Breakage of the oligomeric CaMKII hub by the regulatory segment of the kinase
Year: 2020
Type: article
Abstract: /calmodulin-dependent protein kinase II (CaMKII) is an oligomeric enzyme with crucial roles in neuronal signaling and cardiac function. Previously, we showed that activation of CaMKII triggers the exchange of subunits between holoenzymes, potentially increasing the spread of the active state (Stratton et al., 2014; Bhattacharyya et al., 2016). Using mass spectrometry, we show now that unphosphorylated and phosphorylated peptides derived from the CaMKII-α regulatory segment bind to the CaMKII-α hub and break it into smaller oligomers. Molecular dynamics simulations show that the regulatory segments dock spontaneously at the interface between hub subunits, trapping large fluctuations in hub structure. Single-molecule fluorescence intensity analysis of CaMKII-α expressed in mammalian cells shows that activation of CaMKII-α results in the destabilization of the holoenzyme. Our results suggest that release of the regulatory segment by activation and phosphorylation allows it to destabilize the hub, producing smaller assemblies that might reassemble to form new holoenzymes.
Source: eLife
DOI: 10.7554/elife.57784
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,500
Awards: Ion Hydration and Nanocalorimetry in Mass Spectrometry, G1742171491, G179862484, G2206590661, G2288762891, G3147773666, G3226045097, XSEDE 2.0: Integrating, Enabling and Enhancing National Cyberinfrastructure with Expanding Community Involvement, G4956565643, G6056929667, Molecular mechanism for the regulation of activation in calcium/calmodulin-dependent protein kinase II (CaMKII), G7276860779, Breakthrough Molecular Dynamics Research via an Anton2 Supercomputer
OpenAlex ID: W3086248643