A conformational selection mechanism of flavivirus NS5 for species-specific STAT2 inhibition
Abstract Flaviviruses, including Zika virus (ZIKV) and Dengue virus (DENV), rely on their non-structural protein 5 (NS5) for both replication of viral genome and suppression of host IFN signaling. DENV and ZIKV NS5s were shown to facilitate proteosome-mediated protein degradation of human STAT2 (hST...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-01-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-024-05768-8 |
| _version_ | 1827381995989106688 |
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| author | Mahamaya Biswal Wangyuan Yao Jiuwei Lu Jianbin Chen Juliet Morrison Rong Hai Jikui Song |
| author_facet | Mahamaya Biswal Wangyuan Yao Jiuwei Lu Jianbin Chen Juliet Morrison Rong Hai Jikui Song |
| author_sort | Mahamaya Biswal |
| collection | DOAJ |
| description | Abstract Flaviviruses, including Zika virus (ZIKV) and Dengue virus (DENV), rely on their non-structural protein 5 (NS5) for both replication of viral genome and suppression of host IFN signaling. DENV and ZIKV NS5s were shown to facilitate proteosome-mediated protein degradation of human STAT2 (hSTAT2). However, how flavivirus NS5s have evolved for species-specific IFN-suppression remains unclear. Here we report structure-function characterization of the DENV serotype 2 (DENV2) NS5−hSTAT2 complex. The MTase and RdRP domains of DENV2 NS5 form an extended conformation to interact with the coiled-coil and N-terminal domains of hSTAT2, thereby promoting hSTAT2 degradation in cells. Disruption of the extended conformation of DENV2/ZIKV NS5, but not the alternative compact state, impaired their hSTAT2 binding. Our comparative structural analysis of flavivirus NS5s further reveals a conserved protein-interaction platform with subtle amino-acid variations likely underpinning diverse IFN-suppression mechanisms. Together, this study uncovers a conformational selection mechanism underlying species-specific hSTAT2 inhibition by flavivirus NS5. |
| first_indexed | 2024-03-08T14:13:05Z |
| format | Article |
| id | doaj.art-5698f87ffe894d27a933b379cdfd4b67 |
| institution | Directory Open Access Journal |
| issn | 2399-3642 |
| language | English |
| last_indexed | 2024-03-08T14:13:05Z |
| publishDate | 2024-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj.art-5698f87ffe894d27a933b379cdfd4b672024-01-14T12:32:47ZengNature PortfolioCommunications Biology2399-36422024-01-017111210.1038/s42003-024-05768-8A conformational selection mechanism of flavivirus NS5 for species-specific STAT2 inhibitionMahamaya Biswal0Wangyuan Yao1Jiuwei Lu2Jianbin Chen3Juliet Morrison4Rong Hai5Jikui Song6Department of Biochemistry, University of CaliforniaDepartment of Microbiology and Plant Pathology, University of CaliforniaDepartment of Biochemistry, University of CaliforniaDepartment of Biochemistry, University of CaliforniaDepartment of Microbiology and Plant Pathology, University of CaliforniaDepartment of Microbiology and Plant Pathology, University of CaliforniaDepartment of Biochemistry, University of CaliforniaAbstract Flaviviruses, including Zika virus (ZIKV) and Dengue virus (DENV), rely on their non-structural protein 5 (NS5) for both replication of viral genome and suppression of host IFN signaling. DENV and ZIKV NS5s were shown to facilitate proteosome-mediated protein degradation of human STAT2 (hSTAT2). However, how flavivirus NS5s have evolved for species-specific IFN-suppression remains unclear. Here we report structure-function characterization of the DENV serotype 2 (DENV2) NS5−hSTAT2 complex. The MTase and RdRP domains of DENV2 NS5 form an extended conformation to interact with the coiled-coil and N-terminal domains of hSTAT2, thereby promoting hSTAT2 degradation in cells. Disruption of the extended conformation of DENV2/ZIKV NS5, but not the alternative compact state, impaired their hSTAT2 binding. Our comparative structural analysis of flavivirus NS5s further reveals a conserved protein-interaction platform with subtle amino-acid variations likely underpinning diverse IFN-suppression mechanisms. Together, this study uncovers a conformational selection mechanism underlying species-specific hSTAT2 inhibition by flavivirus NS5.https://doi.org/10.1038/s42003-024-05768-8 |
| spellingShingle | Mahamaya Biswal Wangyuan Yao Jiuwei Lu Jianbin Chen Juliet Morrison Rong Hai Jikui Song A conformational selection mechanism of flavivirus NS5 for species-specific STAT2 inhibition Communications Biology |
| title | A conformational selection mechanism of flavivirus NS5 for species-specific STAT2 inhibition |
| title_full | A conformational selection mechanism of flavivirus NS5 for species-specific STAT2 inhibition |
| title_fullStr | A conformational selection mechanism of flavivirus NS5 for species-specific STAT2 inhibition |
| title_full_unstemmed | A conformational selection mechanism of flavivirus NS5 for species-specific STAT2 inhibition |
| title_short | A conformational selection mechanism of flavivirus NS5 for species-specific STAT2 inhibition |
| title_sort | conformational selection mechanism of flavivirus ns5 for species specific stat2 inhibition |
| url | https://doi.org/10.1038/s42003-024-05768-8 |
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