6lnu | pdb_00006lnu
Cryo-EM structure of immature Zika virus
Structural highlights
Function[POLG_ZIKVF] Capsid protein C: 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 a 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.[UniProtKB:P17763] Capsid protein C: Inhibits RNA silencing by interfering with host Dicer.[UniProtKB:P03314] Peptide pr: Prevents premature fusion activity of envelope proteins in trans-Golgi by binding to envelope protein E at pH6.0. After virion release in extracellular space, gets dissociated from E dimers.[UniProtKB:P17763] Protein prM: Plays a role in host immune defense modulation and protection of envelope protein E during virion synthesis. PrM-E cleavage is ineficient, and immature prM-E proteins could have an activity against host immune response. The sequence of PrM 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. prM-E cleavage is inefficient, and many virions are only partially matured. These uncleaved prM could play a role in immune evasion.[UniProtKB:P17763][1] Small envelope protein M: May play a role in virus budding. Exerts cytotoxic effects by activating a mitochondrial apoptotic pathway through M ectodomain. May display a viroporin activity.[UniProtKB:P17763] Envelope protein E: Binds to host cell surface receptor and mediates fusion between viral and cellular membranes. Envelope protein is synthesized in the endoplasmic reticulum in the form of heterodimer with protein prM. They play a role in virion budding in the ER, and the newly formed immature particule is covered with 60 spikes composed of heterodimer between precursor prM and envelope protein E. The virion is transported to the Golgi apparatus where the low pH causes dissociation of PrM-E heterodimers and formation of E homodimers. prM-E cleavage is inefficient, and many virions are only partially matured. These uncleaved prM could play a role in immune evasion.[UniProtKB:P17763] Non-structural protein 1: Involved in immune evasion, pathogenesis and viral replication. Once cleaved off the polyprotein, is targeted to three destinations: the viral replication cycle, the plasma membrane and the extracellular compartment. Essential for viral replication. Required for formation of the replication complex and recruitment of other non-structural proteins to the ER-derived membrane structures. Excreted as a hexameric lipoparticle that plays a role against host immune response. Antagonizing the complement function. Binds to the host macrophages and dendritic cells. Inhibits signal transduction originating from Toll-like receptor 3 (TLR3).[UniProtKB:Q9Q6P4] Non-structural protein 2A: Component of the viral RNA replication complex that functions in virion assembly and antagonizes the host alpha/beta interferon antiviral response (By similarity). Disrupts adherens junction formation and thereby impairs proliferation of radial cells in both embryonic mouse cortex and human forebrain organoids (PubMed:28826723).[UniProtKB:P14335][2] Non-structural protein 2B: Required cofactor for the serine protease function of NS3.[UniProtKB:Q32ZE1] Serine protease NS3: Displays three enzymatic activities: serine protease, NTPase and RNA helicase. NS3 serine protease, in association with NS2B, performs its autocleavage and cleaves the polyprotein at dibasic sites in the cytoplasm: C-prM, NS2A-NS2B, NS2B-NS3, NS3-NS4A, NS4A-2K and NS4B-NS5. NS3 RNA helicase binds RNA and unwinds dsRNA in the 3' to 5' direction (By similarity). Leads to translation arrest when expressed ex vivo (PubMed:28592527).[UniProtKB:Q32ZE1][3] Non-structural protein 4A: Regulates the ATPase activity of the NS3 helicase activity. NS4A allows NS3 helicase to conserve energy during unwinding (By similarity). Cooperatively with NS4B suppress the Akt-mTOR pathway and lead to cellular dysregulation (PubMed:27524440). Leads to translation arrest when expressed ex vivo (PubMed:28592527).[UniProtKB:Q9Q6P4][4] [5] Peptide 2k: Functions as a signal peptide for NS4B and is required for the interferon antagonism activity of the latter. Non-structural protein 4B: Induces the formation of ER-derived membrane vesicles where the viral replication takes place. Inhibits interferon (IFN)-induced host STAT1 phosphorylation and nuclear translocation, thereby preventing the establishment of cellular antiviral state by blocking the IFN-alpha/beta pathway. Inhibits STAT2 translocation in the nucleus after IFN-alpha treatment (By similarity). Cooperatively with NS4A suppress the Akt-mTOR pathway and lead to cellular dysregulation (PubMed:27524440).[UniProtKB:Q9Q6P4][6] RNA-directed RNA polymerase NS5: Replicates the viral (+) and (-) RNA genome, and performs the capping of genomes in the cytoplasm. NS5 methylates viral RNA cap at guanine N-7 and ribose 2'-O positions. Besides its role in RNA genome replication, also prevents the establishment of cellular antiviral state by blocking the interferon-alpha/beta (IFN-alpha/beta) signaling pathway. Inhibits host TYK2 and STAT2 phosphorylation, thereby preventing activation of JAK-STAT signaling pathway.[UniProtKB:Q9Q6P4] Publication Abstract from PubMedStructures of flavivirus (dengue virus and Zika virus) particles are known to near-atomic resolution and show detailed structure and arrangement of their surface proteins (E and prM in immature virus or M in mature virus). By contrast, the arrangement of the capsid proteins:RNA complex, which forms the core of the particle, is poorly understood, likely due to inherent dynamics. Here, we stabilize immature Zika virus via an antibody that binds across the E and prM proteins, resulting in a subnanometer resolution structure of capsid proteins within the virus particle. Fitting of the capsid protein into densities shows the presence of a helix previously thought to be removed via proteolysis. This structure illuminates capsid protein quaternary organization, including its orientation relative to the lipid membrane and the genomic RNA, and its interactions with the transmembrane regions of the surface proteins. Results show the capsid protein plays a central role in the flavivirus assembly process. Capsid protein structure in Zika virus reveals the flavivirus assembly process.,Tan TY, Fibriansah G, Kostyuchenko VA, Ng TS, Lim XX, Zhang S, Lim XN, Wang J, Shi J, Morais MC, Corti D, Lok SM Nat Commun. 2020 Feb 14;11(1):895. doi: 10.1038/s41467-020-14647-9. PMID:32060358[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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