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J. Biol. Chem., Vol. 278, Issue 30, 28193-28200, July 25, 2003
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Importin 
Nuclear Localization Signal Binding Sites for STAT1, STAT2, and Influenza A Virus Nucleoprotein*
From the
Laboratory of Infectious Disease
Immunology, Department of Microbiology, National Public Health Institute,
FIN-00300 Helsinki, Finland, ¶HELIOS Clinic/Franz
Volhard Clinic at the Max Delbrueck Center, Medical Faculty of the
Charité, 13122 Berlin, Germany, and
||Diabetes and Genetic Epidemiology Unit,
Department of Epidemiology and Health Promotion, National Public Health
Institute, FIN-00300 Helsinki, Finland
Proteins actively transported into the nucleus via the classical nuclear
import pathway contain nuclear localization signals (NLSs), which are
recognized by the family of importin 
molecules. Importin
contains 10 armadillo (arm) repeats, of which the N-terminal arm repeats
2–4 have been considered as the "major" NLS binding site.
Interferon-activated, dimerized signal transducers and activators of
transcription (STAT1 and STAT2) directly bind to importin 5 via a
dimeric nonclassical NLS. Here we show by site-directed mutagenesis that the
very C-terminal arm repeats 8 and 9 of importin 5 form a unique binding
site for STAT1 homodimers and STAT1-STAT2 heterodimers. Influenza A virus
nucleoprotein also contains a nonclassical NLS that is recognized by the
C-terminal NLS binding site of importin 5, comprising arm repeats
7–9. Binding of influenza A virus nucleoprotein to importin 3
also occurs via the C-terminal arm repeats. Simian virus 40 large T antigen
instead binds to the major N-terminal arm repeats of importin 3,
indicating that one importin molecule is able to use either its N- or
C-terminal arm repeats for binding various NLS containing proteins.
Received for publication, April 7, 2003 , and in revised form, May 9, 2003.
* This work was supported by the Medical Research Council of the Academy of Finland and by the Sigrid Juselius and the Finnish Cancer Foundations. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
To whom correspondence should be addressed: National Public Health Institute,
Mannerheimintie 166, FIN-00300 Helsinki, Finland. Tel.: 358-9-47448377; Fax:
358-9-47448355; E-mail:
krister.melen{at}ktl.fi.
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