Intersubunit capture of regulatory segments is a component of cooperative CaMKII activation

Nat Struct Mol Biol. 2010 Mar;17(3):264-72. doi: 10.1038/nsmb.1751. Epub 2010 Feb 7.


The dodecameric holoenzyme of calcium-calmodulin-dependent protein kinase II (CaMKII) responds to high-frequency Ca(2+) pulses to become Ca(2+) independent. A simple coincidence-detector model for Ca(2+)-frequency dependency assumes noncooperative activation of kinase domains. We show that activation of CaMKII by Ca(2+)-calmodulin is cooperative, with a Hill coefficient of approximately 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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Binding Sites
  • Caenorhabditis elegans / enzymology
  • Caenorhabditis elegans Proteins / chemistry
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism
  • Calcium / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / chemistry*
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
  • Calmodulin / metabolism
  • Crystallography, X-Ray
  • Humans
  • Models, Biological
  • Phosphorylation
  • Protein Binding / genetics
  • Protein Binding / physiology
  • Protein Structure, Secondary


  • Caenorhabditis elegans Proteins
  • Calmodulin
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium

Associated data

  • PDB/3KK8
  • PDB/3KK9
  • PDB/3KL8