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Molecular and Cellular Biology, October 2002, p. 6871-6882, Vol. 22, No. 19
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.19.6871-6882.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Nuclear Export and Retention Signals in the RS Domain of SR Proteins

Demian Cazalla,1 Jun Zhu,2 Lisa Manche,2 Elisabeth Huber,1 Adrian R. Krainer,2 and Javier F. Cáceres1*

MRC Human Genetics Unit, Western General Hospital, Edinburgh EH4 2XU, Scotland,1 Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724-22082

Received 5 April 2002/ Returned for modification 3 June 2002/ Accepted 20 June 2002

Splicing factors of the SR protein family share a modular structure consisting of one or two RNA recognition motifs (RRMs) and a C-terminal RS domain rich in arginine and serine residues. The RS domain, which is extensively phosphorylated, promotes protein-protein interactions and directs subcellular localization and—in certain situations—nucleocytoplasmic shuttling of individual SR proteins. We analyzed mutant versions of human SF2/ASF in which the natural RS repeats were replaced by RD or RE repeats and compared the splicing and subcellular localization properties of these proteins to those of SF2/ASF lacking the entire RS domain or possessing a minimal RS domain consisting of 10 consecutive RS dipeptides (RS10). In vitro splicing of a pre-mRNA that requires an RS domain could take place when the mutant RD, RE, or RS10 domain replaced the natural domain. The RS10 version of SF2/ASF shuttled between the nucleus and the cytoplasm in the same manner as the wild-type protein, suggesting that a tract of consecutive RS dipeptides, in conjunction with the RRMs of SF2/ASF, is necessary and sufficient to direct nucleocytoplasmic shuttling. However, the SR protein SC35 has two long stretches of RS repeats, yet it is not a shuttling protein. We demonstrate the presence of a dominant nuclear retention signal in the RS domain of SC35.

* Corresponding author. Mailing address: MRC Human Genetics Unit, Western General Hospital, Crewe Rd., Edinburgh EH4 2XU, Scotland, United Kingdom. Phone: (44) 131 467-8426. Fax: (44) 131 343-2620. E-mail: Javier.Caceres{at}hgu.mrc.ac.uk.

Molecular and Cellular Biology, October 2002, p. 6871-6882, Vol. 22, No. 19
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.19.6871-6882.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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