Intramolecular inhibition of activating transcription factor-2 function by its DNA-binding domain.
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.
Li
X Y
XY
Howard Hughes Medical Institute, University of Massachusetts Medical Center, Worcester, Massachusetts 01605, USA.
Green
M R
MR
D051698:Activating Transcription Factor 2; D000818:Animals; D002478:Cells, Cultured; D002846:Chromatography, Affinity; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins; D005656:Fungal Proteins / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D016350:Leucine Zippers / Q000235:genetics / Q000502:physiology; D011485:Protein Binding; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; D017384:Sequence Deletion; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection
C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; C052130:GAL4 protein, S cerevisiae; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors