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Cryo-EM structure of modified Zika virus E protein dimer complexed with a neutralizing antibody OZ-D4 Fab
Structural highlights
FunctionA0A1D6XWI9_ZIKV Binds to host cell surface receptors and mediates fusion between viral and cellular membranes. Efficient virus attachment to cell is, at least in part, mediated by host HAVCR1 in a cell-type specific manner. In addition, host NCAM1 can also be used as entry receptor. Interaction with host HSPA5 plays an important role in the early stages of infection as well. Envelope protein is synthesized in the endoplasmic reticulum and forms a heterodimer with protein prM. The heterodimer plays a role in virion budding in the ER, and the newly formed immature particle is covered with 60 spikes composed of heterodimers between precursor prM and envelope protein E. The virion is transported to the Golgi apparatus where the low pH causes the dissociation of PrM-E heterodimers and formation of E homodimers. PrM-E cleavage is inefficient, many virions are only partially matured and immature prM-E proteins could play a role in immune evasion.[ARBA:ARBA00053968] Functions as a signal peptide for NS4B and is required for the interferon antagonism activity of the latter.[ARBA:ARBA00003504] Induces the formation of ER-derived membrane vesicles where the viral replication takes place. Also plays a role in the inhibition of host RLR-induced interferon-beta production at TANK-binding kinase 1/TBK1 level. Cooperatively with NS4A suppresses the Akt-mTOR pathway and leads to cellular dysregulation.[ARBA:ARBA00060220] Inhibits RNA silencing by interfering with host Dicer.[ARBA:ARBA00035616] May play a role in virus budding. Exerts cytotoxic effects by activating a mitochondrial apoptotic pathway through M ectodomain. May display a viroporin activity.[ARBA:ARBA00035609] Plays a role in host immune defense modulation and protection of envelope protein E during virion synthesis. PrM-E cleavage is inefficient, many virions are only partially matured and immature prM-E proteins could play a role in immune evasion. Contributes to fetal microcephaly in humans. Acts as a chaperone for envelope protein E during intracellular virion assembly by masking and inactivating envelope protein E fusion peptide. prM is the only viral peptide matured by host furin in the trans-Golgi network probably to avoid catastrophic activation of the viral fusion activity in acidic Golgi compartment prior to virion release.[ARBA:ARBA00053204] Plays a role in the inhibition of host RLR-induced interferon-beta activation by targeting TANK-binding kinase 1/TBK1. In addition, recruits the host deubiquitinase USP8 to cleave 'Lys-11'-linked polyubiquitin chains from caspase-1/CASP1 thus inhibiting its proteasomal degradation. In turn, stabilized CASP1 promotes cleavage of cGAS, which inhibits its ability to recognize mitochondrial DNA release and initiate type I interferon signaling.[ARBA:ARBA00053213] Plays a role in virus budding by binding to the cell membrane and gathering the viral RNA into a nucleocapsid that forms the core of the mature virus particle. During virus entry, may induce genome penetration into the host cytoplasm after hemifusion induced by the surface proteins. Can migrate to the cell nucleus where it modulates host functions. Inhibits the integrated stress response (ISR) in the infected cell.[ARBA:ARBA00053869] Prevents premature fusion activity of envelope proteins in trans-Golgi by binding to envelope protein E at pH 6.0. After virion release in extracellular space, gets dissociated from E dimers.[ARBA:ARBA00054739] Required cofactor for the serine protease function of NS3.[ARBA:ARBA00056013] Publication Abstract from PubMedFlaviviruses are a family of related viruses that cause substantial global morbidity and mortality. Vaccination against one flavivirus can sometimes exacerbate disease caused by related viruses through antibody-dependent enhancement (ADE) or interfere with the efficacy of subsequent vaccines. To address this challenge, we develop a vaccine strategy by introducing G5C/G102C mutations into the flavivirus envelope (E) glycoprotein. These mutations promote E dimerization through the formation of an inter-chain disulfide bond that conceals the immunodominant and ADE-prone fusion loop epitope (FLE). We validate this design on E proteins from multiple flaviviruses through biochemical, antigenic, and structural analyses. The resulting vaccine candidate, CC_FLE sE, derived from the Zika virus (ZIKV) and formulated with an advanced supramolecular adjuvant, provides significant protection in female mice challenged with ZIKV and prevents ADE caused by a related flavivirus, Dengue virus. In genetically modified mice expressing diverse human immunoglobulin loci, ZIKV CC_FLE sE induces robust neutralizing antibody responses targeting key ZIKV E protein epitopes, including the E-dimer-dependent epitope (EDE), indicating that ZIKV CC_FLE sE can elicit protective antibody responses within the human naive B cell repertoire. Therefore, CC_FLE sE represents a promising strategy for developing flavivirus vaccines that minimize ADE risk while maintaining high protective efficacy. Rational design of flavivirus E protein vaccine optimizes immunogenicity and mitigates antibody dependent enhancement risk.,Wang Y, Galkin A, Shang X, Marin A, Jin S, Ye TJ, Bale S, Chiang CI, Chowdhury A, Chenine AL, Turonis A, Greenhouse J, Stone R, Wear J, Kar S, Andersen H, Huang YS, Vanlandingham DL, Higgs S, Lapidus RG, Fuerst T, Weber DJ, Wyatt RT, Iffland C, Pierson TC, Andrianov AK, Pozharski E, Li Y Nat Commun. 2025 Dec 22;16(1):11558. doi: 10.1038/s41467-025-67447-4. PMID:41429771[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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