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Unexpected implications of STAT3 acetylation revealed by genetic encoding of acetyl-lysine

Yael Belo, Zack Mielko, Hila Nudelman, Ariel Afek, Oshrit Ben-David, Anat Shahar, Raz Zarivach, Raluca Gordan, View ORCID ProfileEyal Arbely
doi: https://doi.org/10.1101/537696
Yael Belo
†Department of Chemistry, Ben-Gurion University of the Negev, Beer-Sheva, 8410501, Israel
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Zack Mielko
‡Center for Genomic and Computational Biology, Department of Biostatistics and Bioinformatics, Duke University, Durham, NC 27708, USA
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Hila Nudelman
†Department of Chemistry, Ben-Gurion University of the Negev, Beer-Sheva, 8410501, Israel
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Ariel Afek
‡Center for Genomic and Computational Biology, Department of Biostatistics and Bioinformatics, Duke University, Durham, NC 27708, USA
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Oshrit Ben-David
†Department of Chemistry, Ben-Gurion University of the Negev, Beer-Sheva, 8410501, Israel
¶The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, 8410501, Israel
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Anat Shahar
¶The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, 8410501, Israel
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Raz Zarivach
§Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 8410501, Israel
¶The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, 8410501, Israel
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Raluca Gordan
‡Center for Genomic and Computational Biology, Department of Biostatistics and Bioinformatics, Duke University, Durham, NC 27708, USA
||Department of Computer Science, Department of Molecular Genetics and Microbiology, Duke University, Durham, NC 27708, USA
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Eyal Arbely
†Department of Chemistry, Ben-Gurion University of the Negev, Beer-Sheva, 8410501, Israel
§Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 8410501, Israel
¶The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, 8410501, Israel
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  • ORCID record for Eyal Arbely
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Abstract

The signal transducer and activator of transcription 3 (STAT3) protein is activated by phosphorylation of a specific tyrosine residue (Tyr705) in response to various extracellular signals. STAT3 activity was also found to be regulated by acetylation of Lys685. However, the molecular mechanism by which Lys685 acetylation affects the transcriptional activity of STAT3 remains elusive. By genetically encoding the co-translational incorporation of acetyl-lysine into position Lys685 and co-expression with the Elk receptor tyrosine kinase, we were able to biochemically characterize site-specifically acetylated, and simultaneously acetylated and phosphorylated STAT3. We measured the effect of acetylation on the crystal structure, and DNA binding affinity and specificity of Tyr705-phosphorylated and non-phosphorylated STAT3. In addition, we monitored the deacetylation of acetylated Lys685 by reconstituting the mammalian enzymatic deacetylation reaction in live bacteria. Surprisingly, we found that acetylation, per se, had no effect on the crystal structure, and DNA binding affinity or specificity of STAT3, implying that the previously observed acetylation-dependent transcriptional activity of STAT3 involves an additional cellular component. In addition, we discovered that Tyr705-phosphorylation protects Lys685 from deacetylation in bacteria, providing a new possible explanation for the observed correlation between STAT3 activity and Lys685 acetylation.

Footnotes

  • E-mail: arbely{at}bgu.ac.il, Phone: +972 (0)8 6428739. Fax: +972 (0)8 6428449

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted February 01, 2019.
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Unexpected implications of STAT3 acetylation revealed by genetic encoding of acetyl-lysine
Yael Belo, Zack Mielko, Hila Nudelman, Ariel Afek, Oshrit Ben-David, Anat Shahar, Raz Zarivach, Raluca Gordan, Eyal Arbely
bioRxiv 537696; doi: https://doi.org/10.1101/537696
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Unexpected implications of STAT3 acetylation revealed by genetic encoding of acetyl-lysine
Yael Belo, Zack Mielko, Hila Nudelman, Ariel Afek, Oshrit Ben-David, Anat Shahar, Raz Zarivach, Raluca Gordan, Eyal Arbely
bioRxiv 537696; doi: https://doi.org/10.1101/537696

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