Tubulin tails and their modifications regulate protein diffusion on microtubules

Microtubules (MTs) are essential components of the eukaryotic cytoskeleton that serve as “highways” for intracellular trafficking. In addition to the well-known active transport of cargo by motor proteins, many MT-binding proteins appear to adopt diffusional motility as a transportation mechanism. However, because of the limited spatial resolution of current experimental techniques, the detailed mechanism of protein diffusion has not been elucidated. In particular, the precise role of the disordered tubulin tails and tail modifications in the diffusion process is unclear. Here, using coarse-grained molecular dynamics simulations, calibrated against atomistic simulations, we explore the molecular mechanism of protein diffusion along MTs. We found that electrostatic interactions play a central role in protein diffusion; the disordered tubulin tails slow down diffusion; and diffusion occurs in discrete steps. While diffusion along wild-type MT is performed in steps of dimeric tublin, the removal of the tails results in a step of monomeric tubulin. We found that the energy barrier for diffusion is larger when protein diffusion on MTs is mediated primarily by the MT tails rather than the MT body. In addition, globular proteins (EB1 and PRC1) diffuse more slowly than an intrinsically disordered protein (Tau) on MTs. Finally, we found that poly-glutamylation of tubulin tails leads to slower protein diffusion on MTs, whereas poly-glycylation of the tails leads to faster diffusion on MTs. Taken together, our results explain experimentally observed data and shed light on the roles played by disordered tubulin tails and tail modifications in the molecular mechanism of protein diffusion along MTs.