A coherent structural picture of the interaction of Tau with tubulin provides a link to its aggregation.

Tauopathies are a group of neurodegenerative diseases characterized by the presence of insoluble filaments of the Tau protein in the brain. In physiological conditions, Tau is involved in the regulation of microtubule dynamics. The study of its interaction with different tubulin assemblies, using various experimental approaches, leads to a seemingly disparate picture. Here, we propose to integrate this information into a model of how Tau participates in microtubule assembly and stabilization. Related to its intrinsically disordered nature, the binding of Tau to microtubules involves both specific interactions, along protofilaments, and nonspecific ones, with the C-terminal region of tubulin subunits. In addition, the recent determination of a Tau:tubulin structure provides a model for a functional dimer of Tau targeting a microtubule aperture between protofilaments. Therefore, Tau regulates microtubule dynamics by modulating both longitudinal and lateral contacts. Finally, we discuss a possible connection of this dimer of Tau with its oligomerization, whether physiological or pathological.