A fundamental question in mechanobiology is how mechanical stimuli are sensed and converted into signals that regulate cellular responses to the external environment. This ability of cells to sense the mechanical properties of the microenvironment is critical for diverse biological processes ranging from tissue development to cancer metastasis.
Talin, and its interactions with the protein vinculin, are central in the mechanosensing processes of cell-matrix adhesions. Both exist in autoinhibited, inactive forms, yet how forces affect their interaction is not fully understood.
Using state-of-the-art single-molecule assays, steered full-atom molecular dynamics simulation, principal component analysis, and theoretical modelling based on statistical mechanics, Dr Wang Yinan showed that the mechanical unfolding of talin releases its autoinhibitory conformation, enabling high-affinity vinculin binding. The high-binding energy drives a conformational change of vinculin that activates vinculin for downstream signaling.
The results resolve an outstanding debate on vinculin activation mechanism and advances our understanding of how the interplay between force and biomolecular conformations provides exquisite complexity within the major mechanosensing module in numerous cellular processes.