Simple biochemical features underlie transcriptional activation domain diversity and dynamic, fuzzy binding to Mediator
Abstract
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Apr 27, 2021
- Source ID
- 10.7554/elife.68068
Entities
People
- Adrian L. Sanborn
- Benjamin Yeh
- Cynthia V. Hao
- Erez Lieberman Aiden
- Jordan T Feigerle
- Raphael J.l. Townshend
- Roger D. Kornberg
- Ron Ofer Dror
Organizations
- Baylor College of Medicine
- Illumina
- International Business Machines Corporation (Armonk, NY)
- National Institutes of Health
- National Science Foundation
- Rice University
- Robert A. Welch Foundation
- Robert and Janice McNair Foundation
- Stanford University
- United States Department of Defense
- United States Department of Energy
- United States – Israel Binational Science Foundation