Integrin tail-membrane interactions and high-affinity ligand binding. (A) NMR-derived model of αIIb (blue) and β3 (red) cytoplasmic tails. In resting cells (left), the 2 tails contact each other and are also embedded in the membrane via their N-terminal α-helices and the “middle” NPLY region of β3. Under these conditions, talin is not bound to β3. When cells and talin are activated (right), the head domain of talin (H) is released from inhibition by its rod domain (R) and binds to β3. This disrupts the relatively weak integrin tail-tail and tail-membrane interactions, leading to splaying of the tails and bidirectional signaling. Changes similar to those induced by talin binding may be induced by the binding of fibrinogen to αIIbβ3. From Vinogradova et al32 with permission. (B) The deadbolt model of inside-out integrin activation. In the nonactivated integrin, the elongated CD loop of βTD is in close proximity to the βA domain, allowing it to effectively “deadbolt” the F/α7 loop in place, preventing ligands (transparent blue circle) from making contact with βA residues necessary for high-affinity binding. Inside-out signaling is hypothesized to induce conformational changes in the cytoplasmic tails that when transmitted through the transmembrane domains would unlock the deadbolt. The resulting loss of constraints imposed by the CD loop would allow the F/α7 loop to rock back (exaggerated as shown) from the ligand contact site, making the latter available for binding. Certain LIBS antibodies may also move the deadbolt, promoting ligand binding independent of inside-out signals. Adapted from Xiong et al14 with permission.
