Structural highlights
Function
STAT2_HUMAN Signal transducer and activator of transcription that mediates signaling by type I IFNs (IFN-alpha and IFN-beta). Following type I IFN binding to cell surface receptors, Jak kinases (TYK2 and JAK1) are activated, leading to tyrosine phosphorylation of STAT1 and STAT2. The phosphorylated STATs dimerize, associate with IRF9/ISGF3G to form a complex termed ISGF3 transcription factor, that enters the nucleus. ISGF3 binds to the IFN stimulated response element (ISRE) to activate the transcription of interferon stimulated genes, which drive the cell in an antiviral state.[1]
Publication Abstract from PubMed
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.
A conformational selection mechanism of flavivirus NS5 for species-specific STAT2 inhibition.,Biswal M, Yao W, Lu J, Chen J, Morrison J, Hai R, Song J Commun Biol. 2024 Jan 10;7(1):76. doi: 10.1038/s42003-024-05768-8. PMID:38195857[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Bluyssen HA, Levy DE. Stat2 is a transcriptional activator that requires sequence-specific contacts provided by stat1 and p48 for stable interaction with DNA. J Biol Chem. 1997 Feb 14;272(7):4600-5. PMID:9020188
- ↑ Biswal M, Yao W, Lu J, Chen J, Morrison J, Hai R, Song J. A conformational selection mechanism of flavivirus NS5 for species-specific STAT2 inhibition. Commun Biol. 2024 Jan 10;7(1):76. PMID:38195857 doi:10.1038/s42003-024-05768-8
