The Molecular Interplay of Tau and Motor Proteins on Microtubules

Tau, a microtubule-associated protein, plays a crucial role in neuronal cytoskeletal organization and intracellular transport. However, the precise way in which tau regulates motor proteins remains unclear. To unravel this, researchers employed single-molecule imaging, cryo-electron microscopy, and molecular dynamics simulations to explore the molecular mechanisms involved in tau-mediated inhibition of kinesin-1 and cytoplasmic dynein motility.

The study revealed that tau suppresses microtubule (MT) landing and induces frequent pausing and premature detachment when motors encounter tau-enriched patches. Interestingly, tau affects each motor protein using distinct mechanisms. Kinesin-1 and tau compete for the same surface on tubulin, preventing them from simultaneously binding to the same MT site. In contrast, while dynein and tau can co-occupy the same tubulin, tau hinders the transition of dynein into its high-affinity MT-binding state.

Through these findings, tau functions as either a physical or a conformational roadblock, exerting concentration-dependent structural constraints on kinesin and dynein transport. This research establishes a structural framework for understanding tau-mediated regulation of axonal transport.