Biology subjects

General, I. J.

Publications and source records attributed to General, I. J..

2 recordsLinked to original sources

bioRxiv2020

Physical Interactions Driving the Activation/Inhibition of Calcium/Calmodulin Dependent Protein Kinase II

CaMKII is a protein kinase whose function is regulated by the binding of the Calcium/Calmodulin complex (Ca2+/CaM). It is a major player in the Long Term Potentiation process where it acts as a molecular switch, oscillating between inhibited and active conformations. The mechanism for the switching is thought to be initiated by Ca2+/CaM binding, which allows the trans-phosphorylation of a subunit of CaMKII by a neighboring kinase, leading to the active state of the system. A combination of all-atom and coarse-grained MD simulations with free energy calculations, led us to reveal an interplay of electrostatic forces exerted by Ca2+/CaM on CaMKII, which initiate the activation process. The highly electrically charged Ca2+/CaM neutralizes basic regions in the linker domain of CaMKII, facilitating its opening and consequent activation. The emerging picture of CaMKIIs behavior highlights the preponderance of electrostatic interactions, which are modulated by the presence of Ca2+/CaM and the phosphorylation of key sites.

biophysics↗

bioRxiv2020

Disulfide bridge formation prevents CaMKII/Calmodulin interaction in Parkinson's disease

There is increasing evidence for disordered Ca2+ signaling in dopamine neurons in Parkinsons 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 vitro and in vivo investigations 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.

neuroscience↗