Iron Redox Chemistry Promotes Antiparallel Oligomerization of α-Synuclein

Abeyawardhane, Dinendra L; Fernández, Ricardo D.; Murgas, Cody J.; Heitger, Denver R.; Forney, Ashley K.; Crozier, Madeleine K; Lucas, Heather R.

doi:10.1021/jacs.8b02013

Cited by 52 publications

(51 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Tetrameric NAc αS was expressed and purified as previously described [1] , [2] . Verification of the multimeric conformer was confirmed by BN-PAGE, and the associated native gel for the intact protein has been described in the related research article [1] .…”

Section: Experimental Design Materials and Methodsmentioning

confidence: 99%

Mass spectrometry data confirming tetrameric α-synuclein N-terminal acetylation

Fernández

Lucas

2018

Data in Brief

Self Cite

View full text Add to dashboard Cite

Tetrameric α-synuclein (αS) is an elusive multimer of the dynamic neuronal protein implicated in Parkinson׳s disease. Through the data reported herein, we demonstrate that this high molecular weight multimer is N-acetylated. Coexpression of tetrameric αS in Escherichia coli with the NatB acetylase derived from yeast enables access to N-terminally acetylated αS (NAcαS), the native form in humans. Following purification and characterization as previously described by us in “Isolation of Recombinant Tetrameric N-acetylated α-synuclein” (Fernández and Lucas, 2018), the purified protein was excised from a native gel for confirmation of N-terminal acetylation. Through high-resolution mass spectrometry techniques, the identification of this helical tetramer as NAcαS has been clearly demonstrated.

show abstract

Section: Experimental Design Materials and Methodsmentioning

confidence: 99%

Mass spectrometry data confirming tetrameric α-synuclein N-terminal acetylation

Fernández

Lucas

2018

Data in Brief

Self Cite

View full text Add to dashboard Cite

show abstract

“…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: 91%

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

Curry

Fernández

Pagani

et al. 2020

Life

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…Efforts are also being made to elucidate the participation of other molecules in the α-Syn altered dynamics. Namely, Abeyawardhane et al reported the contribution of oxygen and redox active iron in conformational change and oligomerization of α-Syn, which can be useful in understanding the mechanisms of its physiological and/or pathological role [13]. The strong ability of α-Syn to form complexes with other biomolecules such as lipid moieties and cholesterol has also been reported.…”

Section: Synucleins Family-new Insights and Prospectsmentioning

confidence: 99%

Alpha-Synuclein Aggregation, Cholesterol Transport, and the 18-kDa Translocator Protein

Dimitrova-Shumkovska¹,

Krstanoski²

2020

Synucleins - Biochemistry and Role in Diseases

View full text Add to dashboard Cite

The molecular responses to counteract diseases, including insulting conditions such as injury and pathogen infection, involve coordinated modulation of gene expression programs. The association of alpha synuclein (α-Syn) with several progressive disorders has focused the research on its induced conformational behavior as critical for uncovering the "secrets" for progression of α-synucleinopathies. Cholesterol is one of the lipid components crucial for regular proliferation of the nervous tissue. Its interaction with α-Syn may offer other insights to α-Syn normal expression. Discovering that the molecular regulatory mechanisms responsible for prevention of α-Syn aggregation may be manifested through microRNA (miRNA) regulated gene expression is also crucial for widening the perception of neuropathology. The 18-kDa translocator protein (TSPO) localized on the outer mitochondrial membrane is able to regulate various cellular and tissue functions, with key role as cholesterol transporter for neurosteroid synthesis. TSPO up-regulation, has been connected to several diseases, including cancer, neuronal damage, and inflammation. Connection may also be established between TSPO expression and fatty acid oxidation, thus unveiling new possibilities in the research of α-Syn overexpression. However, expression of TSPO in the neuroinflammatory environment is probably the best starting point for targeting TSPO as a suitable therapeutic target.

show abstract

Iron Redox Chemistry Promotes Antiparallel Oligomerization of α-Synuclein

Cited by 52 publications

References 51 publications

Mass spectrometry data confirming tetrameric α-synuclein N-terminal acetylation

Mass spectrometry data confirming tetrameric α-synuclein N-terminal acetylation

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

Alpha-Synuclein Aggregation, Cholesterol Transport, and the 18-kDa Translocator Protein

Contact Info

Product

Resources

About