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

Abstract

which induces cascades of intracellular signaling events, including protein phosphorylation and cytoskel-etal reorganization (Schwartz et al., 1995; Shattil and Ginsberg, 1997). However, ligand binding to integrins is not simply controlled by ligand availability but also through " inside-out " signaling: cellular stimulation clus-3 Joseph J. Jacobs Center for Thrombosis and ters integrins or alters conformation to increase their Vascular Biology avidity or affinity for ligands (Ginsberg et al. The proto-The Cleveland Clinic Foundation typic example of such integrin activation via inside-out 9500 Euclid Avenue signaling occurs with ␣ IIb ␤ 3. Platelets express ␣ IIb ␤ 3 on Cleveland, Ohio 44195 their surface, but only if the cells have been stimulated with an agonist that induces the appropriate inside-out signal does the receptor engage fibrinogen. Such inside-Summary out regulation of ␣ IIb ␤ 3 affinity allows for rapid platelet aggregation to prevent excess bleeding while pre-Activation of the ligand binding function of integrin venting uncontrolled receptor occupancy, resulting in heterodimers requires transmission of an " inside-out " thrombosis (Plow and Byzova, 1999). signal from their small intracellular segments to their As the trigger point of inside-out signaling, the integrin large extracellular domains. The structure of the cyto-cytoplasmic face has been the focus of intense investi-plasmic domain of a prototypic integrin ␣ IIb ␤ 3 has been gations (reviewed in Woodside et al., 2001). These stud-solved by NMR and reveals multiple hydrophobic and ies have revealed that (1) while intact integrin can remain electrostatic contacts within the membrane-proximal latent both in unstimulated cells and in a purified state, helices of its ␣ and the ␤ cytoplasmic tails. The inter-deletion of the cytoplasmic and transmembrane region face interactions are disrupted by point mutations or activates the receptor (Peterson et al., 1998); (2) point the cytoskeletal protein talin that are known to activate mutations in the membrane-proximal regions of the cy-the receptor. These results provide a structural mech-toplasmic tails or deletion of either can result in constitu-anism by which a handshake between the ␣ and the tive activation of the receptor (O'Toole et al., 1994; ␤ cytoplasmic tails restrains the integrin in a resting replacement of the cyto-state and unclasping of this interaction triggers the plasmic-transmembrane regions by heterodimeric inside-out conformational signal that leads to receptor coiled-coil peptides or an artificial linkage of the tails activation. inactivates the receptor, and breakage of the coiled-coil or clasp activates the receptor (Lu et al., 2001; …

DOI: 10.1016/S0092-8674(02)00906-6

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@article{Vinogradova2002ASM, title={A Structural Mechanism of Integrin αIIbβ3 “Inside-Out” Activation as Regulated by Its Cytoplasmic Face}, author={Olga Vinogradova and Algirdas Velyvis and Asta Velyviene and Bin Hu and Thomas A. Haas and Edward F. Plow and Jun Qin}, journal={Cell}, year={2002}, volume={110}, pages={587-597} }