Picornaviral 2C proteins: A unique ATPase family critical in virus replication

The 2C proteins of Picornaviridae are unique members of AAA+ protein family. Although picornavirus 2C shares many conserved motifs with Super Family 3 DNA helicases, duplex unwinding activity of many 2C proteins remains undetected, and high-resolution structures of 2C hexamers are unavailable. All characterized 2C proteins exhibit ATPase activity, but the purpose of ATP hydrolysis is not fully understood. 2C is highly conserved among picornaviruses and plays crucial roles in nearly all steps of the virus lifecycle. It is therefore considered as an effective target for broad-spectrum antiviral drug development. Crystallographic investigation of enterovirus 2C proteins provide structural details important for the elucidation of 2C function and development of antiviral drugs. This chapter summarizes not only the findings of enzymatic activities, biochemical and structural characterizations of the 2C proteins, but also their role in virus replication, immune evasion and morphogenesis. The linkage between structure and function of the 2C proteins is discussed in detail. Inhibitors targeting the 2C proteins are also summarized to provide an overview of drug development. Finally, we raise several key questions to be addressed in this field and provide future research perspective on this unique class of ATPases.