Recent work has shown that the microtubule lattice possesses remarkable structural plasticity, with its conformation modulated by microtubule-associated proteins and motor proteins. However, how this plasticity responds to mechanical forces remains poorly understood. Here, we developed optical tweezers and fluorescence microscopy assays to measure the effect of tensile forces on single microtubules. Quantum dot decoration enabled nanometre-precision measurement of lattice distortions of ~0.33% under a change of mean tensile force = 10.6 pN, within the range of Fmin = 1.29 pN to Fmax = 22.3 pN - comparable to forces from one to three kinesin-1 motors. Within this force range, the binding rate of kinesin-1 isoform KIF5B decreased reversibly within seconds by ~20% and the dissociation rate increased by ~10%, reducing mean run length, that in extreme cases decreased by up to 46%. Substantial heterogeneity was also observed along individual microtubules, where distinct lattice regions responded differently to applied force, implying that lattice expansion is not always uniform. Consistent heterogeneity was observed in cells, where MAPs with competing conformational preferences assembled in non-overlapping patches along the same microtubule. A cooperatively-switching lattice Ising model based on tubulin conformational bistability, supported by dynamics simulations, quantitatively reproduces these observations with a critical switching force Fc = 8.5 pN, similar to established mechanosensory proteins such as talin and E-catenin. Strikingly, no significant effects were observed for KIF5C, revealing a kinesin isoform-dependent mechanoresponse. Together, these findings establish microtubules as mechanochemical signal transducers, converting mechanical forces into biochemical signals with the speed, spatial precision and sensitivity required for rapid cellular responses.
Lurz, Y., Fischer, B. S. J., Mishra, J., Muras, L., Schaeffer, E., Ostap, E. M., Mohd Rafiq, N., Kulic, I., Pyrpassopoulos, S.
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