A Structural Mechanism of Integrin αIIbβ3 “Inside-Out” Activation as Regulated by Its Cytoplasmic Face

Activation of the ligand binding function of integrin heterodimers requires transmission of an “inside-out” signal from their small intracellular segments to their large extracellular domains. The structure of the cytoplasmic domain of a prototypic integrin αIIbβ3 has been solved by NMR and reveals multiple hydrophobic and electrostatic contacts within the membrane-proximal helices of its α and the β cytoplasmic tails. The interface interactions are disrupted by point mutations or the cytoskeletal protein talin that are known to activate the receptor. These results provide a structural mechanism by which a handshake between the α and the β cytoplasmic tails restrains the integrin in a resting state and unclasping of this interaction triggers the inside-out conformational signal that leads to receptor activation.