Structural mechanisms of interaction of triphosphorylated 2'- 5'- triadenylates with S100A1 protein

Abstract

We study the structural mechanisms of interaction of dephosphorylated 2'- 5'- triadenylates with S100A1 protein by NMR spectroscopy and computer simulation methods. Earlier, it was demonstrated that 2'- 5'- triadenylates are capable of stimulating the muscle contraction via a direct or indirect interaction with the Ryano dine receptor (RyR). One of the key regulators of this intracellular Ca²⁺ pump is a calciumbinding protein S100A1. We assumed that the naturally occurring 2'- 5'- triadenylate may interact with S100A1 directly, by exhibiting its effect, and took a detailed look at the interaction. It is shown that dephosphorylated 2'- 5'- triadenylate binds to S100A1 within the Ca²⁺binding loop/linker interface, where the aminoacids within the S100A1 homodimer displayed the highest amplitude of chemical shifts. Complex formation turned out to be stabilized by the formation of two electrostatic and one hydrogen bonds. The data obtained may suggest an insight into how the naturally occurring 2'- 5'- triadenylate exhibits its purely biological function. An alternative possible scenario is the interaction between 2'- 5'- triadenylate and CAM kinase, which leads to the alteration of the latter’s functioning, which further affects the RyR. S100A1’s antagonist regarding the RyR functioning, Calmodulin, was earlier shown to interact with 2'- 5'- triadenylate, which led to the Ca²⁺ affinity alteration of the latter. Collectively, these data assume that 2'- 5'- triadenylate interacts with both major regulators of RyR’s Ca²⁺releasing activity.