An AlphaFold guided model for the evolution of the CaMKII interactome

The neuronal functions of mammalian calcium calmodulin (Ca²⁺.CAM) dependent protein kinase II (CaMKII) are orchestrated by an interactome of multiple CaMKII-protein interactions when Ca²⁺.CAM opens the kinase domain to bind Ca²⁺ response regulators and substrates to its regulatory helix and C-lobe, respectively. We analyzed over forty 3D-atomic structures and models of CaMKII-target complexes to track the evolution of the neuronal CaMKII interactome over three model organisms and the early metazoan Trichoplax adhaerans. We report the conservation of the molecular interactome based on binding surface overlap, energy frustration and fold evolution. Transcriptome databases informed on Ca²⁺ CaMKII response regulation and colocalization with substrates. The activation machinery was invariant, but the co-expression of CaMKII and its substrates relative to the mammalian α isoform was progressively reduced in simpler organisms. We propose CaMKII architecture for autoinhibition, Ca²⁺ response and substrate association was formed for neurosecretion, then specialized for synaptic signalling with the α-isoform.