One possible model for the cooperative activation of αIIbβ3 by kindlin-3 and talin-1. In resting platelets, the 2 distal helices of the β3 cytoplasmic tail interact with the membrane bilayer and are not competent to bind talin-1 or kindlin-3 because the membrane obstructs their access to β3. However, the dynamic nature of the tail makes protein-protein interaction motifs accessible. As depicted in the model, kindlin-3 binding to the distal β3 tail removes the proximal tail from the membrane, thereby allowing it to bind to the talin-1 FERM domain. In turn, talin-1 FERM domain binding causes separation of the αIIbβ3 transmembrane domain heterodimer and subsequent αIIbβ3 activation. Adapted from Metcalf et al⁶  with permission. Professional illustration by Patrick Lane, ScEYEnce Studios.