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

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...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2013-10, Vol.110 (44), p.17826
Main Authors: Thomas-Chollier, Morgane, Watson, Lisa C, Cooper, Samantha B, Pufall, Miles A, Liu, Jennifer S, Borzym, Katja, Vingron, Martin, Yamamoto, Keith R, Meijsing, Sebastiaan H
Format: Article
Language:English
Subjects:
Alternative Splicing - genetics
Amino Acids - genetics
Cell Line, Tumor
Chromatin Immunoprecipitation
Electrophoretic Mobility Shift Assay
Gene Expression Regulation - genetics
Humans
Immunoblotting
Microarray Analysis
Models, Molecular
Mutagenesis, Insertional - genetics
Protein Conformation
Protein Isoforms - genetics
Protein Isoforms - physiology
Real-Time Polymerase Chain Reaction
Receptors, Glucocorticoid - genetics
Receptors, Glucocorticoid - physiology
Transcription, Genetic - genetics
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Summary: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.
ISSN:1091-6490
DOI:10.1073/pnas.1316235110