A novel membrane-dependent on/off switch mechanism of talin FERM domain at sites of cell adhesion

The activation of heterodimeric (α/β) integrin transmembrane receptors bycytosolic protein talin is crucial for regulating diverse cell-adhesion-dependentprocesses, including blood coagulation, tissue remodeling, and cancer metastasis. Thisprocess is triggered by the coincident binding of N-terminal FERM(four-point-one-protein/ezrin/radixin/moesin) domain of talin (talin-FERM) to the innermembrane surface and integrin β cytoplasmic tail, but how these binding events arespatiotemporally regulated remains obscure. Here we report the crystal structure of adormant talin, revealing how a C-terminal talin rod segment (talin-RS) self-masks a keyintegrin-binding site on talin-FERM via a large interface. Unexpectedly, the structurealso reveals a distinct negatively charged surface on talin-RS that electrostaticallyhinders the talin-FERM binding to the membrane. Such a dual inhibitory topology for talinis consistent with the biochemical and functional data, but differs significantly from aprevious model. We show that upon enrichment with phosphotidylinositol-4,5-bisphosphate(PIP2) – a known talin activator, membrane strongly attracts a positively chargedsurface on talin-FERM and simultaneously repels the negatively charged surface ontalin-RS. Such an electrostatic “pull-push” process promotes the relief of thedual inhibition of talin-FERM, which differs from the classic “steric clash”model for conventional PIP2-induced FERM domain activation. These data therefore unravel anew type of membrane-dependent FERM domain regulation and illustrate how it mediates thetalin on/off switches to regulate integrin transmembrane signaling and cell adhesion.