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Abstract

The α and β isoforms of CaMKII are central orchestrators of the neuronal cytoskeleton, assembling into complex heterododecamers to regulate dendritic spine morphology. While the direct binding of CaMKIIβ to F-actin is crucial for structural plasticity, the physical principles governing this multivalent interaction remain poorly understood. Leveraging our previous high-speed atomic force microscopy (HS-AFM) observations that β subunits preferentially occupy adjacent positions within the CaMKIIα/β heterooligomer, we developed a statistical mechanics-based mathematical model to elucidate the CaMKII-actin interface. Our model successfully captures the in vivo correlation between CaMKIIα/β expression ratios and F-actin affinity, revealing that β-subunit adjacency–rather than simple stoichiometry–is the primary determinant of stable binding. We demonstrate that this spatial clustering significantly enhances binding avidity by optimizing the geometric fit to the F-actin filament, a process further modulated by the intrinsic flexibility of the β-subunit linkers. These findings identify the non-random spatial organization of CaMKII subunits as a key structural mechanism for tuning the neuronal cytoskeleton, providing a quantitative framework for understanding how protein complex architecture governs biological function.