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Molecular and Cellular Biology, December 1999, p. 8400-8411, Vol. 19, No. 12
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

RanBP3 Contains an Unusual Nuclear Localization Signal That Is Imported Preferentially by Importin-alpha 3

Katie Welch,1,* Jacqueline Franke,2 Matthias Köhler,2 and Ian G. Macara1

Markey Center for Cell Signaling, University of Virginia, Charlottesville, Virginia 22908,1 and Max Delbrück Center for Molecular Medicine, 13125 Berlin-Buch, Germany2

Received 11 May 1999/Returned for modification 9 June 1999/Accepted 15 September 1999

The full range of sequences that constitute nuclear localization signals (NLSs) remains to be established. Even though the sequence of the classical NLS contains polybasic residues that are recognized by importin-alpha , this import receptor can also bind cargo that contains no recognizable signal, such as STAT1. The situation is further complicated by the existence of six mammalian importin-alpha family members. We report the identification of an unusual type of NLS in human Ran binding protein 3 (RanBP3) that binds preferentially to importin-alpha 3. RanBP3 contains a variant Ran binding domain most similar to that found in the yeast protein Yrb2p. Anti-RanBP3 immunofluorescence is predominantly nuclear. Microinjection of glutathione S-transferase-green fluorescent protein-RanBP3 fusions demonstrated that a region at the N terminus is essential and sufficient for nuclear localization. Deletion analysis further mapped the signal sequence to residues 40 to 57. This signal resembles the NLSs of c-Myc and Pho4p. However, several residues essential for import via the c-Myc NLS are unnecessary in the RanBP3 NLS. RanBP3 NLS-mediated import was blocked by competitive inhibitors of importin-alpha or importin-beta or by the absence of importin-alpha . Binding assays using recombinant importin-alpha 1, -alpha 3, -alpha 4, -alpha 5, and -alpha 7 revealed a preferential interaction of the RanBP3 NLS with importin-alpha 3 and -alpha 4, in contrast to the simian virus 40 T-antigen NLS, which interacted to similar extents with all of the isoforms. Nuclear import of the RanBP3 NLS was most efficient in the presence of importin-alpha 3. These results demonstrate that members of the importin-alpha family possess distinct preferences for certain NLS sequences and that the NLS consensus sequence is broader than was hitherto suspected.

* Corresponding author. Mailing address: Box 577, HSC, University of Virginia, Charlottesville, VA 22908. Phone: (804) 982-0083. Fax: (804) 924-1236. E-mail: kaw6n{at}virginia.edu.

Molecular and Cellular Biology, December 1999, p. 8400-8411, Vol. 19, No. 12
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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