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J Biol Chem, Vol. 274, Issue 37, 26493-26502, September 10, 1999

GTP Hydrolysis Links Initiation and Termination of Nuclear Import on the Nucleoporin Nup358

Nabeel R. Yaseen^§ and Günter Blobel

From the  Laboratory of Cell Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, New York 10021 and the ^§ Department of Pathology, Weill Medical College, Cornell University, New York, New York 10021

Binding of GTP-bound Ran (RanGTP) to karyopherin 1 (Kap1) releases import cargo into the nucleus. Using an ultrastructural, biochemical, and functional approach, we have studied the mechanism by which Kap1·RanGTP is recycled at the nuclear pore complex for repeated rounds of import. In vitro, Kap1 bound to the RanBP1-homologous (RBH) domains of Nup358 in the presence of either RanGTP or RanGDP, forming trimeric complexes. The Kap1·RanGTP·RBH complex resisted dissociation by RanBP1 and GTP hydrolysis by Ran GTPase activating protein 1. Ran-dependent binding of gold-conjugated Kap1 to the cytoplasmic fibers of the nuclear pore complex in digitonin-permeabilized cells and RanBP1 competition confirmed the in vitro binding data. Interaction of karyopherin  and a classical nuclear localization sequence peptide with the Kap1·RanGTP·RBH complex stimulated GTP hydrolysis by Ran GTPase activating protein 1 both in vitro and in permeabilized cells. This GTP hydrolysis was required for reinitiation of import of a nuclear localization sequence-bearing substrate in permeabilized cells. These data suggest that GTP hydrolysis on the RBH domains of Nup358 couples the termination of one cycle of nuclear import with the initiation of the next.

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