Structure of the Immature Dengue Virus at Low pH Primes Proteolytic Maturation

Yu, I-Mei; Zhang, Wei; Holdaway, Heather A.; Li, Long; Kostyuchenko, V.A.; Chipman, Paul R.; Kühn, Richard; Rossmann, Michael G.; Chen, Jue

doi:10.1142/9789814513357_0047

Cited by 426 publications

(120 citation statements)

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“…Thus, it appears that the N67 and N153 glycosylation sites in DENV E are utilized to differing degrees, and the glycans positioned at each site are differentially matured. Considering that structural studies of DENV prM and E have demonstrated partial occlusion of one or both E glycans by the pr peptide Yu et al, 2008), and that DENV has a demonstrated tendency towards incomplete prM cleavage by furin (Rodenhuis-Zybert et al, 2011), these results raise the interesting possibility that the degree of prM processing controls the maturation status of one or both glycans. Such a hypothesis remains to be properly explored, although it would be intriguing to investigate whether partially matured DENV displays a greater capacity to infect DC-SIGN-expressing cells.…”

Section: Glycan Modificationmentioning

confidence: 90%

“…The pr peptide forms a tightly folded protein domain consisting of two small b-sheets linked by disulfide bridges, with the entire structure positioned at the distal end of E domain II (DII) within the heterodimer where it obscures the fusion loop and facilitates pr glycan presentation at the tip of trimeric spikes Yu et al, 2008;Zhang et al, 2003). The C-terminal region of the M protein ectodomain is also predicted to form a helical domain (prM-H) that may assist in prM/E heterodimer formation (Hsieh et al, 2011;Peng & Wu, 2014;Zhang et al, 2012).…”

Section: Prm Proteinmentioning

confidence: 99%

“…2) (Stadler et al, 1997). Interestingly, in vitro furin cleavage assays show that maturation of prM only occurs at low pH, even though the enzymic activity of furin is optimal at neutral pH (Stadler et al, 1997;Yu et al, 2008). This suggests that the low-pH-induced structural rearrangement of the particle is required to expose the furin cleavage site on prM.…”

Section: Maturation Of Prm By Furin Cleavagementioning

confidence: 99%

“…Although immature flavivirus particles have been demonstrated to be non-infectious in vitro (Elshuber et al, 2003;Elshuber & Mandl, 2005;Moesker et al, 2010;Stadler et al, 1997;Yu et al, 2008Yu et al, , 2009), opsonization of immature DENV virions with anti-prM antibodies has been demonstrated to enhance the infection of Fc-receptor-positive cells (Dejnirattisai et al, 2010;Rodenhuis-Zybert et al, 2010). Bound virions are endocytosed, with acidification of the endosome allowing furin-mediated cleavage of prM and subsequent virus fusion.…”

Section: Maturation Of Prm By Furin Cleavagementioning

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

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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: Glycan Modificationmentioning

confidence: 90%

Section: Prm Proteinmentioning

confidence: 99%

Section: Maturation Of Prm By Furin Cleavagementioning

confidence: 99%

Section: Maturation Of Prm By Furin Cleavagementioning

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

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“…1. Possible hemifusion route to virus (upper)-host (lower) membrane fusion, illustrated through alignment of E protein to: a) dimeric, mature viral assembly (3C6R [101]); b) an intermediate structure during trimerization approximated by the two cryo-EM structures with exposed fusion loops, 3C6D [101] and 3IXY [9]; c) target, fused state with trimeric form (1OK8 [6]) as proposed in earlier works [6,77], arbitrarily positioned to interact with a catenoid-shaped, zero mean curvature, membrane. Panels (b) and (d) are marked by * to illustrate the state defining the free energy barrier for this process.…”

Section: Membrane Bending Free Energymentioning

confidence: 99%

Molecular basis of endosomal-membrane association for the dengue virus envelope protein

Rogers

Kent

Rempe

2015

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Dengue virus is coated by an icosahedral shell of 90 envelope protein dimers that convert to trimers at low pH and promote fusion of its membrane with the membrane of the host endosome. We provide the first estimates for the free energy barrier and minimum for two key steps in this process: host membrane bending and protein-membrane binding. Both are studied using complementary membrane elastic, continuum electrostatics and all-atom molecular dynamics simulations. The predicted host membrane bending required to form an initial fusion stalk presents a 22-30 kcal/mol free energy barrier according to a constrained membrane elastic model. Combined continuum and molecular dynamics results predict a 15 kcal/mol free energy decrease on binding of each trimer of dengue envelope protein to a membrane with 30% anionic phosphatidylglycerol lipid. The bending cost depends on the preferred curvature of the lipids composing the host membrane leaflets, while the free energy gained for protein binding depends on the surface charge density of the host membrane. The fusion loop of the envelope protein inserts exactly at the level of the interface between the membrane's hydrophobic and head-group regions. The methods used in this work provide a means for further characterization of the structures and free energies of protein-assisted membrane fusion.

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Flaviviruses and Autophagy

Jordan

Randall

2014

Autophagy, Infection, and the Immune Response

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Structure of the Immature Dengue Virus at Low pH Primes Proteolytic Maturation

Cited by 426 publications

References 0 publications

Post-translational regulation and modifications of flavivirus structural proteins

Post-translational regulation and modifications of flavivirus structural proteins

Molecular basis of endosomal-membrane association for the dengue virus envelope protein

Flaviviruses and Autophagy

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