An AlphaFold guided model for the evolution of the CaMKII interactome

Area of Science:

• Neuroscience
• Molecular Biology
• Evolutionary Biology

Background:

• Neuronal functions rely on calcium calmodulin-dependent protein kinase II (CaMKII) interactions.
• CaMKII's kinase domain binds regulators and substrates upon Ca2+ activation.
• Understanding CaMKII's evolutionary trajectory is key to its diverse roles.

Purpose of the Study:

• To analyze the evolution of the CaMKII interactome across different organisms.
• To investigate the conservation of CaMKII molecular interactions.
• To trace the functional specialization of CaMKII from neurosecretion to synaptic signaling.

Main Methods:

• Analysis of over forty 3D-atomic structures and models of CaMKII-target complexes.
• Comparative analysis of binding surface overlap, energy frustration, and fold evolution.
• Utilizing transcriptome databases for Ca2+ response regulation and substrate colocalization studies.

Main Results:

• The molecular interactome of CaMKII shows significant conservation across species, including Trichoplax adhaerans.
• CaMKII activation machinery is invariant, but co-expression with substrates decreases in simpler organisms.
• A progressive reduction in CaMKII and substrate co-expression was observed from mammals to simpler organisms.

Conclusions:

• CaMKII architecture for autoinhibition, Ca2+ response, and substrate association likely originated for neurosecretion.
• The CaMKII interactome specialized for synaptic signaling with the emergence of the alpha isoform in mammals.
• Evolutionary analysis provides insights into the functional diversification of CaMKII in neuronal processes.