Crystal structure of the human FOXO3a-DBD/DNA complex suggests the effects of post-translational modification

By K. Tsai, Yuh-Ju Sun, Cheng-Yang Huang, Jer-Yen Yang, M. Hung, C. Hsiao. Nucleic Acids Research, 2007

120 citations recorded by the source corpus.

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.

Subfields: Geriatrics and Gerontology, Molecular Biology, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/fab44642536c2230a0c5f6231ffbb8a7224006a7