Cell
Volume 110, Issue 5, 6 September 2002, Pages 587-597
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Article
A Structural Mechanism of Integrin αIIbβ3 “Inside-Out” Activation as Regulated by Its Cytoplasmic Face

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Abstract

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.

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Correspondence: Edward F. Plow, (216)-445-8200 (phone), (216)-445-8206 (fax); e-mail: [email protected]