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MBC in Press, published online ahead of print October 17, 2007
Mol. Biol. Cell 10.1091/mbc.E07-02-0185

A more recent version of this article appeared on December 1, 2007 Originally published as MBC in Press, 10.1091/mbc.E07-02-0185 on October 24, 2007
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Submitted on February 28, 2007
Revised on September 19, 2007
Accepted on October 5, 2007

Dual Mechanism of a Natural CaMKII Inhibitor

Rebekah S. Vest,* Kurtis D. Davies,* Heather O’Leary, J. David Port, and K. Ulrich Bayer

Department of Pharmacology, University of Colorado at Denver and Health Sciences Center, Aurora, CO 80045

Monitoring Editor: Tom U. Martin

Ca2+/calmodulin(CaM)-dependent protein kinase II (CaMKII) is a major mediator of cellular Ca2+-signaling. Several inhibitors are commonly used to study CaMKII function, but these all lack specificity. CaM-KIIN is a natural, specific CaMKII inhibitor protein. CN21 (derived from CaM-KIIN amino acids 43–63) showed full specificity and potency of CaMKII inhibition. CNs completely blocked Ca2+-stimulated and autonomous substrate phosphorylation by CaMKII, as well as auto-phosphorylation at T305. However, T286 auto-phosphorylation (the auto-phosphorylation generating autonomous activity) was only mildly affected. Two mechanisms can explain this unusual differential inhibitor effect. First, CNs inhibited activity by interacting with the CaMKII T-site (and thereby also interfered with NMDA-receptor binding to the T-site). Because of this, the CaMKII region surrounding T286 competed with CNs for T-site interaction, while other substrates did not. Second, the intersubunit T286 auto-phosphorylation requires CaM binding both to the "kinase" and the "substrate" subunit. CNs dramatically decreased CaM dissociation, thus facilitating the ability of CaM to make T286 accessible for phosphorylation. Tat-fusion made CN21 cell-penetrating, as it strongly inhibited filopodia motility in neurons and insulin secrection from isolated Langerhans’ islets. These results reveal the inhibitory mechanism of CaM-KIIN and establish a powerful new tool for dissecting CaMKII function.

*These authors contributed equally to this work.

Address correspondence to: K. Ulrich Bayer (ulli.bayer{at}uchsc.edu)




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