A model of talin-dependent integrin activation. The tilt angle of β3 TMD is maintained by the interaction between the positively charged end of K716 and negatively charged-phosphate head group. TMD packing interaction of integrin αIIb and β3 is mediated through glycine residues (G972, G976 in αIIb and G708 in β3) in the middle of the TMDs. The TMD interaction is also stabilized by electrostatic interaction between D723 and R995. The membrane distal region of β3 cytoplasmic tail interacts with talin through an NPXY motif, which is part of the primary talin-binding site. The membrane proximal region of β3 cytoplasmic tail interacts with talin via hydrophobic interaction between two Phe residues (F727 and F730) in β3 and L325 in talin. The positively charged residues (K322, K272, K274, R277, and K256) on the surface of talin can interact with lipid bilayer. Talin binding to the β3 membrane proximal region and lipid bilayer increases the tilt angle of β3 TMD thereby disrupting the helical packing interaction of the TMD leading to their rearrangement and resulting long range conformational change in the integrin. The amino acid residues of integrin αIIb (blue), β3 (green), and talin1 (red) are numbered.