| Structural highlights
Function
POLG_SAFV Forms a complex with host RAN and probably binds to exportins carrying activated MAPK in order to mediate the hyperphosphorylation of host Phe/Gly containing nuclear pore proteins (Nups) resulting in cessation of active nucleocytoplasmic transport (Probable). Proteins with NLS signals fail to import, cellular mRNAs fail to export, and some proteins small enough for diffusion are not retained anymore (efflux) (By similarity). The resulting inhibition of cellular protein synthesis serves to ensure maximal viral gene expression and to evade host immune response (By similarity).[UniProtKB:Q66765][1] Forms an icosahedral capsid of pseudo T=3 symmetry with capsid proteins VP2 and VP3. Together they form an icosahedral capsid composed of 60 copies of each VP1, VP2, and VP3, with a diameter of approximately 300 Angstroms.VP4 lies on the inner surface of the protein shell formed by VP1, VP2 and VP3. All the three latter proteins contain a beta-sheet structure called beta-barrel jelly roll. VP1 is situated at the 12 fivefold axes, whereas VP2 and VP3 are located at the quasi-sixfold axes.[2] Forms an icosahedral capsid of pseudo T=3 symmetry with capsid proteins VP2 and VP3. Together they form an icosahedral capsid composed of 60 copies of each VP1, VP2, and VP3, with a diameter of approximately 300 Angstroms.VP4 lies on the inner surface of the protein shell formed by VP1, VP2 and VP3. All the three latter proteins contain a beta-sheet structure called beta-barrel jelly roll. VP1 is situated at the 12 fivefold axes, whereas VP2 and VP3 are located at the quasi-sixfold axes.[3] Forms an icosahedral capsid of pseudo T=3 symmetry with capsid proteins VP2 and VP3. Together they form an icosahedral capsid composed of 60 copies of each VP1, VP2, and VP3, with a diameter of approximately 300 Angstroms.VP4 lies on the inner surface of the protein shell formed by VP1, VP2 and VP3. All the three latter proteins contain a beta-sheet structure called beta-barrel jelly roll. VP1 is situated at the 12 fivefold axes, whereas VP2 and VP3 are located at the quasi-sixfold axes.[4] Lies on the inner surface of the capsid shell (PubMed:27279624). After binding to the host receptor, the capsid undergoes conformational changes (By similarity). Capsid protein VP4 is released, capsid protein VP1 N-terminus is externalized, and together, they shape a pore in the host membrane through which the viral genome is translocated into the host cell cytoplasm. After genome has been released, the channel shrinks (By similarity).[UniProtKB:P03300][5] VP0 precursor is a component of immature procapsids.[UniProtKB:P08617] Involved in host translation shutoff by inhibiting cap-dependent mRNA translation (By similarity). Nuclear localization is required for this function (By similarity). The resulting inhibition of cellular protein synthesis serves to ensure maximal viral gene expression and to evade host immune response (By similarity). Inhibits the phosphorylation of the leader protein (PubMed:25210192).[UniProtKB:Q66765][6] Affects membrane integrity and causes an increase in membrane permeability. Associates with and induces structural rearrangements of intracellular membranes (By similarity). It displays RNA-binding, nucleotide binding and NTPase activities (By similarity).[UniProtKB:P03305][UniProtKB:P08545] Serves as membrane anchor via its hydrophobic domain. Forms a primer, VPg-pU, which is utilized by the polymerase for the initiation of RNA chains.[UniProtKB:P03304] Cysteine protease that generates mature viral proteins from the precursor polyprotein (By similarity). In addition to its proteolytic activity, it binds to viral RNA, and thus influences viral genome replication. RNA and substrate cooperatively bind to the protease. Cleaves host PABP1, this cleavage is important for viral replication (By similarity).[UniProtKB:P03304][UniProtKB:P12296] Replicates the genomic and antigenomic RNAs by recognizing replications specific signals (By similarity). Performs VPg uridylylation (By similarity).[UniProtKB:P12296]
Publication Abstract from PubMed
