Design principles of acidic transcriptional activation domains

Abstract

Acidic activation domains are intrinsically disordered regions of transcription factors that bind coactivators. The intrinsic disorder and low conservation of activation domains have made it difficult to identify general rules governing their function. To address this problem, we designed thousands of variants in seven acidic activation domains and measured their activities with a new high-throughput assay in human cell culture. From these data we identify three design principles of acidic activation domains: hydrophobic motifs must be balanced by acidic residues; acidic residues make large contributions to activity when they are adjacent to motifs; and motif composition reflects the structural constraints of coactivator interactions. These design principles motivated a simple predictor of activation domains in the human proteome: scanning for clusters of aromatic and leucine residues embedded in regions of high acidity identifies known activation domains and accurately predicts new ones. Our results support a flexible model in which acidic residues solubilize hydrophobic motifs so that they can interact with coactivators.