Domain organization and structure of talin-1. (A) Illustration of autoinhibited (i) and linear (ii) talin-1. Talin-1 consists of a talin head domain (THD) comprising a FERM domain (F0, F1, F2, F3, orange), and a talin rod domain (magenta). (B) Cryo-EM structure of autoinhibited human talin-1. The autoinhibited talin-1 is compactly folded with the talin-1 head interacting with the rod domains. (C) Two intramolecular interactions between the FERM domain and the rod domain, namely F3 (purple)–R9 (mint) and F2 (pink)–R12 (dark green), are shown to be critical for autoinhibition. The F0 and F1 structure is not resolved because of their flexibility. (D) A model of talin-1 in direct interaction with Rap1. A linear conformation of talin-1 head domain (green) is displayed in this model. Rap1b is bound to the plasma membrane using its C-terminal geranyl-geranyl moieties. The THD regions (blue) known to interact with the negatively charged PIP2 phospholipids face the membrane: the fly-casting F1 loop; the F2 membrane orientation patch (MOP); and the F3 association patch (FAP). Panels B and C are adapted from Dedden et al³³ and panel D from Gingras et al⁶⁹ with permission.