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Cavally virus (CavV) and related viruses in the familyMesoniviridae diverged profoundly from other nidovirus lineages but largely retained the characteristic set of replicative enzymes conserved in theCoronaviridae andRoniviridae . The expression of these enzymes in virus-infected cells requires the extensive proteolytic processing of two large replicase polyproteins, pp1a and pp1ab, by the viral 3C-like protease (3CLpro ). Here, we show that CavV 3CLpro autoproteolytic cleavage occurs at two N-terminal (N1 and N2) and one C-terminal (C1) processing site(s). The mature form of 3CLpro was revealed to be a 314-residue protein produced by cleavage at FKNK1386 |SAAS (N2) and YYNQ1700 |SATI (C1). Site-directed mutagenesis data suggest that the mesonivirus 3CLpro employs a catalytic Cys-His dyad comprised of CavV pp1a/pp1ab residues Cys-1539 and His-1434. The study further suggests that mesonivirus 3CLpro substrate specificities differ from those of related nidovirus proteases. The presence of Gln (or Glu) at the P1 position was not required for cleavage, although residues that control Gln/Glu specificity in related viral proteases are retained in the CavV 3CLpro sequence. Asn at the P2 position was identified as a key determinant for mesonivirus 3CLpro substrate specificity. Other positions, including P4 and P1′, each are occupied by structurally related amino acids, indicating a supportive role in substrate binding. Together, the data identify a new subgroup of nidovirus main proteases and support previous conclusions on phylogenetic relationships between the main nidovirus lineages.IMPORTANCE Mesoniviruses have been suggested to provide an evolutionary link between nidovirus lineages with small (13 to 16 kb) and large (26 to 32 kb) RNA genome sizes, and it has been proposed that a specific set of enzymes, including a proofreading exoribonuclease and other replicase gene-encoded proteins, play a key role in the major genome expansion leading to the currently known lineages of large nidoviruses. Despite their smaller genome size (20 kb), mesoniviruses retained most of the replicative domains conserved in large nidoviruses; thus, they are considered interesting models for studying possible key events in the evolution of RNA genomes of exceptional size and complexity. Our study provides the first characterization of a mesonivirus replicase gene-encoded nonstructural protein. The data confirm and extend previous phylogenetic studies of mesoniviruses and related viruses and pave the way for studies into the formation of the mesonivirus replication complex and functional and structural studies of its functional subunits.

Characterization of an Alphamesonivirus 3C-Like Protease Defines a Special Group of Nidovirus Main Proteases