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.
journal_name
Proc Natl Acad Sci U S Aauthors
Thomas-Chollier M,Watson LC,Cooper SB,Pufall MA,Liu JS,Borzym K,Vingron M,Yamamoto KR,Meijsing SHdoi
10.1073/pnas.1316235110subject
Has Abstractpub_date
2013-10-29 00:00:00pages
17826-31issue
44eissn
0027-8424issn
1091-6490pii
1316235110journal_volume
110pub_type
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