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J. Biol. Chem., Vol. 278, Issue 51, 51937-51949, December 19, 2003

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Molecular Basis for the Rapid Dissociation of Nuclear Localization Signals from Karyopherin in the Nucleoplasm^*

Daniel Gilchrist and Michael Rexach

From the Department of Biological Sciences, Stanford University, Stanford, California 94305-5020

The yeast karyopherin heterodimer Kap60p·Kap95p facilitates nuclear import of proteins bearing a classic nuclear localization signal (NLS). The subunit Kap60p binds to the NLS of cargo molecules in the cytoplasm, forming stable complexes that must ultimately dissociate in the nucleoplasm. Although Kap60p can release NLSs on its own using an autoinhibitory sequence (AIS) motif that can occupy the NLS binding site, that mechanism is too slow to support rapid nuclear import. We previously showed that the nuclear basket nucleoporin Nup2p and the exportin complex Cse1p·Gsp1p·GTP function as karyopherin release factors (KaRFs) because they can accelerate the rate of dissociation of NLSs from Kap60p. Here we dissect the molecular mechanics of their KaRF activity. We show that Cse1p accelerates dissociation of Kap60p·NLS-cargo complexes and Kap60p·Nup2p complexes by increasing the affinity of Kap60p for its AIS motif. In contrast, Nup2p uses a conserved sequence motif (VMXXRKIA) coupled to an AIS-like motif to accelerate dissociation of Kap60p·NLS complexes in a vectorial reaction mechanism. Mutation of either motif in Nup2p leads to a loss of KaRF activity and to the accumulation of Kap60p·NLS-cargo complexes in the nucleoplasm of yeast. We discuss a model whereby Nup2p, Cse1p, and Gsp1p cooperate to establish directionality in the movement of Kap60p and NLS-cargos across the nuclear pore complex.

Received for publication, July 9, 2003 , and in revised form, September 18, 2003.

^* 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. Tel.: 650-725-4814; Fax: 650-723-0155; E-mail: rexach{at}stanford.edu.

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