Structural and functional analysis of integrin alpha2I domain interaction with echovirus 1

Area of Science:

• Structural biology
• Virology
• Cell biology

Background:

• Integrins are cell surface receptors involved in pathogen binding.
• Echovirus 1 (EV1), a picornavirus, utilizes integrins for host cell entry.
• Understanding the molecular basis of EV1-integrin interaction is crucial for antiviral strategies.

Purpose of the Study:

• To determine the structural basis of the interaction between human alpha(2)beta(1) integrin and echovirus 1 (EV1).
• To elucidate the mechanism of EV1 binding to the alpha(2)I integrin domain.
• To investigate the implications of this interaction for viral entry and cellular signaling.

Main Methods:

• Cryo-electron microscopy (Cryo-EM) to determine the three-dimensional structure of the EV1-integrin complex.
• Molecular modeling to analyze the binding interface and potential steric clashes.
• In vitro binding assays to compare affinities and assess viral uncoating.

Main Results:

• The functional alpha(2)I domain of alpha(2)beta(1) integrin binds to a specific depression on the EV1 capsid.
• EV1 binds to alpha(2)I with 10-fold higher affinity than collagen, the physiological ligand.
• Integrin binding does not induce in vitro uncoating of EV1.
• Multiple alpha(2)beta(1) heterodimers can bind adjacent sites on the EV1 capsid without steric hindrance.
• Virus attachment triggers integrin clustering, promoting signaling and caveolae-mediated endocytosis.

Conclusions:

• The structural data provides novel insights into integrin-picornavirus interactions.
• Alpha(2)beta(1) integrin binding to EV1 is a high-affinity interaction distinct from collagen binding.
• Integrin clustering upon EV1 attachment is a key step initiating viral entry via endocytosis.