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Neural Plasticity
Volume 2017, Article ID 9601046, 13 pages
Research Article

Activation State-Dependent Substrate Gating in Ca2+/Calmodulin-Dependent Protein Kinase II

Biochemistry and Molecular Biology, Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA

Correspondence should be addressed to A. Hudmon; ude.eudrup@nomduha

Received 15 July 2017; Accepted 23 October 2017; Published 17 December 2017

Academic Editor: Yi Zhou

Copyright © 2017 D. E. Johnson and A. Hudmon. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Calcium/calmodulin-dependent protein kinase II (CaMKII) is highly concentrated in the brain where its activation by the Ca2+ sensor CaM, multivalent structure, and complex autoregulatory features make it an ideal translator of Ca2+ signals created by different patterns of neuronal activity. We provide direct evidence that graded levels of kinase activity and extent of T287 (T286 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 T287 autophosphorylation, we demonstrate that increased Ca2+/CaM-dependent activity for all substrates tested, with the extent of weak, low-affinity substrate phosphorylation governed by the extent of T287 autophosphorylation. Our data suggest T287 autophosphorylation regulates substrate gating, an intrinsic property of the catalytic domain, which is amplified within the multivalent architecture of the CaMKII holoenzyme.