Three-dimensional reconstruction of intact human integrin αIIbβ3: new implications for activation-dependent ligand binding

Integrin alpha IIb beta 3 plays a central role in hemostasis and thrombosis. We provide the first 3-dimensional reconstruction of intact purified alpha IIb beta 3 in a nanodisc lipid bilayer. Unlike previous models, it shows that the ligand-binding head domain is on top, pointing away from the membrane. Moreover, unlike the crystal structure of the recombinant ectodomain, the lower legs are not parallel, straight, and adjacent. Rather, the alpha IIb lower leg is bent between the calf-1 and calf-2 domains and the beta 3 Integrin-Epidermal Growth Factor (I-EGF) 2 to 4 domains are freely coiled rather than in a cleft between the beta 3 headpiece and the aIIb lower leg. Our data indicate an important role for the region that links the distal calf-2 and beta-tail domains to their respective transmembrane (TM) domains in transmitting the conformational changes in the TM domains associated with inside-out activation.