Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 17, Issue 3, Pages 264-U23Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.1751
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Funding
- Howard Hughes Medical Institute Funding Source: Medline
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The dodecameric holoenzyme of calcium-calmodulin-dependent protein kinase II (CaMKII) responds to high-frequency Ca2+ pulses to become Ca2+ independent. A simple coincidence-detector model for Ca2+-frequency dependency assumes noncooperative activation of kinase domains. We show that activation of CaMKII by Ca2+-calmodulin is cooperative, with a Hill coefficient of similar to 3.0, implying sequential kinase-domain activation beyond dimeric units. We present data for a model in which cooperative activation includes the intersubunit 'capture' of regulatory segments. Such a capture interaction is seen in a crystal structure that shows extensive contacts between the regulatory segment of one kinase and the catalytic domain of another. These interactions are mimicked by a natural inhibitor of CaMKII. Our results show that a simple coincidence-detection model cannot be operative and point to the importance of kinetic dissection of the frequency-response mechanism in future experiments.
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