Activation-triggered subunit exchange between CaMKII holoenzymes facilitates the spread of kinase activity
Margaret Stratton,
Il-Hyung Lee,
Moitrayee Bhattacharyya,
Sune M Christensen,
Luke H Chao,
Howard Schulman,
Jay T Groves,
John Kuriyan
Affiliations
Margaret Stratton
Department of Molecular and Cell Biology, Berkeley, Berkeley, United States; California Institute for Quantitative Biosciences, (QB3), University of California, Berkeley, Berkeley, United States; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States
Il-Hyung Lee
California Institute for Quantitative Biosciences, (QB3), University of California, Berkeley, Berkeley, United States; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States; Department of Chemistry, University of California, Berkeley, Berkeley, United States
Moitrayee Bhattacharyya
Department of Molecular and Cell Biology, Berkeley, Berkeley, United States; California Institute for Quantitative Biosciences, (QB3), University of California, Berkeley, Berkeley, United States; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States
Sune M Christensen
California Institute for Quantitative Biosciences, (QB3), University of California, Berkeley, Berkeley, United States; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States; Department of Chemistry, University of California, Berkeley, Berkeley, United States
Luke H Chao
Department of Molecular and Cell Biology, Berkeley, Berkeley, United States; California Institute for Quantitative Biosciences, (QB3), University of California, Berkeley, Berkeley, United States; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States
Howard Schulman
Allosteros Therapeutics, Sunnyvale, United States
Jay T Groves
California Institute for Quantitative Biosciences, (QB3), University of California, Berkeley, Berkeley, United States; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States; Materials Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, United States; Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, United States
John Kuriyan
Department of Molecular and Cell Biology, Berkeley, Berkeley, United States; California Institute for Quantitative Biosciences, (QB3), University of California, Berkeley, Berkeley, United States; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States; Department of Chemistry, University of California, Berkeley, Berkeley, United States; Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, United States
The activation of the dodecameric Ca2+/calmodulin dependent kinase II (CaMKII) holoenzyme is critical for memory formation. We now report that CaMKII has a remarkable property, which is that activation of the holoenzyme triggers the exchange of subunits between holoenzymes, including unactivated ones, enabling the calcium-independent phosphorylation of new subunits. We show, using a single-molecule TIRF microscopy technique, that the exchange process is triggered by the activation of CaMKII, and that exchange is modulated by phosphorylation of two residues in the calmodulin-binding segment, Thr 305 and Thr 306. Based on these results, and on the analysis of molecular dynamics simulations, we suggest that the phosphorylated regulatory segment of CaMKII interacts with the central hub of the holoenzyme and weakens its integrity, thereby promoting exchange. Our results have implications for an earlier idea that subunit exchange in CaMKII may have relevance for information storage resulting from brief coincident stimuli during neuronal signaling.
