Structural and Functional Analysis of Integrin α₂I Domain Interaction with Echovirus 1

Integrins are cell surface receptors for several microbial pathogens including echovirus 1 (EV1), a picornavirus. Cryo-electron microscopy revealed that the functional domain (α₂I) of human α ₂β₁ integrin binds to a surface depression on the EV1 capsid. This three-dimensional structure of EV1 bound to α ₂I domain provides the first structural details of an integrin interacting with a picornavirus. The model indicates that α ₂β₁ integrin cannot simultaneously bind both EV1 and the physiological ligand collagen. Compared with collagen binding to the α₂I domain, the virus binds with a 10-fold higher affinity but in vitro uncoating of EV1 was not observed as a result of attachment of α₂I. A molecular model, constructed on the basis of the EV1-integrin complex, shows that multiple α₂β₁ heterodimers can bind at adjacent sites around the virus 5-fold symmetry axes without steric hindrance. In agreement with this, virus attachment to α₂β₁ integrin on the cell surface was found to result in integrin clustering, which can give rise to signaling and facilitate the initiation of the viral entry process that takes place via caveolae-mediated endocytosis.