Sequence features of transcriptional activation domains are consistent with the surfactant mechanism of gene activation

Summary Transcriptional activation domains (ADs) of gene activators remain enigmatic for decades as they are short, extremely variable in sequence, structurally disordered, and interact fuzzily to a spectrum of targets. We showed that the single required characteristic of the most common acidic ADs is an amphiphilic aromatic–acidic surfactant-like property which is the key for the local gene-promoter chromatin phase transition and 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 only 18 additional glycine residues. We demonstrate that breaking the amphipathic α-helix in AD by prolines increases AD functionality. The proposed mechanism is paradigm-shifting for gene activation area and generally for biochemistry as it relies on near-stochastic allosteric interactions critical for the key biological function.