Integrin activation and interaction with the actin cytoskeleton is mediated by the adaptor protein talin. Talin contains an N-terminal FERM domain comprising F1, F2 and F3 domains, and F1 contains an atypical large insert and is preceded by an extra domain F0. Although F3 was previously shown to bind to β integrin tails and to activate integrins, F0 and F1 are also required for efficient integrin activation. In The EMBO Journal, Ben Goult, Dave Critchley, Igor Barsukov and colleagues now report the solution structures of the F0 and F1 domains. 1
Using NMR spectroscopy, they show that both F0 and F1 have ubiquitin-like folds joined in a novel fixed orientation, which has not previously been seen in other tandem ubiquitin-like domains. The large loop in F1 is unstructured, but binding to acidic phospholipids induces formation of a helix with basic residues aligned along one face.
Charge reversal mutations compromise the phospholipid binding and the ability of the talin head to activate integrins. The authors propose a so-called 'fly-casting model' in which the contact between the F1 loop and phosphatidylinositol 4,5-biphosphate-rich membrane microdomains induces helix formation, and this in turn shortens the loop, pulling the talin head close to the membrane.
Interestingly, in a related study in the Journal of Molecular Biology, 2 the authors show that kindlins, which are required for talin-mediated integrin activation, have the same domain architecture as the talin FERM domain.