Breakage of the oligomeric CaMKII hub by the regulatory segment of the kinase.

Autor:	Karandur D; Department of Molecular and Cell Biology, University of California, 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., Bhattacharyya M; Department of Molecular and Cell Biology, University of California, 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., Xia Z; Department of Chemistry, University of California, Berkeley, Berkeley, United States., Lee YK; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.; California Institute for Quantitative Biosciences (QB3), University of California, Berkeley, Berkeley, United States.; Department of Chemistry, University of California, Berkeley, Berkeley, United States., Muratcioglu S; Department of Molecular and Cell Biology, University of California, 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., McAffee D; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.; California Institute for Quantitative Biosciences (QB3), University of California, Berkeley, Berkeley, United States.; Department of Chemistry, University of California, Berkeley, Berkeley, United States., McSpadden ED; Department of Molecular and Cell Biology, University of California, 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., Qiu B; Department of Molecular and Cell Biology, University of California, 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., Groves JT; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.; California Institute for Quantitative Biosciences (QB3), 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., Williams ER; California Institute for Quantitative Biosciences (QB3), University of California, Berkeley, Berkeley, United States.; Department of Chemistry, University of California, Berkeley, Berkeley, United States., Kuriyan J; Department of Molecular and Cell Biology, University of California, 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.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2020 Sep 09; Vol. 9. Date of Electronic Publication: 2020 Sep 09.
DOI:	10.7554/eLife.57784
Abstrakt:	Ca 2+ /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. Competing Interests: DK, MB, ZX, YL, SM, DM, EM, BQ, JG, EW No competing interests declared, JK Senior editor, eLife (© 2020, Karandur et al.)
Databáze:	MEDLINE
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