Dissecting cooperative calmodulin binding to CaM kinase II: a detailed stochastic model.
Calmodulin (CaM) is a major Ca(2+) binding protein involved in two opposing processes of synaptic plasticity of CA1 pyramidal neurons: long-term potentiation (LTP) and depression (LTD). The N- and C-terminal lobes of CaM bind to its target separately but cooperatively and introduce complex dynamics that cannot be well understood by experimental measurement. Using a detailed stochastic model constructed upon experimental data, we have studied the interaction between CaM and Ca(2+)-CaM-dependent protein kinase II (CaMKII), a key enzyme underlying LTP. The model suggests that the accelerated binding of one lobe of CaM to CaMKII, when the opposing lobe is already bound to CaMKII, is a critical determinant of the cooperative interaction between Ca(2+), CaM, and CaMKII. The model indicates that the target-bound Ca(2+) free N-lobe has an extended lifetime and may regulate the Ca(2+) response of CaMKII during LTP induction. The model also reveals multiple kinetic pathways which have not been previously predicted for CaM-dissociation from CaMKII.
Byrne
Michael J
MJ
Department of Neurobiology and Anatomy, University of Texas Medical School, Houston, TX 77030, USA.
Putkey
John A
JA
Waxham
M Neal
MN
Kubota
Yoshihisa
Y
D000465:Algorithms; D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D020013:Calcium Signaling / Q000502:physiology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D017774:Long-Term Potentiation / Q000502:physiology*; D008954:Models, Biological; D013269:Stochastic Processes; D013997:Time Factors
D002147:Calmodulin; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002118:Calcium