Fig. 5.

The structural basis for Ca²⁺/calmodulin regulating the binding between CaMKII and actin. (A) The binding complex between the regulatory domain (colored in red), part of the linker (colored in yellow), and F-actin (colored in cyan). The structure of Ca²⁺/calmodulin (colored in purple) is docked to the regulatory domain by utilizing the crystal structure of Ca²⁺/calmodulin–CaMKII peptide binding complex (PDB ID code 1CDM). There are atom clashes between Ca²⁺/calmodulin and F-actin (shown by the red arrow). (B) Kinetic model for CaMKII binding to actin regulated by Ca²⁺/calmodulin. The letter “R” represents the regulatory domain, “L” represents the linker, “A” represents the association domain, and “C” represents Ca²⁺/calmodulin. The cyan line represents F-actin. Arrows represent the association or dissociation events; k₀ represents the association rate of Ca²⁺/calmodulin to CaMKII, while [C] represents the concentration of Ca²⁺/calmodulin. Once Ca²⁺/calmodulin binds to the regulatory domain (dashed arrow), the regulatory domain cannot bind to F-actin (red cross). (C) Free-energy profiles of individual CaMKII domains binding to F-actin measured in simulations, as a function of the distance between the center of mass of each individual CaMKII domain and the center of mass of the conserved binding pocket of actin. The free-energy barriers, ∆G, are used to estimate the relative rates in the kinetic model shown in B. (Left) The regulatory domain. (Middle) The linker. (Right) The association domain. (D) The overall dissociation rate of CaMKII from F-actin with increasing concentrations of Ca²⁺/calmodulin divided by the dissociation rate without Ca²⁺/calmodulin.