Copper Induced Radical Dimerization of α-Synuclein Requires Histidine.

Autor: Abeyawardhane DL; Department of Chemistry , Virginia Commonwealth University , Richmond , Virginia 23284 , United States., Fernández RD; Department of Chemistry , Virginia Commonwealth University , Richmond , Virginia 23284 , United States., Heitger DR; Department of Chemistry , Virginia Commonwealth University , Richmond , Virginia 23284 , United States., Crozier MK; Department of Chemistry , Virginia Commonwealth University , Richmond , Virginia 23284 , United States., Wolver JC; Department of Chemistry , Virginia Commonwealth University , Richmond , Virginia 23284 , United States., Lucas HR; Department of Chemistry , Virginia Commonwealth University , Richmond , Virginia 23284 , United States.
Jazyk: angličtina
Zdroj: Journal of the American Chemical Society [J Am Chem Soc] 2018 Dec 12; Vol. 140 (49), pp. 17086-17094. Date of Electronic Publication: 2018 Nov 28.
DOI: 10.1021/jacs.8b08947
Abstrakt: Aggregation of the neuronal protein α-synuclein (αS) is a critical factor in the pathogenesis of Parkinson's disease. Analytical methods to detect post-translational modifications of αS are under development, yet the mechanistic underpinnings of biomarkers like dityrosine formation within αS have yet to be established. In our work, we demonstrate that Cu I -bound N-terminally acetylated αS ( NAc αS) activates O 2 resulting in both intermolecular dityrosine cross-linking within the fibrillar core as well as intramolecular cross-linking within the C-terminal region. Substitution of the H50 residue with a disease relevant Q mutation abolishes intermolecular dityrosine cross-linking and limits the Cu I /O 2 promoted cross-linking to the C-terminal region. Such a dramatic change in reaction behavior establishes a previously unidentified role for H50 in facilitating intermolecular cross-linking. Involvement of H50 in the reaction profile implies that long-range histidine coordination with the upstream Cu I coordination site is necessary to stabilize the transition of Cu I to Cu II as is a required mechanistic outcome of Cu I /O 2 reactivity. The aggregation propensity of NAc H50Q-Cu I is also enhanced in comparison to NAc αS-Cu I , suggesting a potential functional role for both copper and intermolecular cross-linking in attenuating NAc αS fibrillization.
Databáze: MEDLINE
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