Activation mechanisms of ?V?3 integrin by binding to fibronectin: A computational study.

ABSTRACT: Integrin ?V?3 plays an important role in regulating cellular activities and in human diseases. Although the structure of ?V?3 has been studied by crystallography and electron microscopy, the detailed activation mechanism of integrin ?V?3 induced by fibronectin remains unclear. In this study, we investigated the conformational and dynamical motion changes of Mn2+ -bound integrin ?V?3 by binding to fibronectin with molecular dynamics simulations. Results showed that fibronectin binding to integrin ?V?3 caused the changes of the conformational flexibility of ?V?3 domains, the essential mode of motion for the domains of ?V subunit and ?3 subunit and the degrees of correlated motion of residues between the domains of ?V subunit and ?3 subunit of integrin ?V?3. The angle of Propeller domain with respect to the Calf-2 domain of ?V subunit and the angle of Hybrid domain with respect to ?A domain of ?3 subunit significantly increased when integrin ?V?3 was bound to fibronectin. These changes could result in the conformational change tendency of ?V?3 from a bend conformation to an extended conformation and lead to the open swing of Hybrid domain relative to ?A domain of ?3 subunit, which have demonstrated their importance for ?V?3 activation. Fibronectin binding to integrin ?V?3 significantly decreased the relative position of ?1 helix to ?A domain and that to metal ion-dependent adhesion site, stabilized Mn2+ ions binding in integrin ?V?3 and changed fibronectin conformation, which are important for ?V?3 activation. Results from this study provide important molecular insight into the "outside-in" activation mechanism of integrin ?V?3 by binding to fibronectin.

SUBMITTER: Wang L 

PROVIDER: S-EPMC5441423 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature