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Picornavirus proteins and their precursors take their names from sequential locations in the polyprotein open reading frame (ORF). Polyprotein processing occurs through a three tiered cascade of primary, secondary, and maturation cleavages. The first, or primary, cleavage is almost always cotranslational, as ribosomes traverse the middle (P2) region of the genome. For hepatoviruses, the first (2A/2B junction) and most subsequent cleavages within the polyprotein require downstream synthesis of viral protease 3Cpro, the central enzyme in the overall cleavage cascade. The third (final) tier of polyprotein cleavage, maturation of the 1AB peptide (VP4/VP2), is normally observed in vivo only during the final stages of virion morphogenesis and is believed to occur concomitantly with RNA assembly into large capsid structures. Unlike negative-strand or double-strand RNA viruses, which require nucleoproteins or preattached polymerases for infectivity, picornavirus genomes are infectious as naked RNA. The most recently described additions to the picornavirus RNA structural library are cis-acting replication elements (CREs). Proteolytic cleavage of the P1 precursor generates the proteins VP0 (precursor of VP4 and VP2), VP1, and VP3. The leader proteins encoded by various picornaviruses can differ considerably in length and function, even for viruses within the same genus. Viruses with the smallest 2A apparently maintain only the minimum segment required for this activity and for subsequent upstream cleavage of P1/2A by 3Cpro. The essential genome organization, especially with regard to the L-4-3-4 layout of the polyprotein, remains canonical and is a diagnostic identifier for any virus in this family.
RNA structural motifs. (A) Base pairing within the 5′-terminal stem and adjacent type 1 pseudoknots for ERAV. (B) 5′-terminal stem, adjacent pseudoknots, and location of the poly(C) tract for EMCV. (C) 5′-terminal stem for HAV. (D) 5′-terminal stem for SVV. (E) 5′-terminal cloverleaf and adjacent spacer region for HRV-A (derived from reference 65 ). (F) ERAV ORF initiation stem, showing tandem AUG codons paired within the stem. The second of each AUG pair initiates synthesis of leader protease Lab (upstream) or Lb, respectively. (G) ORF initiation stem for HRV-A (from reference 65 ). (H to J) CREs for HRV-A, EMCV, and FMDV (from reference 86 ). The location of each element within the genome is indicated. (K) 3′ UTR tertiary structure (“kissing interaction”) for SVV (from reference 36 ). (L) 3′ UTR tertiary structure interactions for HEV-B (from reference 102 ). (M) 3′ UTR stem for HRV-A (from reference 65 ). (N) Extended 3′ UTR stem from ERAV. Gen-Bank accession numbers for included sequences are as in Color Plate 1, except for enterovirus HRV-A (accession no. l02316) and enterovirus HEV-B (accession no. af231765).
IRES elements. Picornavirus genomes encode IRESs, which confer cap-independent translation properties. Examples of type I (A), type II (B), type III (C), and type IV (D) IRES structures are shown. The type I structure (illustration derived from reference 5 ) also includes the linked 5′ cloverleaf (domain I) motif, which may function as part of this IRES. The type III IRES (illustration derived from reference 12 ) is drawn in the context of a complete 5′ UTR. The type IV IRES has an internal tertiary pseudoknot structure at its base (illustration derived from reference 39 ). These depicted IRES motif arrangements have been suggested or confirmed by RNA-protein mapping but do not necessarily represent the minimum energy configurations for any individual region ( 67 ).
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