrosine across Fe-Bound N-Acetylated α-Synuclein

Curry

Fernández

Pagani

et al. 2020

Life

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Parkinson’s disease (PD) is the second most common neurological disease and belongs to a group of neurodegenerative disorders called synucleinopathies in which pathological aggregates of N-terminally acetylated α-synuclein (NAcα-Syn) accumulate in various regions of the brain. In PD, these NAcα-Syn aggregates have been found to contain covalent dityrosine crosslinks, which can occur either intermolecularly or intramolecularly. Cerebral metal imbalance is also a hallmark of PD, warranting investigations into the effects of brain biometals on NAcα-Syn. NAcα-Syn is an intrinsically disordered protein, and metal-mediated conformational modifications of this structurally dynamic protein have been demonstrated to influence its propensity for dityrosine formation. In this study, a library of tyrosine-to-phenylalanine (Y-to-F) NAcα-Syn constructs were designed in order to elucidate the nature and the precise residues involved in dityrosine crosslinking of Fe-bound NAcα-Syn. The structural capacity of each mutant to form dityrosine crosslinks was assessed using Photo-Induced Cross-Linking of Unmodified Proteins (PICUP), demonstrating that coordination of either FeIII or FeII to NAcα-Syn inhibits dityrosine crosslinking among the C-terminal residues. We further demonstrate that Y39 is the main contributor to dityrosine formation of Fe-bound NAcα-Syn, while Y125 is the main residue involved in dityrosine crosslinks in unmetalated NAcα-Syn. Our results confirm that iron coordination has a global effect on NAcα-Syn structure and reactivity.

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“…Physiologically, aSyn is acetylated at the N‐terminus, and this PTM stabilizes the binding of Cu(I) ions, and increases the alpha‐helical content and, therefore, the binding of aSyn to membranes (Abeyawardhane et al, ). Interestingly, acetylation was recently reported on lysines 6 and 10, and found to reduce aSyn aggregation and toxicity (de Oliveira et al, ).…”

Section: Posttranslational Modifications Metals and Asyn: Cause Or Cmentioning

confidence: 99%

Synucleinopathies: Where we are and where we need to go

Brás

Dominguez-Meijide

Gerhardt

et al. 2020

Journal of Neurochemistry

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All authors contributed equally to this manuscript. This artic le is relat ed to the Speci al Issue "Synuc lein" Abbreviations: A30P, aSyn substitution of an alanine for a proline at position 30; A53E, aSyn substitution of an alanine for a glutamic acid at position 53; A53T, aSyn substitution of an alanine for a tyrosine at position 53; ALP, autophagy-lysosomal pathway; APLP1, Aβ precursor-like protein 1; aSyn, alpha-synuclein; BiFC, bimolecular fluorescence complementation; CMA, Chaperone-mediated autophagy; CNS, central nervous system; co-IP, co-immunoprecipitation; Cryo-EM, cryo-electron microscopy; CSF, cerebrospinal fluid; Cu, copper; DLB, dementia with Lewy bodies; E46K, aSyn substitution of a glutamic acid for a lysine at position 46; ENS, enteric nervous system; ER, endoplasmic reticulum; Fe, iron; FRET, fluorescence resonance energy transfer; G51D, aSyn substitution of a glycine for a aspartic acid at position 51Abstract Synucleinopathies are a group of disorders characterized by the accumulation of inclusions rich in the a-synuclein (aSyn) protein. This group of disorders includes Parkinson's disease, dementia with Lewy bodies (DLB), multiple systems atrophy, and pure autonomic failure (PAF). In addition, genetic alterations (point mutations and multiplications) in the gene encoding for aSyn (SNCA) are associated with familial forms of Parkinson's disease, the most common synucleinopathy. The Synuclein Meetings are a series that has been taking place every 2 years for about 12 years. The Synuclein Meetings bring together leading experts in the field of Synuclein and related human conditions with the goal of discussing and advancing the research. In 2019, the Synuclein meeting took place in Ofir, a city in the outskirts of Porto, Portugal. The meeting, entitled "Synuclein Meeting 2019:Where we are and where we need to go", brought together >300 scientists studying both clinical and molecular aspects of synucleinopathies. The meeting covered a many of the open questions in the field, in a format that prompted open discussions between the participants, and underscored the need for additional research that, hopefully, will lead to future therapies for a group of as of yet incurable disorders. Here, we provide a summary of the topics discussed in each session and highlight what we know, what we do not know, and what progress needs to be made in order to enable the field to continue to advance. We are confident this systematic assessment of where we stand will be useful to steer the field and contribute to filling knowledge gaps that may form the foundations for future therapeutic strategies, which is where we need to go.

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Copper Induced Radical Dimerization of α-Synuclein Requires Histidine

Cited by 29 publications

References 60 publications

Effects of alpha‐synuclein post‐translational modifications on metal binding

Effects of alpha‐synuclein post‐translational modifications on metal binding

Mapping of Photochemically-Derived Dityrosine across Fe-Bound N-Acetylated α-Synuclein

Synucleinopathies: Where we are and where we need to go

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