2002
DOI: 10.1074/jbc.m205886200
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Agonist-specific Structural Rearrangements of Integrin αIIbβ3

Abstract: Concrete structural features of integrin ␣-287), demonstrate the existence of ␣ IIb ␤ 3 agonist-specific activation states, explain the specificity for ligand binding and functional inhibition for some agonists, and predict the existence of agonist-specific final effectors and receptor activation mechanisms. The distinct non-reciprocal competition patterns observed at rest and after activation support the agonist-specific activation states and the existence of intrasubunit and intersubunit allosteric effects, … Show more

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Cited by 35 publications
(9 citation statements)
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“…Destabilization of the ␤ head/stalk interface releases the ␤A-hybrid domains from the constraint that prevents the swing-out of the hybrid domain, thus greatly potentiating integrin activation. However, this may not be sufficient to induce extension because mAb cross-competition studies implicate that ␣IIb␤3 still assumes a bent conformer on agonist-stimulated platelets (48). Consistently, agonist stimulation alone is not sufficient but requires ligand binding to induce LIBS epitope expression in platelet ␣IIb␤3 (19,49).…”
Section: Discussionmentioning
confidence: 88%
“…Destabilization of the ␤ head/stalk interface releases the ␤A-hybrid domains from the constraint that prevents the swing-out of the hybrid domain, thus greatly potentiating integrin activation. However, this may not be sufficient to induce extension because mAb cross-competition studies implicate that ␣IIb␤3 still assumes a bent conformer on agonist-stimulated platelets (48). Consistently, agonist stimulation alone is not sufficient but requires ligand binding to induce LIBS epitope expression in platelet ␣IIb␤3 (19,49).…”
Section: Discussionmentioning
confidence: 88%
“…Recently (39), investigators using transmission electron microscope have shown that a stable complex of Mn 2ϩ -bound extracellular domain of ␣V␤3 integrin with FN-type III domains 7-10 displayed compact triangular shape, indicative of bent conformation. Others have earlier suggested that straightening is not required to render integrin competent to bind physiological ligands (42,43). It is premature to draw any definitive conclusions regarding the mechanism of integrin activation by uPAR but with the identification of an integrin binding site on uPAR and the solving of its structure such analyses may now be possible.…”
Section: Discussionmentioning
confidence: 99%
“…In addition, the soluble Mn 2ϩ -bound r-␣V␤3 ectodomain, the complex of this ectodomain with a fibronectin fragment (with type III domains 7-10 and the extradomain B), and Mn 2ϩ -activated ␣IIb␤3 were equally in the bent configuration, as determined by electron microscopy (EM) 2 (13,14). Finally, ␣IIb␤3 in resting and physiologically activated platelets were also in the bent configuration, as found by epitope mapping and competition among monoclonal antibodies directed to the C-terminal region of the ␣IIb subunit and to the N-terminal domain of the ␤3 subunit (9) and by fluorescence intramolecular energy transfer (15). However, all of these results are inconsistent to some extent with the extended conformation found: in whole ␣IIb␤3 observed by cryo-EM (16); in different recombinant ectodomain products of ␣V␤3 in the presence of Mn 2ϩ alone or Mn 2ϩ with an RGD peptide or other ligand-mimetic antagonists, observed by EM (5); and in experiments of fluorescence intermolecular energy transfer between a fluorescent peptide bound to integrin ␣4␤1, expressed at the surface of Mn 2ϩ or chemokine-activated monoblastoid cells, and a fluorescent lipophilic probe incorporated into their membrane (17).…”
mentioning
confidence: 83%
“…After 20 years of molecular genetics and 10 years of high resolution structural biology of integrins, the disposition of an integrin in the membrane is unknown, the modifications in the cytoplasmic domains and the transmembrane segments related with the receptor activation are still not definitively defined, and the molecular mechanism of activation and molecular properties of the activated receptor are still under discussion (1)(2)(3)(4). Structural and cell biological information reported recently suggests different models (the switchblade, the deadbolt, and the disulfide reduction models) (5)(6)(7)(8) for the mechanism of signal transduction between the cytoplasmic domains and the extracellular ligand binding domains, as well as different activation states (9), which require both, to clear the disagreement between some experimental observations and to carry out more comprehensive experimental tests at different levels of structural and functional organization.…”
mentioning
confidence: 99%