An Allosteric Model of Calmodulin Explains Differential Activation of PP2B and CaMKII

Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10768-73. doi: 10.1073/pnas.0804672105. Epub 2008 Jul 31.

Abstract

Calmodulin plays a vital role in mediating bidirectional synaptic plasticity by activating either calcium/calmodulin-dependent protein kinase II (CaMKII) or protein phosphatase 2B (PP2B) at different calcium concentrations. We propose an allosteric model for calmodulin activation, in which binding to calcium facilitates the transition between a low-affinity [tense (T)] and a high-affinity [relaxed (R)] state. The four calcium-binding sites are assumed to be nonidentical. The model is consistent with previously reported experimental data for calcium binding to calmodulin. It also accounts for known properties of calmodulin that have been difficult to model so far, including the activity of nonsaturated forms of calmodulin (we predict the existence of open conformations in the absence of calcium), an increase in calcium affinity once calmodulin is bound to a target, and the differential activation of CaMKII and PP2B depending on calcium concentration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Calcineurin / metabolism*
  • Calcium / metabolism*
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
  • Calmodulin / chemistry*
  • Calmodulin / metabolism*
  • Computer Simulation
  • Enzyme Activation / genetics
  • Kinetics
  • Models, Molecular*
  • Protein Binding
  • Synapses / metabolism*

Substances

  • Calmodulin
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcineurin
  • Calcium