Figure 1: Representative kymographs showing single GFP-tagged ATAT-2 molecules on GMPCPP-stabilized MEC-12/MEC-7 (left) and TBA-2/TBB-2 (right) microtubules. Similar results were obtained from at least three independent experiments.
Constructed with tubulin heterodimers connected into a hollow cylinder, the microtubule, an essential component of the cytoskeleton, plays a vital role in various intracellular processes. In a groundbreaking study, a cross-disciplinary research team led by Professor Yuan Lin from the Department of Mechanical Engineering in the Faculty of Engineering, and Professor Jeff Ti from the School of Biomedical Sciences in the Li Ka Shing Faculty of Medicine at the University of Hong Kong (HKU), has revealed how the biological function of microtubules is achieved through mechanical regulation at the tubulin level.
Microtubules are hollow, cylindrical filamentous polymers of tubulins that function as force-bearing scaffolds or cargo-transport tracks in cells. To execute their biological functions, microtubules need to interact with groups of proteins—some binding to the microtubule's exterior and others to its lumen. While the microtubule exterior is readily accessible to proteins, how luminal binding proteins gain access to the confined inner surface of microtubules remains a mystery. Specifically, the molecular mechanism by which the microtubule lattice determines the luminal accessibility has been elusive.
Combining single-molecule fluorescence microscopy-based assays with direct mechanical characterisation by force microscopy (Figure 1), Professor Ti's team, for the first time, revealed that tubulin isotypes (i.e., different variants of the tubulin protein) serve as the force-sensing element that regulates the accessibility of microtubule lumen for enzymes to interact with the substrates on the inner surface of the lattice.
To elucidate the mechanistic insight into the roles of tubulin isotypes in regulating the luminal accessibility, Professor Lin's team developed a 3D computational model of the microtubule (Figure 2). Simulations revealed that the relatively weak lateral interaction of specific tubulin isotypes enables the reversible formation of inter-filament gaps when compressed. Experimentally validated, these transient gaps are large enough to allow entry of luminal binding proteins. Together, these findings unveil a fundamental mechanism by which tubulin isotypes influence the strength of inter-protofilament lateral interactions, thereby governing luminal accessibility through reversible protofilament separation (i.e., lattice breathing). This demonstrates that the mechano-plasticity of microtubules can be regulated by their constituent tubulin isotypes, enabling distinct responses to thermally- or stress-induced mechanical deformation.
"In addition to significantly advancing our understanding of the phenomenon of mechano-transduction of cells, findings from this study could also provide critical insights for the development of novel active biomaterials in the future", said Professor Lin and Professor Ti.
The research findings have been published in the prestigious international journal Nature Physics, titled: "Tubulin isotypes of C. elegans harness the mechanosensitivity of the lattice for microtubule luminal accessibility".
Link to the paper: https://doi.org/10.1038/s41567-025-02983-w
About Professor Jeff Ti
Professor Jeff Shih-Chieh Ti joined the School of Biomedical Sciences as an Assistant Professor in 2019. Before joining HKU, Professor Ti received his B.S. in Chemistry from National Taiwan University, PhD in Biochemistry and Biophysics from Yale University, and then worked as a postdoctoral fellow at the Rockefeller University. Professor Ti's team is a pioneer in using interdisciplinary approaches, including biochemistry, biophysics, structural biology, and cell biology, to dissect the molecular mechanism by which cytoskeleton proteins adopt diverse biological organisations and functions. The earlier research work has been published in prestigious international academic journals, including Cell, Science, Developmental Cell, Cell Reports, and Nature Structural & Molecular Biology.
About Professor Yuan Lin
Professor Yuan Lin earned his B.S. and M.S. in Engineering Mechanics from Tsinghua University, followed by another M.S. in Applied Mathematics and a PhD in Solid Mechanics from Brown University. He joined The University of Hong Kong in 2008 and is now a full Professor in the Department of Mechanical Engineering. His research on cell/tissue mechanics and mechanics of functional materials led to publications in top journals, including Nature, PNAS, Nature Communications, Science Advances and PRL. Prof. Lin has served as Chair of the Gordon Research Conference on Nano-Mechanical Interfaces and keynote speaker in numerous international conferences. As the PI or Co-PI, he has secured more than 15 research grants. Prof. Lin currently serves as the Secretary for the Hong Kong Society of Theoretical and Applied Mechanics. Professor Lin's team is among the world leaders in investigating mechano-regulation and mechano-sensitivity of cells. For example, they were the first to demonstrate that the viscosity of the extracellular matrix affects cell adhesion and spreading. In addition, their recent studies also revealed how internally generated cellular forces drive the structural evolution and deformation of tissues during processes such as embryo development and morphogenesis. These earlier research works have been published in prestigious international academic journals such as Nature, Science Advances, and PNAS.
