Model of αIIbβ3 based on αVβ3 crystal structure and depiction of switchblade model of αIIbβ3 conformational changes associated with activation and ligand binding. Inside-out signaling ultimately results in the binding of the talin head (H) domain binding to the cytoplasmic domain of the β3 subunit, resulting in subunit separation. This is transmitted through the transmembrane domains to the ectodomain where it results in extension of the α and β subunits and perhaps additional changes in the ligand binding region of β3. Ligand then binds, resulting in a swing-out motion of the β3 hybrid and PSI domains that may initiate outside-in signaling. Additional post-ligand binding events may occur, including homo-oligomerization of integrin transmembrane domains, leading to receptor clustering. The “deadbolt” hypothesis posits that modest changes in the β3 βA (I-like) domain brought about by movement of a nearby β3 β-terminal domain loop results in ligand binding, which is then followed by receptor extension and the swing-out motion. Adapted from Qin et al.143 The molecular models of αIIbβ3 were constructed using MODELLER 8v2 and the PDBs ITY6, IU8C, and IYUK as previously described.241 I-EGF, integrin epidermal growth factor domain; β-TD, β-terminal domain.
