First Structure of Picornaviral 2C Protein Bound to RNA Reveals Novel AAA+ Protein-Substrate Interaction
Researchers have determined the first three-dimensional structure of the picornaviral 2C protein bound to RNA, showing how this conserved viral protein specifically recognizes and binds single-stranded RNA in its central pore. The 2C protein is a member of the AAA+ family of ATPases and is one of the most conserved nonstructural proteins in picornaviruses, which cause billions of infections annually with serious clinical consequences. This structural insight could inform the development of broad-spectrum antivirals targeting picornaviruses, which currently lack effective treatments.
Picornaviruses cause an estimated 8 billion infections per year in humans and animals, leading to diverse clinical manifestations including respiratory failure and acute flaccid myelitis. The 2C protein, a highly conserved nonstructural component, is a member of the AAA+ family of ATPases that plays a crucial role in the viral life cycle and represents a promising antiviral target. Until now, no structural information existed for 2C bound to its RNA substrate. This study presents the first cryo-EM structure of 2C as a hexamer with single-stranded RNA threaded through its central pore—a novel mode of AAA+ protein-substrate interaction. Functional studies confirm that mutations to key RNA-binding residues impair both RNA binding and viral replication in Apthovirus and Enterovirus systems, and these residues are conserved across picornaviruses and related viruses. The structural analysis reveals that the 2C:RNA complex more closely resembles protein translocases adapted for RNA binding than other viral DNA-binding helicases, demonstrating how the AAA+ protein scaffold can be functionally adapted for different biochemical substrates.
What's missing
The study does not discuss potential limitations of the cryo-EM structure determination (such as resolution constraints, conformational heterogeneity, or artifacts from sample preparation), nor does it address whether the observed RNA-binding mode reflects the physiological state during active viral replication or whether additional viral or host factors modulate 2C activity in vivo.
What different sources said
- bioRxivCenter
The Structure of the Picornaviral 2C:RNA holoenzyme: Molecular Basis of RNA binding and specificity by a AAA+ protein
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