In order to initiate an infection, viruses need to deliver their genomes into cells. This involves uncoating the genome and transporting it to the cytoplasm. The process of genome delivery is not well understood for non-enveloped viruses. We address this gap in our current knowledge by studying the uncoating of the non-enveloped human cardiovirus Saffold virus-3 (SAFV-3) of the family Picornaviridae SAFVs cause diseases ranging from gastrointestinal disorders to meningitis. We present a structure of a native SAFV-3 virion determined to 2.5 A by X-ray crystallography and an 11 A-resolution cryo-electron microscopy reconstruction of an "altered" particle that is primed for genome release. The altered particles are expanded relative to the native virus and contain pores in the capsid that might serve as channels for the release of VP4 subunits, N-termini of VP1, and the RNA genome. Unlike in the related enteroviruses, pores in SAFV-3 are located roughly between the icosahedral threefold and fivefold axes at an interface formed by two VP1 and one VP3 subunit. Furthermore, in native conditions many cardioviruses contain a disulfide bond formed by cysteins that are separated by just one residue. The disulfide bond is located in a surface loop of VP3. We determined the structure of the SAFV-3 virion in which the disulfide bonds are reduced. Disruption of the bond had minimal effect on the structure of the loop, but it increased the stability and decreased the infectivity of the virus. Therefore, compounds specifically disrupting or binding to the disulfide bond might limit SAFV infection. IMPORTANCE: A capsid assembled from viral proteins protects the virus genome during transmission from one cell to another. However, when a virus enters a cell the virus genome has to be released from the capsid in order to initiate infection. This process is not well understood for non-enveloped viruses. We address this gap in our current knowledge by studying the genome release of human Saffold virus-3. Saffold viruses cause diseases ranging from gastrointestinal disorders to meningitis. We show that before the genome is released, the Saffold virus-3 particle expands and holes form in the previously compact capsid. These holes serve as channels for the release of the genome and small capsid proteins VP4 that in related enteroviruses facilitate subsequent transport of the virus genome into the cell cytoplasm.
Structure and genome release mechanism of human cardiovirus Saffold virus-3.,Mullapudi E, Novacek J, Palkova L, Kulich P, Lindberg AM, van Kuppeveld FJ, Plevka P J Virol. 2016 Jun 8. pii: JVI.00746-16. PMID:27279624[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Ciomperlik JJ, Basta HA, Palmenberg AC. Three cardiovirus Leader proteins equivalently inhibit four different nucleocytoplasmic trafficking pathways. Virology. 2015 Oct;484:194-202. PMID:26115166 doi:10.1016/j.virol.2015.06.004
- ↑ Mullapudi E, Novacek J, Palkova L, Kulich P, Lindberg AM, van Kuppeveld FJ, Plevka P. Structure and genome release mechanism of human cardiovirus Saffold virus-3. J Virol. 2016 Jun 8. pii: JVI.00746-16. PMID:27279624 doi:http://dx.doi.org/10.1128/JVI.00746-16
- ↑ Mullapudi E, Novacek J, Palkova L, Kulich P, Lindberg AM, van Kuppeveld FJ, Plevka P. Structure and genome release mechanism of human cardiovirus Saffold virus-3. J Virol. 2016 Jun 8. pii: JVI.00746-16. PMID:27279624 doi:http://dx.doi.org/10.1128/JVI.00746-16
- ↑ Mullapudi E, Novacek J, Palkova L, Kulich P, Lindberg AM, van Kuppeveld FJ, Plevka P. Structure and genome release mechanism of human cardiovirus Saffold virus-3. J Virol. 2016 Jun 8. pii: JVI.00746-16. PMID:27279624 doi:http://dx.doi.org/10.1128/JVI.00746-16
- ↑ Mullapudi E, Novacek J, Palkova L, Kulich P, Lindberg AM, van Kuppeveld FJ, Plevka P. Structure and genome release mechanism of human cardiovirus Saffold virus-3. J Virol. 2016 Jun 8. pii: JVI.00746-16. PMID:27279624 doi:http://dx.doi.org/10.1128/JVI.00746-16
- ↑ Petty RV, Basta HA, Bacot-Davis VR, Brown BA, Palmenberg AC. Binding interactions between the encephalomyocarditis virus leader and protein 2A. J Virol. 2014 Nov;88(22):13503-9. PMID:25210192 doi:10.1128/JVI.02148-14
- ↑ Mullapudi E, Novacek J, Palkova L, Kulich P, Lindberg AM, van Kuppeveld FJ, Plevka P. Structure and genome release mechanism of human cardiovirus Saffold virus-3. J Virol. 2016 Jun 8. pii: JVI.00746-16. PMID:27279624 doi:http://dx.doi.org/10.1128/JVI.00746-16
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