Simple biochemical features underlie transcriptional activation domain diversity and dynamic, fuzzy binding to Mediator
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...
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eLife Sciences Publications Ltd
2021-04-01
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Series: | eLife |
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Online Access: | https://elifesciences.org/articles/68068 |
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author | Adrian L Sanborn Benjamin T Yeh Jordan T Feigerle Cynthia V Hao Raphael JL Townshend Erez Lieberman Aiden Ron O Dror Roger D Kornberg |
author_facet | Adrian L Sanborn Benjamin T Yeh Jordan T Feigerle Cynthia V Hao Raphael JL Townshend Erez Lieberman Aiden Ron O Dror Roger D Kornberg |
author_sort | Adrian L Sanborn |
collection | DOAJ |
description | 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. |
first_indexed | 2024-04-12T16:48:52Z |
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id | doaj.art-5549d912586745288fbfbf368dffa631 |
institution | Directory Open Access Journal |
issn | 2050-084X |
language | English |
last_indexed | 2024-04-12T16:48:52Z |
publishDate | 2021-04-01 |
publisher | eLife Sciences Publications Ltd |
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series | eLife |
spelling | doaj.art-5549d912586745288fbfbf368dffa6312022-12-22T03:24:28ZengeLife Sciences Publications LtdeLife2050-084X2021-04-011010.7554/eLife.68068Simple biochemical features underlie transcriptional activation domain diversity and dynamic, fuzzy binding to MediatorAdrian L Sanborn0https://orcid.org/0000-0002-4725-8012Benjamin T Yeh1https://orcid.org/0000-0001-9397-6392Jordan T Feigerle2Cynthia V Hao3https://orcid.org/0000-0003-2183-0698Raphael JL Townshend4Erez Lieberman Aiden5Ron O Dror6Roger D Kornberg7https://orcid.org/0000-0002-2425-7519Department of Structural Biology, Stanford University School of Medicine, Stanford, United States; Department of Computer Science, Stanford University, Stanford, United StatesDepartment of Computer Science, Stanford University, Stanford, United StatesDepartment of Structural Biology, Stanford University School of Medicine, Stanford, United StatesDepartment of Structural Biology, Stanford University School of Medicine, Stanford, United StatesDepartment of Computer Science, Stanford University, Stanford, United StatesThe Center for Genome Architecture, Baylor College of Medicine, Houston, United States; Center for Theoretical Biological Physics, Rice University, Houston, United StatesDepartment of Computer Science, Stanford University, Stanford, United StatesDepartment of Structural Biology, Stanford University School of Medicine, Stanford, United StatesGene 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.https://elifesciences.org/articles/68068transcription factoractivation domainmediator complexmachine learninghigh-throughput screeningmolecular simulation |
spellingShingle | Adrian L Sanborn Benjamin T Yeh Jordan T Feigerle Cynthia V Hao Raphael JL Townshend Erez Lieberman Aiden Ron O Dror Roger D Kornberg Simple biochemical features underlie transcriptional activation domain diversity and dynamic, fuzzy binding to Mediator eLife transcription factor activation domain mediator complex machine learning high-throughput screening molecular simulation |
title | Simple biochemical features underlie transcriptional activation domain diversity and dynamic, fuzzy binding to Mediator |
title_full | Simple biochemical features underlie transcriptional activation domain diversity and dynamic, fuzzy binding to Mediator |
title_fullStr | Simple biochemical features underlie transcriptional activation domain diversity and dynamic, fuzzy binding to Mediator |
title_full_unstemmed | Simple biochemical features underlie transcriptional activation domain diversity and dynamic, fuzzy binding to Mediator |
title_short | Simple biochemical features underlie transcriptional activation domain diversity and dynamic, fuzzy binding to Mediator |
title_sort | simple biochemical features underlie transcriptional activation domain diversity and dynamic fuzzy binding to mediator |
topic | transcription factor activation domain mediator complex machine learning high-throughput screening molecular simulation |
url | https://elifesciences.org/articles/68068 |
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