Structure of Immature West Nile Virus

Zhang, Ying; Kaufmann, Bärbel; Chipman, Paul R.; Kühn, Richard; Rossmann, Michael G.

doi:10.1128/jvi.00037-07

Cited by 132 publications

(122 citation statements)

References 20 publications

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“…The release of prM-containing immature particles is consistently observed along with release of mature particles (Zhang et al, 2007a), as well as partially mature particles (Junjhon et al, 2010;Plevka et al, 2011), suggesting that either furin cleavage is not 100 % efficient or the speed of prM/E conformational rearrangement on the particle is slower than the rate of cell-driven particle secretion through the trans-Golgi compartment. This phenomenon appears to be dependent upon the identity of the virus, as high rates of immature/partially mature virions are most consistently observed for DENV (Rodenhuis-Zybert et al, 2011), and this phenotype has been linked to a DENV-conserved acidic residue at position 89 in prM (P3 within the furin cleavage site) (Junjhon et al, 2008;Keelapang et al, 2004).…”

Section: Maturation Of Prm By Furin Cleavagementioning

confidence: 99%

“…Heterodimerization may facilitate the arrangement of prM/E at the ER membrane forming heterotrimeric spikes (Zhang et al, 2007a). In turn, the ordered arrangement of these prM/E spikes may induce curvature of the ER membrane, resulting in budding of nascent virions into the ER lumen (Zhang et al, 2013a).…”

Section: Heterodimerization Of Prm and Ementioning

confidence: 99%

“…After completion of the viral budding process, an immature particle pf about 600 Å in diameter is formed in the lumen of the ER and consists of 60 prM/E heterotrimeric spikes arranged with icosahedral symmetry (Zhang et al, 2004(Zhang et al, , 2007a (Fig. 4) ER through to the trans-Golgi compartment involves a drop in pH from 7.2 to 6.0, which induces a structural rearrangement from 60 prM/E heterotrimeric spikes to 90 prM/E heterodimers arranged in a herringbone pattern that is flattened parallel to the virion Zhang et al, 2003), a process that is reversible prior to furin cleavage (Fig.…”

Section: Particle Trafficking and Secretionmentioning

confidence: 99%

Section: Particle Trafficking and Secretionmentioning

confidence: 99%

“…Indeed, the currently accepted model of flavivirus maturation within the trans-Golgi involves the stem region of the prM protein interacting with the associated E protein DII in a manner that pulls E down from a trimeric spike into a flat dimeric conformation parallel to the virion surface (Zhang et al, 2012(Zhang et al, , 2013b, with this interaction dependent upon decreasing pH and originating from one or more discrete nucleation centres (Plevka et al, 2011(Plevka et al, , 2014. In addition, the low-pH environment in the trans-Golgi compartment allows the pr peptide to remain associated with E (Yu et al, 2009), effectively preventing premature fusion within the cell.The release of prM-containing immature particles is consistently observed along with release of mature particles (Zhang et al, 2007a), as well as partially mature particles (Junjhon et al, 2010; Plevka et al, 2011), suggesting that either furin cleavage is not 100 % efficient or the speed of prM/E conformational rearrangement on the particle is slower than the rate of cell-driven particle secretion through the trans-Golgi compartment. This phenomenon appears to be dependent upon the identity of the virus, as high rates of immature/partially mature virions are most consistently observed for DENV (Rodenhuis-Zybert et al …”

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confidence: 99%

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Post-translational regulation and modifications of flavivirus structural proteins

Roby

Setoh

Hall

et al. 2015

Journal of General Virology

102

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Flaviviruses are a group of single-stranded, positive-sense RNA viruses that generally circulate between arthropod vectors and susceptible vertebrate hosts, producing significant human and veterinary disease burdens. Intensive research efforts have broadened our scientific understanding of the replication cycles of these viruses and have revealed several elegant and tightly co-ordinated post-translational modifications that regulate the activity of viral proteins. The three structural proteins in particular -capsid (C), pre-membrane (prM) and envelope (E) -are subjected to strict regulatory modifications as they progress from translation through virus particle assembly and egress. The timing of proteolytic cleavage events at the C-prM junction directly influences the degree of genomic RNA packaging into nascent virions. Proteolytic maturation of prM by host furin during Golgi transit facilitates rearrangement of the E proteins at the virion surface, exposing the fusion loop and thus increasing particle infectivity. Specific interactions between the prM and E proteins are also important for particle assembly, as prM acts as a chaperone, facilitating correct conformational folding of E. It is only once prM/E heterodimers form that these proteins can be secreted efficiently. The addition of branched glycans to the prM and E proteins during virion transit also plays a key role in modulating the rate of secretion, pH sensitivity and infectivity of flavivirus particles. The insights gained from research into post-translational regulation of structural proteins are beginning to be applied in the rational design of improved flavivirus vaccine candidates and make attractive targets for the development of novel therapeutics. FlavivirusesThe genus Flavivirus in the family Flaviviridae comprises small, enveloped viruses with non-segmented genomes consisting of single-stranded, positive-sense RNA. These RNA genomes are flanked by 59 and 39 untranslated regions (UTRs) and encode a single polyprotein that is cleaved coand post-translationally to generate between 10 and 11 viral proteins. The 59 UTR contains a type 1 m 7 GpppNm cap structure and the 39 UTR lacks a polyadenylated tail. Structural elements within the UTRs regulate genome replication, translation and host immune responses. Viral proteins are divided between structural proteins, which form the virion, and non-structural proteins, which are involved in genomic replication and modulating host immunity (Fig. 1a) (Lindenbach et al., 2007;Roby et al., 2012).Flaviviruses are maintained predominantly in natural transmission cycles between vertebrate reservoir species (normally mammalian or avian) and haematophagous arthropod vectors (mosquitoes or ticks). Notable exceptions are the viruses that are maintained solely in mosquito hosts (insectspecific flaviviruses) and viruses with no known invertebrate vector (Cook et al., 2012;Mackenzie et al., 2004). As of 2013, the International Committee on Taxonomy of Viruses has classified 53 different viral species as belonging to ...

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Section: Maturation Of Prm By Furin Cleavagementioning

confidence: 99%

Section: Heterodimerization Of Prm and Ementioning

confidence: 99%

Section: Particle Trafficking and Secretionmentioning

confidence: 99%

Section: Particle Trafficking and Secretionmentioning

confidence: 99%

mentioning

confidence: 99%

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Post-translational regulation and modifications of flavivirus structural proteins

Roby

Setoh

Hall

et al. 2015

Journal of General Virology

102

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Propagation, Quantification, Detection, and Storage of West Nile Virus

2013

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West Nile virus (WNV) is a member of the Flaviviridae family of enveloped, singlestranded, positive-sense RNA viruses. WNV, an emerging viral pathogen, is transmitted by mosquitoes to birds and mammals and is responsible for an increasing incidence of human disease in North America and Europe. Due to its ease of use in the laboratory and the availability of robust mouse models of disease, WNV provides an excellent experimental system for studying molecular virology and pathogenesis of infection by flaviviruses. Here, we describe common laboratory techniques used to propagate, quantify, detect, and store WNV. We also briefly describe appropriate safety precautions required for the laboratory use of WNV, which is classified as a Biosafety Level 3 pathogen by the United States Centers for Disease Control and Prevention.

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