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Abstract

The microtubule-associated protein Tau promotes the polymerization of tubulin and modulates the function of microtubules. Because of the dynamic nature of the Tau/tubulin interaction, the structural basis of this complex has remained largely elusive. Using a combination of NMR methods optimized for ligand-receptor interactions and site-directed mutagenesis we demonstrate that the flanking domain downstream of the four microtubule-binding repeats of Tau binds competitively to a site on the α-tubulin surface. The binding process of this Tau region to tubulin is complex, involves partial coupling of different interacting regions and is modulated by phosphorylation at Y394 and S396. Our study strengthens the intimate relationship between Tau phosphorylation and tubulin binding and highlights the power of INPHARMA NMR to characterize the interaction of peptides derived from intrinsically disordered proteins with molecular partners.