The puzzle of integrin & talin interaction

Integrins are central proteins for cell communication and cell adhesion. They play essential roles in almost all physiological mechanisms, such as for example the insulin regulation described in a recent paper in the Journal of Biological Chemistry. Their transmembrane position allows them to transmit mechanical information from their extracellular domain to the interior of the cell with the help of intracellular adapter proteins, such as talin. Despite the essential function of talin for integrin receptors, its physical structure and mode of operation remains a mystery, as previous descriptions of its physical structure are incompatible with its biological function.

Changing the orientation of a single loop to solve the puzzle

The head domain of talin, composed of four linearly arranged subdomains, is crucial for the interaction with and the regulation of integrins at the cell surface. Prof. Bernhard Wehrle-Haller in collaboration with other researchers from Finland and the United States of America propose a new, compact, clover-leaf-like structure of the four subdomains of the talin head (see Figure below), important for its biological functioning. They imagined that slight changes in one of the subdomains of the head, the F3 subdomain, would induce this clover-leaf arrangement. These changes would modify the orientation of a flexible loop from another subdomain, F1, allowing this loop to be directed towards the integrin receptor and to regulate its activation. A crystallization of the full head domain in this compact conformation allowed them confirming this exciting hypothesis.

And it works biologically

If the structure was confirmed physically, its function remained to be tested. With modeling and mutagenesis analyses, Prof. Bernhard Wehrle-Haller proved in his recent paper in the Journal of Cell Science the biological function of the F1 loop and the importance of its orientation towards integrins to allow interaction. The team of Prof. Bernhard Wehrle-Haller laboratory is now investigating the role played by other adaptors in integrin activation and their implication in specific diseases, such as cancer and fibrosis.

In contrast to previous descriptions (left), the new compact cloverleaf model (right) changes the orientation of the loop from the F1 subdomain of talin (in orange) and allows the regulation of the integrin receptor (green/blue rods) . © adapted from Kukkurainen et al. 2020, Journal of Cell Science

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