科研之友
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摘要
Integrin alpha V beta 3 plays an important role in regulating cellular activities and in human diseases. Although the structure of alpha V beta 3 has been studied by crystallography and electron microscopy, the detailed activation mechanism of integrin alpha V beta 3 induced by fibronectin remains unclear. In this study, we investigated the conformational and dynamical motion changes of Mn 21-bound integrin alpha V beta 3 by binding to fibronectin with molecular dynamics simulations. Results showed that fibronectin binding to integrin alpha V beta 3 caused the changes of the conformational flexibility of alpha V beta 3 domains, the essential mode of motion for the domains of alpha V subunit and beta 3 subunit and the degrees of correlated motion of residues between the domains of alpha V subunit and beta 3 subunit of integrin alpha V beta 3. The angle of Propeller domain with respect to the Calf-2 domain of alpha V subunit and the angle of Hybrid domain with respect to beta A domain of beta 3 subunit significantly increased when integrin alpha V beta 3 was bound to fibronectin. These changes could result in the conformational change tendency of alpha V beta 3 from a bend conformation to an extended conformation and lead to the open swing of Hybrid domain relative to beta A domain of beta 3 subunit, which have demonstrated their importance for alpha V beta 3 activation. Fibronectin binding to integrin alpha V beta 3 significantly decreased the relative position of alpha 1 helix to beta A domain and that to metal ion-dependent adhesion site, stabilized Mn 21 ions binding in integrin alpha V beta 3 and changed fibronectin conformation, which are important for alpha V beta 3 activation. Results from this study provide important molecular insight into the "outside-in" activation mechanism of integrin alpha V beta 3 by binding to fibronectin.
- 出版日期2017-6
