Molecular Underpinnings of Postsynaptic Calmodulin-dependent Calcium Signaling

Calcium (Ca²⁺) signaling is a dynamic system where Ca²⁺ concentration fluctuates in range of 0.1-10μM with time. These short transient Ca²⁺ around the entry sites activate Ca²⁺-binding proteins such as calmodulin (CaM). The prototypical pathway describes CaM as encoding a Ca²⁺ signal by selectively activating downstream CaM-dependent proteins through molecular binding. However, CaM’s intrinsic Ca²⁺-binding properties alone appear insufficient to decode rapidly fluctuating Ca²⁺ signals. It has been proposed that the temporally varying mechanism for producing target selectivity requires CaM-target interactions that directly tune the Ca²⁺-binding properties of CaM through reciprocal interactions. I will focus on two unique and distinct CaM binding targets, neurogranin (Ng) and CaM-dependent kinase II (CaMKII), which are abundant in postsynaptic neuronal cells and are biochemically known to tune CaM’s affinity for Ca²⁺ in opposite directions. By employing an integrative approach of quantum mechanical calculations, all-atomistic molecular dynamics, and coarse-grained molecular simulations, we have revealed the molecular mechanisms of CaM’s reciprocal interaction between target binding and Ca²⁺binding.