Model of agonist-induced αIIbβ3 activation.

(A) Stimulation of a platelet agonist receptor (e.g., PAR1) by an agonist leads to the activation of Rap1, resulting in targeting of its effector, RIAM, to the plasma membrane. (B) Cell stimulation also releases talin from its auto-inhibitory state, resulting in separation of the THD from the talin rod domain and recruitment of talin to the membrane-bound Rap1/RIAM complex. (C) Membrane-bound talin is recruited to αIIbβ3 by interaction of the THD with membrane-distal residues in the β3 cytoplasmic domain. (D) Further interactions of the THD with membrane-proximal β3 tail residues and membrane phospholipids leads to separation of the αIIb and β3 tail and transmembrane domains, triggering propagated changes in the extracellular domains leading to high-affinity binding of adhesive ligands, such as fibrinogen. While kindlins, like talin, can interact with the β3 cytoplasmic tail, they can also bind to other proteins [20], [42], and the molecular basis of their integrin co-activating function remains unclear. This working model is based on published studies summarized in [2].