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Published 28 March 2005. doi:10.1083/jcb.200409024
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 168, Number 7, 1027-1038
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Article

 A systems analysis of importin-{alpha}–ß mediated nuclear protein import

Gregory Riddick and Ian G. Macara

Center for Cell Signaling, Department of Biochemistry and Molecular Genetics, and Department of Microbiology, University of Virginia School of Medicine, Charlottesville, VA 22908

Correspondence to Ian G. Macara: igm9c{at}virginia.edu

Importin-ß (Impß) is a major transport receptor for Ran-dependent import of nuclear cargo. Impß can bind cargo directly or through an adaptor such as Importin-{alpha} (Imp{alpha}). Factors involved in nuclear transport have been well studied, but systems analysis can offer further insight into regulatory mechanisms. We used computer simulation and real-time assays in intact cells to examine Imp{alpha}–ß-mediated import. The model reflects experimentally determined rates for cargo import and correctly predicts that import is limited principally by Imp{alpha} and Ran, but is also sensitive to NTF2. The model predicts that CAS is not limiting for the initial rate of cargo import and, surprisingly, that increased concentrations of Impß and the exchange factor, RCC1, actually inhibit rather than stimulate import. These unexpected predictions were all validated experimentally. The model revealed that inhibition by RCC1 is caused by sequestration of nuclear Ran. Inhibition by Impß results from depletion nuclear RanGTP, and, in support of this mechanism, expression of mRFP-Ran reversed the inhibition.

Abbreviations used in this paper: GGNLS, GST-GFP-NLS; Imp{alpha}, importin-{alpha}; Impß, importin-ß; NPC, nuclear pore complex; ODE, ordinary differential equation; OGI, Oregon green isothiocyanate.


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