Phosphorylation at \(Ser^{26}\) in the ATP-Binding Site of \(Ca^{2+}\)/Calmodulin-Dependent Kinase II as a Mechanism for Switching off the Kinase Activity

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Phosphorylation at \(Ser^{26}\) in the ATP-Binding Site of \(Ca^{2+}\)/Calmodulin-Dependent Kinase II as a Mechanism for Switching off the Kinase Activity

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Title: Phosphorylation at \(Ser^{26}\) in the ATP-Binding Site of \(Ca^{2+}\)/Calmodulin-Dependent Kinase II as a Mechanism for Switching off the Kinase Activity
Author: Yilmaz, Mehtap; Gangopadhyay, Samudra Saurabh; Leavis, Paul Clifton; Grabarek, Zenon; Morgan, Kathleen G.

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Citation: Yilmaz, Mehtap, Samudra Saurabh Gangopadhyay, Paul Clifton Leavis, Zenon Grabarek, and Kathleen G. Morgan. 2013. Phosphorylation at \(Ser^{26}\) in the ATP-binding site of \(Ca^{2+}\)/calmodulin-dependent kinase II as a mechanism for switching off the kinase activity. Bioscience Reports 33(2): e00024.
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Abstract: CaMKII \((Ca^{2+}\)/calmodulin-dependent kinase II) is a serine/threonine phosphotransferase that is capable of long-term retention of activity due to autophosphorylation at a specific threonine residue within each subunit of its oligomeric structure. The \(\gamma\) isoform of CaMKII is a significant regulator of vascular contractility. Here, we show that phosphorylation of CaMKII \(\gamma\) at \(Ser^{26}\), a residue located within the ATP-binding site, terminates the sustained activity of the enzyme. To test the physiological importance of phosphorylation at \(Ser^{26}\), we generated a phosphospecific \(Ser^{26}\) antibody and demonstrated an increase in \(Ser^{26}\) phosphorylation upon depolarization and contraction of blood vessels. To determine if the phosphorylation of \(Ser^{26}\) affects the kinase activity, we mutated \(Ser^{26}\) to alanine or aspartic acid. The S26D mutation mimicking the phosphorylated state of CaMKII causes a dramatic decrease in \(Thr^{287}\) autophosphorylation levels and greatly reduces the catalytic activity towards an exogenous substrate (autocamtide-3), whereas the S26A mutation has no effect. These data combined with molecular modelling indicate that a negative charge at \(Ser^{26}\) of CaMKII \(\gamma\) inhibits the catalytic activity of the enzyme towards its autophosphorylation site at \(Thr^{287}\) most probably by blocking ATP binding. We propose that \(Ser^{26}\) phosphorylation constitutes an important mechanism for switching off CaMKII activity.
Published Version: doi:10.1042/BSR20120116
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3566533/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:10646382
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