The adhesions between the cell and the surrounding extracellular matrix (ECM), mediated by the integrin family of transmembrane receptors, are exquisitely sensitive to biochemical, structural, and mechanical features of the ECM. This integrated biochemical and mechanosensitive regulation is central to many cellular processes. The mechanosensitive aspect involves both the exertion of physical forces by cells that create prestress and the transduction of the mechanical properties of the external environment into cellular responses.
Figure: The protein Talin - each domain serves as a force-dependent switch.
Despite their structural complexity, containing hundreds of proteins, adhesions between the cell and the ECM contain a simple and robust core of just 3 proteins: integrins linked to the actin cytoskeleton, by the protein talin. Talin contains a globular “head” domain that binds integrins and a rod-like “tail” made of 13 domains arranged like beads on a string that contain binding sites for actin and numerous other proteins. These rod domains unfold when force is applied to talin, behaving like switches, each one unfolding under different degrees of force. This enables us to envisage a talin molecule as a series of mechanochemical switches simultaneously decorated with numerous ligand proteins to form the signaling complex that we name the MSH (Goult et al., 2018).
In our previous HFSP funded study (Bouchet et al., 2016) we reported that one of the talin switches, through its interaction with KANK proteins, regulates the connection of adhesions to microtubules. Therefore, the talin MSH is able to orchestrate multiple cytoskeletal systems in the cell to influence cell shape, dynamics and signaling outputs.
The ability of talin to parse diverse multiple inputs to determine robust, reproducible signaling responses leads us to view the role of talin as an MSH as a type of “code”; that is, a network of binding events organized in time and space that confers meaning in the form of signaling outputs. Such a “talin code” may explain how cells interpret complex chemical and physical information to coordinate their behaviors.
Our current studies are focused on deciphering the talin code in the face of multiple ligands, different force thresholds, and different structural configurations. We are currently combining single-molecule approaches with systems biology to reveal and integrate the vast amounts of information encodable within this network.