1. Disulfide bridge formation prevents CaMKII/Calmodulin interaction in Parkinson’s disease
- Author
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Ignacio J. General, J.T. Greenamyre, Emily C. Furbee, Filippo Pullara, Ivet Bahar, Roberto Di Maio, Joseph C Ayoobc, and Sandra L. Castro
- Subjects
Methionine ,Calmodulin ,biology ,Oxidative phosphorylation ,medicine.disease_cause ,Cell biology ,chemistry.chemical_compound ,chemistry ,Docking (molecular) ,Dopamine ,Ca2+/calmodulin-dependent protein kinase ,biology.protein ,medicine ,Oxidative stress ,Cysteine ,medicine.drug - Abstract
There is increasing evidence for disordered Ca2+signaling in dopamine neurons in Parkinson’s disease (PD), and this likely involves altered Ca2+/calmodulin-dependent protein kinase II (CaMKII) function. Previous work suggests that oxidative stress - a major feature in PD pathogenesis - affects regulatory methionine residues that sustain CaMKII activity in a Ca2+/CaM-independent manner. Here, applying computational modeling, we predicted formation of a defined disulfide bridge close to the CaMKII docking site for Ca2+/CaM binding.In vitroandin vivoinvestigations using PD models revealed formation of a disulfide bridge and loss of the CaMKII–calmodulin interaction. Mutagenesis of the relevant cysteine residues abrogated disulfide bridge formation and recovered the CaMKII–calmodulin interaction. Importantly, dopamine neurons from post-mortem PD brain specimens also lost this regulatory protein-protein interaction, providing relevance in the human disease. This study provides novel insights into oxidative CaMKII-CaM dysfunction, which may contribute to the pathophysiology of PD.
- Published
- 2020