Role of Phosphorylation and Hyperphosphorylation of Tau in Its Interaction withβα Dimeric Tubulin Studied from a Bioinformatics Perspective

Background: Tau is a disordered Microtubule Associated Protein (MAP) which prefersto bind and stabilize microtubules. Phosphorylation of tau in particular enhances tautubulininteraction which otherwise detaches from tubulin during hyperphosphorylation.The reason behind their destabilization, detachment and the role of β subunit(from microtubule) and the projection domain (Tau) in microtubule stability remainselusive till date. Thus, a complete 3D structural investigation of tau protein is muchneeded to address these queries as the existing crystal structures are in fragments andquite limited.Methods: In this study, the modelled human tau protein was subjected to phosphorylationand hyperphosphorylation which were later considered for docking with microtubules(βα subunits-inter dimer) and vinblastine.Results: Phosphorylated tau protein interacts with both α- and β subunits. But strongerbonding was with α- compared to β subunits. Regarding β subunit, proline richloop and projection domain actively participated in tau binding. Interestingly, hyperphosphorylationof tau increases MAP domain flexibility which ultimately results intau detachment, the main reason behind tangle formation in Alzheimer’s disease.Conclusion: This study being the first of its kind emphasizes the role of projection domainand proline rich region of β-subunit in stabilizing the tau-tubulin interactionand also the effect of hyperphosphorylation in protein-protein and protein-drugbinding.