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dc.contributor.authorChang, Hung-Weien_US
dc.contributor.authorYang, Cheng-Hanen_US
dc.contributor.authorLuo, Yu-Chunen_US
dc.contributor.authorSu, Bo-Gangen_US
dc.contributor.authorCheng, Huei-Yinen_US
dc.contributor.authorTung, Shu-Yunen_US
dc.contributor.authorCarillo, Kathleen Joyce D.en_US
dc.contributor.authorLiao, Yi-Tingen_US
dc.contributor.authorTzou, Der-Lii M.en_US
dc.contributor.authorWang, Hao-Chingen_US
dc.contributor.authorChang, Wenen_US
dc.date.accessioned2019-09-02T07:46:10Z-
dc.date.available2019-09-02T07:46:10Z-
dc.date.issued2019-06-01en_US
dc.identifier.issn1553-7366en_US
dc.identifier.urihttp://dx.doi.org/10.1371/journal.ppat.1007826en_US
dc.identifier.urihttp://hdl.handle.net/11536/152582-
dc.description.abstractVaccinia mature virus requires A26 envelope protein to mediate acid-dependent endocytosis into HeLa cells in which we hypothesized that A26 protein functions as an acid-sensitive membrane fusion suppressor. Here, we provide evidence showing that N-terminal domain (aa1-75) of A26 protein is an acid-sensitive region that regulates membrane fusion. Crystal structure of A26 protein revealed that His48 and His53 are in close contact with Lys47, Arg57, His314 and Arg312, suggesting that at low pH these His-cation pairs could initiate conformational changes through protonation of His48 and His53 and subsequent electrostatic repulsion. All the A26 mutant mature viruses that interrupted His-cation pair interactions of His48 and His 53 indeed have lost virion infectivity. Isolation of revertant viruses revealed that second site mutations caused frame shifts and premature termination of A26 protein such that reverent viruses regained cell entry through plasma membrane fusion. Together, we conclude that viral A26 protein functions as an acid-sensitive fusion suppressor during vaccinia mature virus endocytosis. Author summary Vaccinia virus is a complex large DNA virus with a large number of viral membrane proteins to facilitate cell entry. Although it is well established that vaccinia mature virus uses endocytosis to enter cells, it remains unclear how it triggers membrane fusion in the acidic environment of endosomes. Recently, we hypothesized that A26 protein in vaccinia mature virus functions as an acid-sensitive membrane fusion suppressor, which suggests a novel viral regulation not present in other enveloped viruses. We postulated that conformational changes of A26 protein at low pH result in de-repression of viral fusion complex activity to trigger viral and endosomal membrane fusion. Here, we provide structural, biochemical and biological evidence demonstrating that vaccinia A26 protein does indeed function as an acid-sensitive fusion suppressor protein to regulate vaccinia mature virus membrane fusion during endocytosis. Our data reveal an important and unique checkpoint for vaccinia mature virus endocytosis that has not been described for other viruses. Furthermore, by isolating adaptive vaccinia mutants that escaped endocytic blockage, we discovered that mutations within the A26L gene serve as an effective strategy for switching the viral infection route from endocytosis to plasma membrane fusion, expanding viral host range.en_US
dc.language.isoen_USen_US
dc.titleVaccinia viral A26 protein is a fusion suppressor of mature virus and triggers membrane fusion through conformational change at low pHen_US
dc.typeArticleen_US
dc.identifier.doi10.1371/journal.ppat.1007826en_US
dc.identifier.journalPLOS PATHOGENSen_US
dc.citation.volume15en_US
dc.citation.issue6en_US
dc.citation.spage0en_US
dc.citation.epage0en_US
dc.contributor.department應用化學系zh_TW
dc.contributor.departmentDepartment of Applied Chemistryen_US
dc.identifier.wosnumberWOS:000479154700028en_US
dc.citation.woscount0en_US
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