A structural mechanism of integrin alpha(IIb)beta(3) "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 alpha(IIb)beta(3) has been solved by NMR and reveals multiple hydrophobic and electrostatic contacts within the membrane-proximal helices of its alpha and the beta 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 alpha and the beta 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.
Vinogradova
Olga
O
Structural Biology Program, Cleveland, OH 44195, USA.
Velyvis
Algirdas
A
Velyviene
Asta
A
Hu
Bin
B
Haas
Thomas
T
Plow
Edward
E
Qin
Jun
J
D000595:Amino Acid Sequence; D000818:Animals; D003593:Cytoplasm / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000737:chemistry*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D016608:Talin / Q000494:pharmacology
D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D016608:Talin