TY - JOUR T1 - Simple biochemical features underlie transcriptional activation domain diversity and dynamic, fuzzy binding to Mediator JF - bioRxiv DO - 10.1101/2020.12.18.423551 SP - 2020.12.18.423551 AU - Adrian L. Sanborn AU - Benjamin T. Yeh AU - Jordan T. Feigerle AU - Cynthia V. Hao AU - Raphael J. L. Townshend AU - Erez Lieberman Aiden AU - Ron O. Dror AU - Roger D. Kornberg Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/12/18/2020.12.18.423551.abstract N2 - Gene activator proteins comprise distinct DNA-binding and transcriptional activation domains (ADs). Because few ADs have been described, we tested domains tiling all yeast transcription factors for activation in vivo and identified 150 ADs. By mRNA display, we showed that 73% of ADs bound the Med15 subunit of Mediator, and that binding strength was correlated with activation. AD-Mediator interaction in vitro was unaffected by a large excess of free activator protein, pointing to a dynamic mechanism of interaction. Structural modeling showed that ADs interact with Med15 without shape complementarity (“fuzzy” binding). ADs shared no sequence motifs, but mutagenesis revealed biochemical and structural constraints. Finally, a neural network trained on AD sequences accurately predicted ADs in human proteins and in other yeast proteins, including chromosomal proteins and chromatin remodeling complexes. These findings solve the longstanding enigma of AD structure and function and provide a rationale for their role in biology.Competing Interest StatementThe authors have declared no competing interest. ER -