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J. Biol. Chem., Vol. 279, Issue 7, 5984-5992, February 13, 2004

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A Novel CRM1-mediated Nuclear Export Signal Governs Nuclear Accumulation of Glyceraldehyde-3-phosphate Dehydrogenase following Genotoxic Stress^*

Victor M. Brown, Eugene Y. Krynetski, Natalia F. Krynetskaia, Dara Grieger, Suraj T. Mukatira¶, Kuruganti G. Murti||, Clive A. Slaughter¶, Hee-Won Park**, and William E. Evans

From the Department of Pharmaceutical Sciences, ^||Scientific Imaging Shared Resource, the ^¶Hartwell Center for Bioinformatics and Biotechnology, the ^**Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105 and the Departments of Pharmaceutical Sciences, Pharmacy and Pediatrics, University of Tennessee, Memphis, Tennessee 38163

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a multifunctional protein with glycolytic and non-glycolytic functions, including pro-apoptotic activity. GAPDH accumulates in the nucleus after cells are treated with genotoxic drugs, and it is present in a protein complex that binds DNA modified by thioguanine incorporation. We identified a novel CRM1-dependent nuclear export signal (NES) comprising 13 amino acids (KKVVKQASEGPLK) in the C-terminal domain of GAPDH, truncation or mutation of which abrogated CRM1 binding and caused nuclear accumulation of GAPDH. Alanine scanning of the sequence encompassing the putative NES demonstrated at least two regions important for nuclear export. Site mutagenesis of Lys²⁵⁹ did not affect oligomerization but impaired nuclear efflux of GAPDH, indicating that this amino acid residue is essential for proper functioning of this NES. This novel NES does not contain multiple leucine residues unlike other CRM1-interacting NES, is conserved in GAPDH from multiple species, and has sequence similarities to the export signal found in feline immunodeficiency virus Rev protein. Similar sequences (KKVV*7-13PLK) were found in two other human proteins, U5 small nuclear ribonucleoprotein, and transcription factor BT3.

Received for publication, July 2, 2003 , and in revised form, October 23, 2003.

^* This work was supported in part by Grant R37-CA36401, Cancer Center Support Grant CA-21765, and by the American Lebanese Syrian Associated Charities. 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: St. Jude Children's Research Hospital, 332 N. Lauderdale St., Memphis, TN 38105-2794. Tel.: 901-495-3663; Fax: 901-525-6869; E-mail: william.evans{at}stjude.org.

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