Biochemical and Biophysical Research Communications
Regular ArticleThree Novel Integrin β3 Subunit Missense Mutations (H280P, C560F, and G579S) in Thrombasthenia, Including One (H280P) Prevalent in Japanese Patients
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Cited by (40)
Disulfide bond exchanges in integrins αiIbβ3 and αvβ3 are required for activation and post-ligation signaling during clot retraction
2014, Thrombosis ResearchCitation Excerpt :Although the precise disulfide bonds involved in the disulfide bond exchange-mediated activation of αIIbβ3 and αvβ3 have not been identified, our previous work suggested that there is a regulatory role for the C560-C583 bond in αIIbβ3 and αvβ3 activation [20,21]. Moreover, the C560S substitution mimics two naturally occurring C560R and C560F mutations that caused the severe bleeding disorder Glanzmann thrombasthenia and resulted in constitutive activation of αIIbβ3 [20,30,31], suggesting that this bond has a physiologic role in αIIbβ3 activation. The C523-C544 bond has an allosteric configuration in the αvβ3 crystal structure, a configuration associated with a functional role of disulfide bonds [21,32].
Specific cysteines in β3 are involved in disulfide bond exchange-dependent and -independent activation of αIIbβ3
2008, Journal of Biological ChemistryCitation Excerpt :All of these mutants were inactive and could not be activated by the activating antibodies, implying that the integrity of the Cys-567–Cys-581 bond is important for the activation of αIIbβ3. So far, activation of αIIbβ3 by disulfide bond disruptions was mainly described for bonds in the EGF domains (14–18) but also in other regions such as the βTD (32). The βTD is unique for β integrins and contains four disulfide bonds, Cys-608–Cys-655, Cys-614–Cys-635, Cys-617–Cys-631, and Cys-663–Cys-687 (7).
Inherited bleeding disorders: Disorders of platelet adhesion and aggregation
2004, Critical Reviews in Oncology/HematologyDisruption of the β<inf>3</inf> 663-687 disulfide bridge confers constitutive activity to β<inf>3</inf> integrins
2003, BloodCitation Excerpt :Studies of binding of platelets to monoclonal antibodies also suggest specific agonist-induced conformational changes in αIIbβ3.36 Furthermore, point mutations in β3 leading to conformational changes are associated with changes in the state of activation of αIIbβ3.37-42 Thus, a variety of experimental approaches support the contention that integrin activation is accompanied by conformational changes; however, the mechanisms by which the putative conformational changes increase the ligand binding affinity remain unclear.35
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H.A. and T.K. contributed equally to this study and should be regarded as cofirst authors.
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To whom correspondence should be addressed. Makoto Handa, M.D., Blood Center, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Fax: 81-3-3353-9706. E-mail:[email protected].