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Abstract Parechoviruses, including Parechovirus A that infects humans as well as Parechovirus B (formerly Ljungan virus) and Parechovirus C (formerly Sebokele virus) that infect rodents, belong to a group of picornaviruses whose 2A proteins, instead of being proteases, contain a conserved H-box and NC-motif and are homologous to a small cellular lipid-modifying enzyme (PLAAT3) that acts as a host factor, enabling the picornavirus life cycle. Despite the common evolutionary origin, 2A H/NC proteins and PLAAT3 have no conserved function, as the active site of the viral proteins cannot support catalysis. Here, we set out to find if all Parechovirus species share the structural rearrangement that destroys the active site configuration of the cellular enzyme. This has revealed a remarkable structural plasticity of these 2A H/NC proteins that arises not only from sequence differences between species, but also from differences in the length of the recombinantly expressed proteins, resulting in large structural rearrangements. These include rerouting of a large internal loop and repositioning of the C-terminal helix with respect to the central β-sheet, and these in turn influence the oligomeric state of the protein. We discuss how this structural plasticity could correlate with the function of these proteins in the viral life cycle and how this could recapitulate the possible evolution of this protein from host factor to viral 2A H/NC protein, with new independent functions in RNA replication.
Zhu et al. (Sat,) studied this question.