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 is the transmission of an agonist-induced cellular signal from the short alpha- and/or beta-cytoplasmic tails to the extracellular domains of the receptor. The structural details of how the cytoplasmic tails mediate such an inside-out signaling process remain unclear. We report herein the NMR structures of a membrane-anchored cytoplasmic tail of the alpha(IIb)-subunit and of a mutant alpha(IIb)-cytoplasmic tail that renders platelet integrin alpha(IIb)beta(3) constitutively active. The structure of the wild-type alpha(IIb)-cytoplasmic tail reveals a "closed" conformation where the highly conserved 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. The structure of the active mutant is significantly different, having an "open" 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 alpha(IIb)beta(3) activation, whereas the mutant peptide did not. These results provide an atomic explanation for extensive biochemical/mutational data and support a conformation-based "on/off switch" model for integrin activation.
Vinogradova
O
O
Department of Molecular Cardiology, Lerner Research Institute, Cleveland, OH 44195, USA.
Haas
T
T
Plow
E F
EF
Qin
J
J
D000595:Amino Acid Sequence; D001792:Blood Platelets / Q000378:metabolism; D018821:CD18 Antigens / Q000737:chemistry* / Q000235:genetics; D002942:Circular Dichroism; D003593:Cytoplasm / Q000737:chemistry; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D015539:Platelet Activation / Q000187:drug effects; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D015398:Signal Transduction
D018821:CD18 Antigens; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D005340:Fibrinogen