Activation State-Dependent Substrate Gating in Ca2+/Calmodulin-Dependent Protein Kinase II. (17th December 2017)

• Record Type: Journal Article
• Authors: Johnson, D. E.; Hudmon, A.
• Other Names: Zhou Yi Academic Editor.
• Is Part Of: Neural plasticity. Volume 2017(2017)
• Publication Date: 2017-12-17
• Subjects: Neuroplasticity -- Periodicals; 612.82
• DOI: 10.1155/2017/9601046
• Languages: English
• ISSNs: 2090-5904

Abstract

Abstract : Calcium/calmodulin-dependent protein kinase II (CaMKII) is highly concentrated in the brain where its activation by the Ca 2+ sensor CaM, multivalent structure, and complex autoregulatory features make it an ideal translator of Ca 2+ signals created by different patterns of neuronal activity. We provide direct evidence that graded levels of kinase activity and extent of T 287 (T 286 α isoform) autophosphorylation drive changes in catalytic output and substrate selectivity. The catalytic domains of CaMKII phosphorylate purified PSDs much more effectively when tethered together in the holoenzyme versus individual subunits. Using multisubstrate SPOT arrays, high-affinity substrates are preferentially phosphorylated with limited subunit activity per holoenzyme, whereas multiple subunits or maximal subunit activation is required for intermediate- and low-affinity, weak substrates, respectively. Using a monomeric form of CaMKII to control T 287 autophosphorylation, we demonstrate that increased Ca 2+ /CaM-dependent activity for all substrates tested, with the extent of weak, low-affinity substrate phosphorylation governed by the extent of T 287 autophosphorylation. Our data suggest T 287 autophosphorylation regulates substrate gating, an intrinsic property of the catalytic domain, which is amplified within the multivalent architecture of the CaMKII holoenzyme.