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J. Biol. Chem., Vol. 277, Issue 39, 36399-36407, September 27, 2002

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The Interdomain Region of Dengue NS5 Protein That Binds to the Viral Helicase NS3 Contains Independently Functional Importin 1 and Importin /-Recognized Nuclear Localization Signals^*

Andrew J. Brooks, Magnus Johansson, Anna V. John^§, Yibin Xu, David A. Jans^§¶, and Subhash G. Vasudevan

From the  Department of Biochemistry and Molecular Biology, James Cook University, Queensland 4811, ^§ Division of Biochemistry and Molecular Biology, John Curtin School of Medical Research, the Australian National University, Canberra, Australian Capital Territory 2601, and the ^¶ Department of Biochemistry and Molecular Biology, Box 13D, Monash University, Victoria 3800, Australia

Dengue virus NS5 protein is a multifunctional RNA-dependent RNA polymerase that is essential for virus replication. We have shown previously that the 37- amino acid interdomain spacer sequence (residues ³⁶⁹X₂KKX₁₄KKKX₁₁RKX₃⁴⁰⁵) of Dengue2 NS5 contains a functional nuclear localization signal (NLS). In this study, -galactosidase fusion proteins carrying point mutations of the positively charged residues or truncations of the interdomain linker region (residues 369-389 or residues 386-405) were analyzed for nuclear import and importin binding activities to show that the N-terminal part of the linker region (residues 369-389, a/bNLS) is critical for nuclear localization and is recognized with high affinity by the conventional NLS-binding importin / heterodimeric nuclear import receptor. We also show that the importin -binding site (residues 320-368, bNLS) adjacent to the a/bNLS, previously identified by yeast two-hybrid analysis, is functional as an NLS, recognized with high affinity by importin , and able to target -galactosidase to the nucleus. Intriguingly, the bNLS is highly conserved among Dengue and related flaviviruses, implying a general role for the region and importin  in the infectious cycle.

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