A structural basis for integrin activation by the cytoplasmic tail of the alpha(IIb)-subunit

A key step in the activation of heterodimeric integrin adhesion receptors i s the transmission of an agonist-induced cellular signal from the short alp ha- and/or beta-cytoplasmic tails to the extracellular domains of the recep tor. The structural details of how the cytoplasmic tails mediate such an in side-out signaling process remain unclear. We report herein the NMR structu res of a membrane-anchored cytoplasmic tail of the alpha(IIb)-subunit and o f a mutant alpha(IIb)-cytoplasmic tail that renders platelet integrin alpha (IIb)beta(3) constitutively active. The structure of the wild-type alpha(II b)-cytoplasmic tail reveals a "closed" conformation where the highly conser ved N-terminal membrane-proximal region forms an alpha-helix followed by a turn, and the acidic C-terminal loop interacts with the N-terminal helix. T he structure of the active mutant is significantly different, having an "op en" conformation where the interactions between the N-terminal helix and C- terminal region are abolished. Consistent with these structural differences , the two peptides differ in function: the wild-type peptide suppressed alp ha(IIb)beta(3) activation, whereas the mutant peptide did not. These result s provide an atomic explanation for extensive biochemical/mutational data a nd support a conformation-based "on/off switch" model for integrin activati on.