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Time-dependent Autoinactivation of Phospho-Thr(286)-alpha Ca2+/Calmodulin-dependent Protein Kinase II

Jama, AM; Fenton, J; Robertson, SD; Török, K (2009) Time-dependent Autoinactivation of Phospho-Thr(286)-alpha Ca2+/Calmodulin-dependent Protein Kinase II. JOURNAL OF BIOLOGICAL CHEMISTRY, 284 (41). 28146 - 28155. ISSN 0021-9258 https://doi.org/10.1074/jbc.M109.005900
SGUL Authors: Torok, Katalin

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Abstract

Ca2+/calmodulin-dependent protein kinase II (αCaMKII) is thought to exert its role in memory formation by autonomous Ca2+-independent persistent activity conferred by Thr286 autophosphorylation, allowing the enzyme to remain active even when intracellular [Ca2+] has returned to resting levels. Ca2+ sequestration-induced inhibition, caused by a burst of Thr305/306 autophosphorylation via calmodulin (CaM) dissociation from the Thr305/306 sites, is in conflict with this view. The processes of CaM binding, autophosphorylation, and inactivation are dissected to resolve this conflict. Upon Ca2+ withdrawal, CaM sequential domain dissociation is observed, starting with the rapid release of the first (presumed N-terminal) CaM lobe, thought to be bound at the Thr305/306 sites. The time courses of Thr305/306 autophosphorylation and inactivation, however, correlate with the slow dissociation of the second (presumed C-terminal) CaM lobe. Exposure of the Thr305/306 sites is thus not sufficient for their autophosphorylation. Moreover, Thr305/306 autophosphorylation and autoinactivation are shown to occur in the continuous presence of Ca2+ and bound Ca2+/CaM by time courses similar to those seen following Ca2+ sequestration. Our investigation of the activity and mechanisms of phospho-Thr286-αCaMKII thus shows time-dependent autoinactivation, irrespective of the continued presence of Ca2+ and CaM, allowing a very short, if any, time window for Ca2+/CaM-free phospho-Thr286-αCaMKII activity. Physiologically, the time-dependent autoinactivation mechanisms of phospho-Thr286-αCaMKII (t½ of ∼50 s at 37 °C) suggest a transient kinase activity of ∼1 min duration in the induction of long term potentiation and thus memory formation

Item Type: Article
Additional Information: © 2009 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version full access. Creative Commons Attribution Non-Commercial License applies to Author Choice Articles.
Keywords: Animals, Calcium, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Calmodulin, Mice, Phosphorylation, Protein Conformation, Temperature, Threonine, Time Factors, Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, LONG-TERM POTENTIATION, D-ASPARTATE RECEPTOR, ALPHA-CAMKII, CALMODULIN, AUTOPHOSPHORYLATION, ACTIVATION, CALCIUM, INACTIVATION, MEMORY, CA2+/CALMODULIN
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Cell Sciences (INCCCS)
Journal or Publication Title: JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN: 0021-9258
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Dates:
DateEvent
9 October 2009Published
Web of Science ID: WOS:000270676300041
Download EPMC Full text (HTML)
URI: https://openaccess.sgul.ac.uk/id/eprint/115
Publisher's version: https://doi.org/10.1074/jbc.M109.005900

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