Impact of multiple phosphorylations on the tau-R2/tubulin interface

Abstract

The phosphorylation of the microtubule-associated tau protein plays a key role in the regulation of its physiological function. In particular, tau hyperphosphorylation affects its binding on the tubulin surface, destabilizing the tau-microtubule interface and leading to the accumulation of fibrillar aggregates in the brain. In this work, we performed classical Molecular Dynamics simulations for the tau-R2/tubulin assembly with various phosphorylations states of serines 285, 289 and 293. We analyze the resulting trajectories to obtain a detailed view of the protein interface in the complex, and the impact of tau phosphorylations on the stability of this assembly, and on the tubulin disordered C-Terminal tails (CTTs) mobility. We show how the tubulin CTTs help maintaining the tau-R2 fragment on the tubulin surface despite the destabilizing effect induced by phosphorylations. Conversely, tau phosphorylation affects the CTTs flexibility and their potential activity as MAP recruiting hooks. Furthermore, counterion mediated bridges between the phosphate groups and tubulin glutamates also contribute to the binding of tau-R2 on the MT. Overall, the complex dynamics of this fuzzy phosphorylated assembly sheds a new light on the importance of the cytoplasmic environment in neurons in the context of Alzheimers disease.