Mechanical tension expands the microtubule lattice stepwise and modulates kinesin-1 binding in an isoform-dependent manner

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 of [<]{Delta}F[>] = 10.6 pN, within the range 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. Significance StatementMicrotubules have been implicated as mechanotransducers in both mammalian and plant cells, yet a physical characterization of how mechanical forces are sensed and transduced into biochemical signals has been lacking. The present study demonstrates that modest tensile forces of less than 20 pN are sufficient to expand cooperatively the microtubule lattice by [~]0.3%, which in turn modulates its biochemical interactions with kinesin-1 in an isoform-dependent manner, selectively affecting KIF5B motor activity but not KIF5C. Strikingly, this mechanotransduction occurs on a timescale of seconds, implying that microtubules are highly efficient conduits for propagating mechanical information across the cell body. These findings establish microtubules as bona fide mechanochemical signal transducers with the speed and sensitivity required for rapid cellular responses.