Conformational Spread Drives the Evolution of the Calcium-calmodulin Protein Kinase II

Abstract

The calcium calmodulin (Ca2+CAM) dependent protein kinase II (CaMKII) decodes Ca2+ frequency oscillations. It has a central role in learning. I matched residue and organismal evolution to collective motions deduced from the atomic structure of the human CaMKIIa holoenzyme. Protein dynamic simulations and bioinformatic analysis showed its stacked ring architecture conformationally couples kinase domains (KDs) via its central hub. The simulations revealed underlying b-sheet collective motions in the hub ab association domain (AD) map onto a coevolved residue network and partition it into two distinct sectors. The holoenzyme evolved in metazoans by stabilization of ancient enzyme dimers and fold elongation to create a second, metastable sector for ring assembly. Continued evolution targeted the ring contacts for lateral conformational spread. The a isoform, predominantly expressed in the brain, emerged last and evolved rapidly in sync with the poikilotherm-homeotherm jump in the evolution of memory. The correlation between CaMKII dynamics and phylogenetics argues single residue evolution fine-tunes hub conformational spread. The central role of CaMKII ringed architecture In the brain could be to increase Ca2+ frequency response range for complex learning functions.