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J. Biol. Chem., Vol. 282, Issue 27, 19292-19301, July 6, 2007

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A Novel Conserved Nuclear Localization Signal Is Recognized by a Group of Yeast Importins^*

Thomas Fries¹, Christian Betz¹, Kai Sohn, Stefanie Caesar, Gabriel Schlenstedt, and Susanne M. Bailer²

From the Universität des Saarlandes, Medizinische Biochemie und Molekularbiologie, Gebaüde 61.4, D-66421 Homburg/Saar, Germany, and the Fraunhofer Institut für Grenzflächen und Bioverfahrenstechnik, Nobelstrasse 12, D-70569 Stuttgart, Germany

Nucleo-cytoplasmic transport of proteins is mostly mediated by specific interaction between transport receptors of the importin β family and signal sequences present in their cargo. While several signal sequences, in particular the classical nuclear localization signal (NLS) recognized by the heterodimeric importin /β complex are well known, the signals recognized by other importin β-like transport receptors remain to be characterized in detail. Here we present the systematic analysis of the nuclear import of Saccharomyces cerevisiae Asr1p, a nonessential alcohol-responsive Ring/PHD finger protein that shuttles between nucleus and cytoplasm but accumulates in the nucleus upon alcohol stress. Nuclear import of Asr1p is constitutive and mediated by its C-terminal domain. A short sequence comprising residues 243–280 is sufficient and necessary for active targeting to the nucleus. Moreover, the nuclear import signal is conserved from yeast to mammals. In vitro, the nuclear localization signal of Asr1p directly interacts with the importins Kap114p, Kap95p, Pse1p, Kap123p, or Kap104p, interactions that are sensitive to the presence of RanGTP. In vivo, these importins cooperate in nuclear import. Interestingly, the same importins mediate nuclear transport of histone H2A. Based on mutational analysis and sequence comparison with a region mediating nuclear import of histone H2A, we identified a novel type of NLS with the consensus sequence R/KxxL(x)_nV/YxxV/IxK/RxxxK/R that is recognized by five yeast importins and connects them into a highly efficient network for nuclear import of proteins.

Received for publication, January 8, 2007 , and in revised form, May 3, 2007.

^* This work was supported by grants (to S. M. B.) from the Deutsche Forschungsgemeinschaft (Ba 1165/3-2), the Forschungsausschuβ (61 CL/TG84), and the HOMFOR program 2005 of the Universität des Saarlandes. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables I and II.

¹ These two authors contributed equally to this project.

² To whom correspondence should be addressed. Tel.: 49-6841-16-47909; Fax: 49-6841-16-26027; E-mail: dr.susanne.bailer{at}med-rz.uni-saarland.de.

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