RESUMO
BACKGROUND: Tau is a disordered Microtubule Associated Protein (MAP) which prefers to bind and stabilize microtubules. Phosphorylation of tau in particular enhances tautubulin interaction which otherwise detaches from tubulin during hyperphosphorylation. The reason behind their destabilization, detachment and the role of ß subunit (from microtubule) and the projection domain (Tau) in microtubule stability remains elusive till date. Thus, a complete 3D structural investigation of tau protein is much needed to address these queries as the existing crystal structures are in fragments and quite limited. METHODS: In this study, the modelled human tau protein was subjected to phosphorylation and hyperphosphorylation which were later considered for docking with micro-tubules (ßα subunits-inter dimer) and vinblastine. RESULTS: Phosphorylated tau protein interacts with both α- and ß subunits. But stronger bonding was with α- compared to ß subunits. Regarding ß subunit, proline rich loop and projection domain actively participated in tau binding. Interestingly, hyperphosphorylation of tau increases MAP domain flexibility which ultimately results in tau 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 domain and proline rich region of ß-subunit in stabilizing the tau-tubulin interaction and also the effect of hyperphosphorylation in protein-protein and protein-drug binding.
