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Title: Surfactant mechanism of gene activation by transcriptional activation domains of sequence-specific factors
Gene expression in all eukaryotes depends critically on the function of transcriptional activation domains of gene activator proteins. The conventional model for activation domain (AD) function is the direct physical recruitment of specific coactivators and transcriptional machinery components. However, ADs are short and astronomically variable sequences, with up to 10^24 possible interchangeable sequence variants for a single gene activator; each variant is intrinsically disordered in structure and interacts with its targets with low specificity and affinity. How these peptides recruit their targets is becoming increasingly difficult to explain, exposing a massive knowledge gap in molecular biology. Here, we show that the single required characteristic of ADs—consistent with their extreme variability, intrinsic structural disorder, and near-stochastic interaction mode—is an amphiphilic aromatic–acidic surfactant-like property. We propose that the AD surfactant, by triggering the local gene-promoter chromatin phase transition, catalyzes the formation of “transcription factory” condensates. We demonstrate that the presence of tryptophan and aspartic acid residues in the AD sequence is sufficient for in vivo functionality, even when present only as a single pair of residues within a 20-amino-acid sequence containing nothing more than additional 18 glycine residues. We demonstrate that the amphipathic α-helix structure, suggested previously as beneficial for AD function, is actually detrimental, and breaking this helix by inserting prolines significantly increases activation domain functionality. The proposed surfactant action mechanism based on near-stochastic interactions implied by the minimalistic activation domains changes not only the paradigm for the explanation of gene activation but also the fundamental biochemistry paradigm based on the specificity of sequence-to-structure-to-functional-interaction. The mechanism of activity regulation by near-stochastic allosteric interactions could easily be applied to other biological processes.  more » « less
Award ID(s):
1925646
NSF-PAR ID:
10340347
Author(s) / Creator(s):
Editor(s):
Sara Osman Carolina Perdigoto
Date Published:
Journal Name:
Nature structural molecular biology
ISSN:
1545-9985
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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