A breakthrough in revealing the mechanosensitive mechanism of microtubules

A research team led by Prof. Yuan Lin and Prof. Jeff Ti, from the Department of Mechanical Engineering and School of Biomedical Sciences respectively, at the University of Hong Kong has made major breakthrough in elucidating the mechanosensitive mechanism of microtubule in cells, a fundamental question not well understood by scientists before. The findings have recently been published in the prestigious international academic journal Nature Physics (https://doi.org/10.1038/s41567-025-02983-w).

Microtubules are hollow cylindrical cytoskeletal polymers of laterally associated protofilaments that contain head-to-tail aligned ɑ/β-tubulin heterodimers. While the exposed microtubule exterior is readily accessible to proteins, the mechanism governing the accessibility of the confined micrometer-long microtubule lumen to the long-observed luminal particles remains unknown. By combining single-molecule experiments with computational modeling, the research team led by Prof. Ti and Prof. Lin showed that mechanical compression alone is enough to create gaps between adjacent protofilaments (Fig. 1) in microtubules consisting of certain tubulin isotypes and result in elevated luminal accessibility. Further analysis suggested that the weakened inter-tubulin interactions associated with those isotypes is responsible for the force-regulated protofilament spraying (Fig. 2) and accessibility of microtubules for different luminal proteins.      

By elucidating the biophysical mechanism behind the force-dependent response of microtubules, this study greatly enhances our basic understanding of, for example, how diverse forms of mechanosensation could be developed in neurons as well as provide insights for the design of novel mechanosensitive molecules/bio-structures in the future. 

Figure 1. Direct characterization of microtubule mechanical plasticity. a, Schematic of the optical tweezer experiments for characterizing the mechanical properties of microtubules. b, Representative image of two laser-trapped NeutrAvidin-coated beads attached to a microtubule under the epifluorescence rhodamine channel (561/605 nm). Similar results were obtained from at least three independent experiments. c,d, Snapshots of the compressive-force-induced lattice deformation of TBA-2/TBB-2 (c) and MEC-12/ MEC-7 (d) microtubules. The TBA-2/TBB-2 microtubule lattice remained intact (arrow), whereas the MEC-12/MEC-7 microtubules were splayed with separate protofilaments (arrowhead). e,f, Schematics of the deformed TBA-2/TBB-2 (e) and MEC-12/ MEC-7 (f) microtubules shown in Fig. 2c,d, respectively. g,h, Raw compression (light blue) and relaxation (light red) force–strain curves of TBA-2/TBB-2 (g) and MEC-12/MEC-7 (h) microtubules are shown. To determine the energy absorption efficiency (orange), the smoothed compression force–strain curves (black) were calculated by binning the detected forces every 0.5% strain. Scale bars, 5 µm (b–d).

Figure 2. The 3D finite element model of microtubule mechanical plasticity. a, Schematic of our microtubule model that uses 13 Euler–Bernoulli cylindrical beams with Young’s modulus (E) to mimic individual protofilaments. A stiffness tensor K is introduced to represent the inter-protofilament lateral interactions. b,c, Simulated compressive force–strain (black) and energy absorption efficiency–strain (orange) curves overlaid with experimental force measurements (grey) of compressed TBA-2/TBB-2 (b) and MEC-12/MEC-7 (c) microtubules. d, Strains with peak compressive force in the simulation of TBA-2/TBB-2 (black) and MEC-12/MEC-7 (green) microtubules with lengths ranging from ~5 µm to ~30 µm. The dashed lines represent the linear fits (black, slope = 0.011, R2 = 0.94; green, slope = 0.002, R2 = 0.9) to the data points. Figure 3a shows the experimental data for comparison. e, Strains with maximum energy absorption efficiency in the simulation of TBA-2/TBB-2 (black) and MEC-12/MEC-7 (green) microtubules with lengths ranging from ~5 µm to ~30 µm. The dashed lines represent linear fits to the data points. f,g, Simulated separation distance between neighbouring protofilaments (grey dotted curves) and average interprotofilament distance across a cross-section (black curves) of 16-µm TBA-2/ TBB-2 (f) and MEC-12/MEC-7 (g) microtubules at 50% strain. Each grey dotted curve represents the distance between a pair of neighbouring protofilaments. The inset shows an enlarged view of the separation distance observed in the TBA-2/TBB-2 microtubules.