Journal article
A naturally occuring insertion of a single amino acid rewires transcriptional regulation by glucocorticoid receptor isoforms
Proceedings of the National Academy of Sciences - PNAS, Vol.110(44), pp.17826-17831
10/29/2013
DOI: 10.1073/pnas.1316235110
PMCID: PMC3816441
PMID: 24127590
Abstract
For proteins to be able to have context-specific activities, they can adopt context-specific conformations that enhance or restrict their activity. For transcriptional regulatory factors, such a context-specific signal is provided by the sequence of the DNA response element to which it binds. Here we show how one signal, an alternative splicing event, rewires a transcriptional regulatory protein to respond differently to a second signal, the DNA sequence to which it binds, by changing the functional interplay between protein domains. Together, our findings argue that bidirectional allosteric signaling between the DNA:protein interface and other regulatory domains fine tunes the activity of transcriptional regulatory factors toward individual target genes.
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.
Details
- Title: Subtitle
- A naturally occuring insertion of a single amino acid rewires transcriptional regulation by glucocorticoid receptor isoforms
- Creators
- Morgane Thomas-Chollier - , 14195 BerlinLisa C Watson - Department of Cellular and Molecular PharmacologySamantha B Cooper - Department of Cellular and Molecular PharmacologyMiles A Pufall - Department of BiochemistryJennifer S Liu - Chemistry and Chemical Biology ProgramKatja Borzym - , 14195 BerlinMartin Vingron - , 14195 BerlinKeith R Yamamoto - Department of Cellular and Molecular PharmacologySebastiaan H Meijsing - , 14195 Berlin
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.110(44), pp.17826-17831
- DOI
- 10.1073/pnas.1316235110
- PMID
- 24127590
- PMCID
- PMC3816441
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- National Academy of Sciences
- Alternative title
- Modulating transcription by splicing & DNA signals
- Language
- English
- Date published
- 10/29/2013
- Academic Unit
- Biochemistry and Molecular Biology
- Record Identifier
- 9984024537202771
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