Conformational Changes of the Flavivirus E Glycoprotein

Zhang, Ying; Zhang, Wei; Ogata, Steven; Clements, David E.; Strauss, James H.; Baker, Timothy S.; Kühn, Richard; Rossmann, Michael G.

doi:10.1016/j.str.2004.06.019

Cited by 416 publications

(427 citation statements)

References 26 publications

Supporting

Mentioning

410

Contrasting

Unclassified

Order By: Relevance

“…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%

“…The E protein consists of three b-barrel structural domains. The central domain (domain I; DI) contains the N terminus and appears to act as an anchor for the hinge point of the large distal domain (domain II; DII) (Zhang et al, 2004). This second domain contains the fusion-loop peptide and is involved in virus fusion during entry (Mukhopadhyay et al, 2005), and in interactions with prM, which occludes the fusion loop in immature particles during cellular transit (Zhang et al, 2003(Zhang et al, , 2012.…”

Section: E Proteinmentioning

confidence: 99%

“…1b) (Mukhopadhyay et al, 2005). All three domains appear to be involved in the dimerization of the E protein through hydrophilic interactions in mature virions (Zhang et al, 2004). The E protein is liberated from the genomic polyprotein at its N and C termini via cleavage with host signal peptidase in the ER lumen.…”

Section: E Proteinmentioning

confidence: 99%

Section: Particle Trafficking and Secretionmentioning

confidence: 99%

See 3 more Smart Citations

Post-translational regulation and modifications of flavivirus structural proteins

Roby

Setoh

Hall

et al. 2015

Journal of General Virology

102

View full text Add to dashboard Cite

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 ...

show abstract

Section: Particle Trafficking and Secretionmentioning

confidence: 99%

Section: E Proteinmentioning

confidence: 99%

Section: E Proteinmentioning

confidence: 99%

Section: Particle Trafficking and Secretionmentioning

confidence: 99%

See 2 more Smart Citations

Post-translational regulation and modifications of flavivirus structural proteins

Roby

Setoh

Hall

et al. 2015

Journal of General Virology

102

View full text Add to dashboard Cite

show abstract

“…The three E monomers per icosahedral asymmetric unit each have distinctly different environments (5,6), contrary to most other icosahedral viruses in which all subunits have at least quasi-similar environments. The ectodomain of E consists of three structural domains, DI, DII, and DIII (7)(8)(9). DI is structurally positioned between DII and DIII.…”

Section: W Est Nile Virus (Wnv) Causes a Febrile Illness In Humansmentioning

confidence: 99%

West Nile virus in complex with the Fab fragment of a neutralizing monoclonal antibody

Kaufmann

Nybakken

Chipman

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

120

122

View full text Add to dashboard Cite

Flaviviruses, such as West Nile virus (WNV), are significant human pathogens. The humoral immune response plays an important role in the control of flavivirus infection and disease. The structure of WNV complexed with the Fab fragment of the strongly neutralizing mAb E16 was determined to 14.5-Å resolution with cryoelectron microscopy. E16, an antibody with therapeutic potential, binds to domain III of the WNV envelope glycoprotein. Because of steric hindrance, Fab E16 binds to only 120 of the 180 possible binding sites on the viral surface. Fitting of the previously determined x-ray structure of the Fab-domain III complex into the cryo-electron microscopy density required a change of the elbow angle between the variable and constant domains of the Fab. The structure suggests that the E16 antibody neutralizes WNV by blocking the initial rearrangement of the E glycoprotein before fusion with a cellular membrane.cryo-electron microscopy ͉ flavivirus ͉ neutralization W est Nile virus (WNV) causes a febrile illness in humans that can progress to encephalitis, paralysis, and death. Although endemic in parts of Africa, Asia, Europe, and the Middle East, it was first isolated in the United States in 1999 and has subsequently spread throughout North America and the Caribbean (1-3). The similar Kunjin virus is found in Australia (4). WNV, a member of the Flaviviridae family, is closely related to other arthropod-borne, medically important viruses, such as dengue, yellow fever, Japanese encephalitis, and tick-borne encephalitis viruses. These small, Ϸ500-Å-diameter, lipidenveloped viruses enter their host cells by receptor-mediated endocytosis. A low pH-triggered conformational rearrangement of the viral surface glycoproteins resulting in a fusion-active state of the virion allows the release of the single-stranded, positivesense RNA genome from the endosomes into the cytoplasm.The outer surface of mature infectious particles is formed by an icosahedral scaffold of 90 homodimers of the membraneanchored envelope glycoprotein (E). The three E monomers per icosahedral asymmetric unit each have distinctly different environments (5, 6), contrary to most other icosahedral viruses in which all subunits have at least quasi-similar environments. The ectodomain of E consists of three structural domains, DI, DII, and DIII (7-9). DI is structurally positioned between DII and DIII. The dimerization DII contains a 12-residue-long loop essential for virus-cell membrane fusion and, in dengue virus, has carbohydrate moieties that mediate receptor binding (10). The C-terminal DIII undergoes a major, pH-triggered, positional rearrangement essential for fusion and may also be involved in receptor binding (7,(11)(12)(13)(14)(15)(16)(17)(18).The humoral immune response is crucial for protection against flavivirus infection and disease (19). Antibodies can prevent infection by interference with functions mediated by viral surface proteins, such as receptor attachment, virus internalization, and membrane fusion. Indeed, the E glycoprotein is the...

show abstract

Biology of ZIKV

2018

Zika Virus and Diseases

View full text Add to dashboard Cite

Conformational Changes of the Flavivirus E Glycoprotein

Cited by 416 publications

References 26 publications

Post-translational regulation and modifications of flavivirus structural proteins

Post-translational regulation and modifications of flavivirus structural proteins

West Nile virus in complex with the Fab fragment of a neutralizing monoclonal antibody

Biology of ZIKV

Contact Info

Product

Resources

About