Intramolecular inhibition of activating transcription factor-2 function by its DNA-binding domain.

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Genes & development, ISSN: 0890-9369, Vol: 10, Issue: 5, Page: 517-27

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Li, Xiao-Yong; Green, Michael R.
Cold Spring Harbor Laboratory
Biochemistry, Genetics and Molecular Biology; Activating Transcription Factor 2; Animals; Cells, Cultured; Chromatography, Affinity; Cyclic AMP Response Element-Binding Protein; inhibitors; DNA Mutational Analysis; Fungal Proteins; *Gene Expression Regulation; Humans; *Leucine Zippers; Protein Binding; Recombinant Fusion Proteins; *Saccharomyces cerevisiae Proteins; Sequence Deletion; Structure-Activity Relationship; Transcription Factors; *Transcription, Genetic; Transfection; Life Sciences; Medicine and Health Sciences
article description
ATF-2 is a cellular basic region-leucine zipper (bZIP) transcription factor that can mediate diverse transcriptional responses, including activation by the adenovirus Ela protein. ATF-2 contains an activation domain, required for transcriptional activity, but in the absence of an appropriate inducer, full-length ATF-2 is transcriptionally inactive. Here we have investigated the mechanism underlying this regulated inhibition of ATF-2 transcriptional activity. We show that the region of ATF-2 that suppresses the activation region is the bZIP DNA-binding domain and that maximal inhibition requires both the basic region and leucine zipper subdomains. Inhibition is activation domain specific: The ATF-2 bZIP suppresses the ATF-2 and the related Ela activation domains but not acidic- and glutamine-rich activation domains. In vitro protein interaction assays demonstrate that the ATF-2 activation domain and bZIP specifically bind to one another. Finally, we show that bZIP-mediated inhibition can be modulated in a cell-type-specific manner by another sequence element within ATF-2. On the basis of these and other data, we propose that the ATF-2 bZIP and activation domain are engaged in an inhibitory intramolecular interaction and that inducers of ATF-2 disrupt this interaction to activate transcription.