Previous Article | Next Article ![]()
Molecular and Cellular Biology, April 2003, p. 2844-2858, Vol. 23, No. 8
0270-7306/03/$08.00+0 DOI: 10.1128/MCB.23.8.2844-2858.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.
Interferes with Corepressor Recruitment and Prevents Transcriptional Repression
Section of Microbiology, Division of Biological Sciences, University of California at Davis, Davis, California
Received 8 October 2002/ Returned for modification 21 November 2002/ Accepted 21 January 2003
Retinoic acid receptors (RARs) are ligand-regulated transcription factors that play multiple roles in vertebrate development and differentiation. RARs as a class are capable of both repressing and activating target gene expression. Transcriptional repression is mediated through the recruitment of corepressor proteins such as SMRT. Notably, vertebrates encode three major forms of RARs,
, ß, and
, and these distinct RAR isotypes differ in the ability to recruit a corepressor. RAR
strongly interacts with SMRT and can repress target gene transcription, whereas RARß and -
interact with SMRT only weakly and fail to repress. We report here the use of a genetic suppressor approach, based on a yeast two-hybrid interaction assay using Saccharomyces cerevisiae, for the isolation of RARß mutants that have gained the RAR
-like corepressor phenotype, i.e., a strong interaction with SMRT and the ability to repress gene expression in vertebrate cells. Analysis of these gain-of-function mutants indicates that the different corepressor interaction properties of RAR
, -ß and -
are determined by a gating mechanism through which amino acid differences in the helix 3 region of these receptors influence the position of the receptor C-terminal helix 12 domain. As a consequence, the RARß and RAR
receptors appear to adopt a constitutively closed helix 12 conformation in the absence of hormone that may approximate the conformation of RAR
when bound to hormone agonist. This closed helix 12 conformation in RARß and RAR
blocks corepressor binding, prevents repression, and permits significant levels of target gene activation even in the absence of hormone. We refer to this phenomenon as a "gate-latch" model of corepressor regulation.
This article has been cited by other articles:
| J. Bacteriol. | J. Virol. | Eukaryot. Cell |
|---|
| Microbiol. Mol. Biol. Rev. | Clin. Vaccine Immunol. | All ASM Journals |
|---|