Nucleic Acids Research Advance Access published online on October 16, 2007
Nucleic Acids Research, doi:10.1093/nar/gkm703
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Structural Biology |
Crystal structure of the human FOXO3a-DBD/DNA complex suggests the effects of post-translational modification
1Institute of Molecular Biology, Academia Sinica, Taipei, 115, 2Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 30043, Taiwan, 3Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA, and 4Center for Molecular Medicine, China Medical University Hospital, Taichung, 404, Taiwan.
*To whom correspondence should be addressed. Tel: +886 2 2788 2743; Fax: +886 2 2782 6085; Email: hsiao{at}gate.sinica.edu.tw
Received June 4, 2007. Revised August 17, 2007. Accepted August 23, 2007.
FOXO3a is a transcription factor of the FOXO family. The FOXO proteins participate in multiple signaling pathways, and their transcriptional activity is regulated by several post-translational mechanisms, including phosphorylation, acetylation and ubiquitination. Because these post-translational modification sites are located within the C-terminal basic region of the FOXO DNA-binding domain (FOXO-DBD), it is possible that these post-translational modifications could alter the DNA-binding characteristics. To understand how FOXO mediate transcriptional activity, we report here the 2.7 Å crystal structure of the DNA-binding domain of FOXO3a (FOXO3a-DBD) bound to a 13-bp DNA duplex containing a FOXO consensus binding sequence (GTAAACA). Based on a unique structural feature in the C-terminal region and results from biochemical and mutational studies, our studies may explain how FOXO-DBD C-terminal phosphorylation by protein kinase B (PKB) or acetylation by cAMP-response element binding protein (CBP) can attenuate the DNA-binding activity and thereby reduce transcriptional activity of FOXO proteins. In addition, we demonstrate that the methyl groups of specific thymine bases within the consensus sequence are important for FOXO3a-DBD recognition of the consensus binding site.
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