Correlating Disordered Activation Domain Ensembles with Gene Expression Levels

Eduardo Flores; Aleah R Camacho; Estefania Cuevas-Zepeda; Mary B McCoy; Feng Yu; Max V Staller; Shahar Sukenik

doi:10.1016/j.bpr.2024.100195

Correlating Disordered Activation Domain Ensembles with Gene Expression Levels

Biophys Rep (N Y). 2025 Jan 2:100195. doi: 10.1016/j.bpr.2024.100195. Online ahead of print.

Authors

Eduardo Flores¹, Aleah R Camacho¹, Estefania Cuevas-Zepeda¹, Mary B McCoy¹, Feng Yu², Max V Staller³, Shahar Sukenik⁴

Affiliations

¹ Department of Chemistry and Biochemistry, University of California Merced, Merced, 95343.
² Department of Chemistry and Biochemistry, University of California Merced, Merced, 95343; Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, 94720 Berkeley, CA, USA.
³ Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, 94720; Center for Computational Biology, University of California Berkeley, Berkeley, 94720; Chan Zuckerberg Biohub-San Francisco, San Francisco, CA 94158.
⁴ Department of Chemistry and Biochemistry, University of California Merced, Merced, 95343; Department of Chemistry, Syracuse University, Syracuse, 13244.

PMID: 39755236
DOI: 10.1016/j.bpr.2024.100195

Abstract

Transcription factor proteins bind to specific DNA promoter sequences and initiate gene transcription. These proteins often contain intrinsically disordered activation domains (ADs) that regulate their transcriptional activity. Like other disordered protein regions, ADs do not have a fixed three-dimensional structure and instead exist in an ensemble of conformations. Disordered ensembles contain sequence-encoded structural preferences which are often linked to their function. We hypothesize this link exists between the structural preferences of AD ensembles and their ability to induce gene expression. To test this, we measured the ensemble dimensions of two ADs, HIF-1α and CITED2, in live cells using FRET microscopy, and correlated this structural information with their transcriptional activity. We find that mutations that expanded the ensemble of HIF-1α increased transcriptional activity while compacting mutations reduced it, highlighting the critical role of structural plasticity in regulating HIF-1α function. Conversely, CITED2 showed no correlation between ensemble dimensions and activity. Our results highlight a possible link between AD ensemble dimensions and their transcriptional activity, with implications to transcriptional regulation and dysfunction.