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A naturally occuring insertion of a single amino acid rewires transcriptional regulation by glucocorticoid receptor isoforms

MPG-Autoren
http://pubman.mpdl.mpg.de/cone/persons/resource/persons50595

Thomas-Chollier,  M.
Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons73747

Borzym,  K.
Mechanisms of Transcriptional Regulation (Sebastiaan H. Meijsing), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons50613

Vingron,  M.
Gene regulation (Martin Vingron), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons50428

Meijsing,  S. H.
Mechanisms of Transcriptional Regulation (Sebastiaan H. Meijsing), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Thomas-Chollier et al.pdf
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Zitation

Thomas-Chollier, M., Watson, L. C., Cooper, S. B., Pufall, M. A., Liu, J. S., Borzym, K., et al. (2013). A naturally occuring insertion of a single amino acid rewires transcriptional regulation by glucocorticoid receptor isoforms. Proceedings of the National Academy of Sciences of the United States of America, 110(44), 17826-17831. doi:10.1073/pnas.1316235110.


Zitierlink: http://hdl.handle.net/11858/00-001M-0000-0014-7B98-9
Zusammenfassung
In addition to guiding proteins to defined genomic loci, DNA can act as an allosteric ligand that influences protein structure and activity. Here we compared genome-wide binding, transcriptional regulation, and, using NMR, the conformation of two glucocorticoid receptor (GR) isoforms that differ by a single amino acid insertion in the lever arm, a domain that adopts DNA sequence-specific conformations. We show that these isoforms differentially regulate gene expression levels through two mechanisms: differential DNA binding and altered communication between GR domains. Our studies suggest a versatile role for DNA in both modulating GR activity and also in directing the use of GR isoforms. We propose that the lever arm is a "fulcrum" for bidirectional allosteric signaling, conferring conformational changes in the DNA reading head that influence DNA sequence selectivity, as well as conferring changes in the dimerization domain that connect functionally with remote regulatory surfaces, thereby influencing which genes are regulated and the magnitude of their regulation.