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bioRxiv · 10.64898/2026.11.02.763819

The Molecular Interplay of Tau and Motor Proteins on Microtubules

He, Y.·Peukes, J.·Golcuk, M.·Jack, A. Y.·Ferro, L. S.·Tan, R.·Gur, M.·Nogales, E.·Yildiz, A.
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Abstract

Tau is a microtubule (MT)-associated protein essential for neuronal cytoskeletal organization and intracellular transport, yet how tau physically regulates motor proteins remains elusive. Here, we integrate single-molecule imaging, cryo-electron microscopy, and molecular dynamics (MD) simulations to investigate the molecular mechanisms underlying tau-mediated inhibition of kinesin-1 and cytoplasmic dynein motility. We show that tau suppresses MT landing and triggers frequent pausing and premature detachment when motors encounter tau-enriched patches. Unexpectedly, tau impairs each motor using different mechanisms. Tau and kinesin-1 compete for the same surface on tubulin, precluding simultaneous binding to the same MT site. On the other hand, while dynein and tau can co-occupy the same tubulin, tau inhibits the transition of dynein into its high-affinity MT-binding state. Thus, tau can act as a physical or a conformational roadblock in a concentration-dependent manner, exerting distinct structural constraints on kinesin and dynein transport. These findings establish a structural framework for tau-mediated regulation of axonal transport.

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He, Y., Peukes, J., Golcuk, M., Jack, A. Y., Ferro, L. S., Tan, R., Gur, M., Nogales, E., Yildiz, A.. 2026-11-04. The Molecular Interplay of Tau and Motor Proteins on Microtubules. https://doi.org/10.64898/2026.11.02.763819

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