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Structure. 2015 Feb 3;23(2):374-84. doi: 10.1016/j.str.2014.11.015. Epub 2015 Jan 15.

Molecular determinants for nuclear import of influenza A PB2 by importin α isoforms 3 and 7.

Author information

1
Department of Biochemistry and Molecular Biology, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107, USA.
2
Division of Physics, School of Engineering, Mathematics and Physics, University of Dundee, Dundee DD1 4NH, UK; Department of Pharmacology and Toxicology, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria.
3
Université Grenoble Alpes, Unit for Virus Host-Cell Interactions, F-38000 Grenoble, France; CNRS, Unit for Virus Host-Cell Interactions, F-38000 Grenoble, France; Unit for Virus Host-Cell Interactions, Université Grenoble Alpes-EMBL-CNRS, 6 Rue Jules Horowitz, 38042 Grenoble, France.
4
Division of Physics, School of Engineering, Mathematics and Physics, University of Dundee, Dundee DD1 4NH, UK; Division of Computational Biology, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
5
Department of Biochemistry and Molecular Biology, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107, USA. Electronic address: gino.cingolani@jefferson.edu.

Abstract

Influenza A virus polymerase subunit PB2 is a major virulence determinant implicated in pathogenicity and host adaptation. During cross-species virus transfer from avian to mammalian cells, PB2 switches specificity from importin α3 to α7. This specificity is not recapitulated in vitro, where PB2 binds all importin α isoforms with comparably high affinity. In this study, we investigated the structure, conformational dynamics, and autoinhibition of importin α isoforms 1, 3, and 7 in complex with PB2. Our data suggest that association of PB2 with α3 and α7 is favored by reduced autoinhibition of these isoforms and by the unique structure of the nuclear localization signal (NLS) domain of PB2. We propose that by recruiting importin α3 or α7 in the absence of importin β, PB2 reduces the complexity of adaptor-mediated import to a pseudo-bimolecular reaction, thereby acquiring a kinetic advantage over classical NLS cargos, which form an import complex only when importin α and β are simultaneously available.

PMID:
25599645
PMCID:
PMC4346194
DOI:
10.1016/j.str.2014.11.015
[Indexed for MEDLINE]
Free PMC Article

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