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

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.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0014-7B98-9 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0014-7B99-7
Genre: Journal Article

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 Creators:
Thomas-Chollier, M.1, Author              
Watson, L. C., Author
Cooper, S. B., Author
Pufall, M. A., Author
Liu, J. S., Author
Borzym, K.2, Author              
Vingron, M.3, Author              
Yamamoto, K. R., Author
Meijsing, S. H.2, Author              
Affiliations:
1Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433547              
2Mechanisms of Transcriptional Regulation (Sebastiaan H. Meijsing), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479641              
3Gene regulation (Martin Vingron), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479639              

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Free keywords: alternative splicing, steroid hormone receptor, sequence motifs
 Abstract: 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.

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Language(s): eng - English
 Dates: 2013-10-142013-10-29
 Publication Status: Published in print
 Pages: -
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 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1073/pnas.1316235110
ISSN: 1091-6490 (Electronic)0027-8424 (Print)
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Title: Proceedings of the National Academy of Sciences of the United States of America
  Other : Proc. Natl. Acad. Sci. U. S. A.
Source Genre: Journal
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Publ. Info: National Academy of Sciences
Pages: - Volume / Issue: 110 (44) Sequence Number: - Start / End Page: 17826 - 17831 Identifier: ISSN: 0027-8424
CoNE: /journals/resource/954925427230