TY - JOUR TI - Breakage of the oligomeric CaMKII hub by the regulatory segment of the kinase AU - Karandur, Deepti AU - Bhattacharyya, Moitrayee AU - Xia, Zijie AU - Lee, Young Kwang AU - Muratcioglu, Serena AU - McAffee, Darren AU - McSpadden, Ethan D AU - Qiu, Baiyu AU - Groves, Jay T AU - Williams, Evan R AU - Kuriyan, John A2 - Griffith, Leslie C A2 - Cole, Philip A A2 - Bayliss, Richard A2 - Kern, Dorothee VL - 9 PY - 2020 DA - 2020/09/09 SP - e57784 C1 - eLife 2020;9:e57784 DO - 10.7554/eLife.57784 UR - https://doi.org/10.7554/eLife.57784 AB - Ca2+/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. KW - CaMKII KW - activation-dependent disassembly KW - spread of activation state KW - molecular dynamics simulation KW - native mass spectrometry JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -