Mechanism of Tau Diffusion along Microtubules

By one-dimensional diffusion, proteins can search biological polymers while remaining associated with them. Tau, an intrinsically disordered microtubule-associated protein, undergoes rapid diffusion along the microtubule (MT) lattice primarily through electrostatic interactions with tubulin C-terminal tails (CTTs), yet the molecular mechanism underlying this behavior has remained unresolved. Here, we performed coarse-grained molecular dynamics simulations to characterize the diffusion mechanism of full-length Tau at domain and subdomain resolution. We show that Tau diffusion emerges from the heterogeneous translational behaviors of multiple weakly coupled MT-interacting subdomains. Although all contribute to diffusion, the proline-rich regions primarily act as persistent anchors, whereas the MT-binding repeats contribute most of the net translational displacement along the lattice. Together, these distinct dynamic roles give rise to a partially coordinated yet asynchronous diffusion mechanism. Electrostatic perturbations primarily altered the dynamics of the directly perturbed domain, supporting a locally regulated mechanism. Both the charge and the flexibility of the CTTs were essential for this mechanism: neutralizing the β-tubulin tails had the strongest effect on Tau binding and mobility, and stiffening the tails weakened PRR anchoring. Moreover, Tau segments transiently wrap around individual CTTs, allowing them to remain attached while rearranging. Together, these findings provide a molecular mechanism for Tau diffusion and illustrate how multivalent intrinsically disordered proteins can reconcile persistent substrate association with efficient one-dimensional exploration.