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Proc Natl Acad Sci U S A. 2013 Oct 29;110(44):17826-31. doi: 10.1073/pnas.1316235110. Epub 2013 Oct 14.

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

Author information

1
Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.

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.

KEYWORDS:

alternative splicing; sequence motifs; steroid hormone receptor

PMID:
24127590
PMCID:
PMC3816441
DOI:
10.1073/pnas.1316235110
[Indexed for MEDLINE]
Free PMC Article
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