8vpu | pdb_00008vpu
Crystal structure of mouse Importin alpha in complex with dengue virus 3 NS5 central NLS peptide
Structural highlights
FunctionIMA1_MOUSE Functions in nuclear protein import as an adapter protein for nuclear receptor KPNB1. Binds specifically and directly to substrates containing either a simple or bipartite NLS motif. Docking of the importin/substrate complex to the nuclear pore complex (NPC) is mediated by KPNB1 through binding to nucleoporin FxFG repeats and the complex is subsequently translocated through the pore by an energy requiring, Ran-dependent mechanism. At the nucleoplasmic side of the NPC, Ran binds to importin-beta and the three components separate and importin-alpha and -beta are re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran from importin. The directionality of nuclear import is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus. Publication Abstract from PubMedDengue virus (DENV) nonstructural protein 5 (NS5), consisting of methyltransferase and RNA-dependent RNA polymerase (RdRp) domains, is critical for viral RNA synthesis within endoplasmic reticulum-derived replication complexes in the cytoplasm. However, a significant proportion of NS5 is localized to the nucleus of infected cells for DENV2, 3, and 4, whereas DENV1 NS5 is localized diffusely in the cytoplasm. We still have an incomplete understanding of how the DENV NS5 subcellular localization is regulated. Within NS5, two putative nuclear localization signal (NLS) sequences have been identified: NLS(Central) residing in the palm of the RdRp domain as well as the recently discovered NLS(C-term) residing in the flexible region at the C-terminal of the RdRp domain. We have previously shown that DENV2 NS5 nuclear localization can be significantly reduced by single-point mutations to the NLS(C-term). Here, we present biochemical, virological, and structural data demonstrating that the relative importance of either NLS in NS5 nuclear localization is unique to each of the four DENV serotypes. DENV1 NS5's cytoplasmic localization appears to be due to a functionally weak interaction between its NLS(Central) and importin-alpha (IMPalpha), while DENV2 NS5 is almost exclusively nuclear through its NLS(C-term)'s strong interaction with IMPalpha. Both NLSs of DENV3 NS5 appear to contribute to directing its nuclear localization. Lastly, in the case of DENV4, the regulation of its NS5 nuclear localization remains an enigma but appears to be associated with its NLS(C-term). Serotype-Specific Regulation of Dengue Virus NS5 Protein Subcellular Localization.,Cheng CX, Tan MJA, Chan KWK, Choy MMJ, Roman N, Arnold DDR, Bifani AM, Kong SYZ, Bist P, Nath BK, Swarbrick CMD, Forwood JK, Vasudevan SG ACS Infect Dis. 2024 Jun 14;10(6):2047-2062. doi: 10.1021/acsinfecdis.4c00054. , Epub 2024 May 29. PMID:38811007[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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