The Structure of Human Parechovirus 1 Reveals an Association of the RNA Genome with the Capsid

Abstract

Parechoviruses are human pathogens that cause diseases ranging from gastrointestinal disorders to encephalitis. Unlike those of most picornaviruses, parechovirus capsids are composed of only three subunits: VP0, VP1, and VP3. Here, we present the structure of a human parechovirus 1 (HPeV-1) virion determined to a resolution of 3.1 Å. We found that interactions among pentamers in the HPeV-1 capsid are mediated by the N termini of VP0s, which correspond to the capsid protein VP4 and the N-terminal part of the capsid protein VP2 of other picornaviruses. In order to facilitate delivery of the virus genome into the cytoplasm, the N termini of VP0s have to be released from contacts between pentamers and exposed at the particle surface, resulting in capsid disruption. A hydrophobic pocket, which can be targeted by capsid-binding antiviral compounds in many other picornaviruses, is not present in HPeV-1. However, we found that interactions between the HPeV-1 single-stranded RNA genome and subunits VP1 and VP3 in the virion impose a partial icosahedral ordering on the genome. The residues involved in RNA binding are conserved among all parechoviruses, suggesting a putative role of the genome in virion stability or assembly. Therefore, putative small molecules that could disrupt HPeV RNA-capsid protein interactions could be developed into antiviral inhibitors.IMPORTANCE Human parechoviruses (HPeVs) are pathogens that cause diseases ranging from respiratory and gastrointestinal disorders to encephalitis. Recently, there have been outbreaks of HPeV infections in Western Europe and North America. We present the first atomic structure of parechovirus HPeV-1 determined by X-ray crystallography. The structure explains why HPeVs cannot be targeted by antiviral compounds that are effective against other picornaviruses. Furthermore, we found that the interactions of the HPeV-1 genome with the capsid resulted in a partial icosahedral ordering of the genome. The residues involved in RNA binding are conserved among all parechoviruses, suggesting an evolutionarily fixed role of the genome in virion assembly. Therefore, putative small molecules disrupting HPeV RNA-capsid protein interactions could be developed into antiviral inhibitors.

Structure of deformed wing virus, a major honey bee pathogen

“…S2 C and D). Integrins serve as cell entry receptors for numerous viruses, including the foot and mouth disease virus and several parechoviruses (19)(20)(21). However, the RGD motif is not present in DWV and other iflaviruses.…”

“…The structural comparison shows that iflaviruses are most similar to the insectinfecting dicistroviruses Israeli acute bee paralysis virus, cricket paralysis virus, and triatoma virus (33)(34)(35). The viruses most similar to DWV and SBPV from the Picornaviridae family are hepatitis A virus and human parechovirus 1 (HPeV-1), which were previously suggested to form evolutionary intermediates between human and insect viruses (21,36) (Fig. 4).…”

“…3B) (40). Reminiscent of the RNAprotein interactions in DWV are structured RNA oligonucleotides that have been recently described in the parechoviruses HPeV-1, HPeV-3, and Ljungan virus, where they also mediate contacts among capsid proteins from different protomers (21,41,42). The conservation of the RNA-binding residues among some of the honey bee iflaviruses, together with the near-complete occupancy of the RNA, indicates that the RNA-capsid binding might play a role in virion stability.…”

Limits of variation, specific infectivity, and genome packaging of massively recoded poliovirus genomes

“…We propose that the "cryptic, sequence-degenerate, dispersed RNA packaging signals" (22) provide a function in step II of morphogenesis. The cocondensation of genome with cognate CP, which have been characterized in genomes of RNA phage MS2 (19,21), of plant virus satellite tobacco necrosis virus (72), and of two human viruses (22,73,74), is to facilitate "cocondensation" (step II). Cocondensation includes highly complex rearrangements of precursor CPs, ultimately leading to mature virions (19,22,50,51,75).…”

Subcellular localisation of Theiler's murine encephalomyelitis virus (TMEV) capsid subunit VP1 vis-á-vis host protein Hsp90

“…Antibodies have been reported to also bind to the internal region of VP1 exposed during capsid breathing in Poliovirus 1 and Parechovirus 1 (Kalynych et al, 2015).…”