Commonly asked questions about transcriptional activation domains

Abstract

Eukaryotic transcription factors activate gene expression with their DNA-binding domains and activation domains. DNA-binding domains bind the genome by recognizing structurally related DNA sequences; they are structured, conserved, and predictable from protein sequences. Activation domains recruit chromatin modifiers, coactivator complexes, or basal transcriptional machinery via structurally diverse protein-protein interactions. Activation domains and DNA-binding domains have been called independent, modular units, but there are many departures from modularity, including interactions between these regions and overlap in function. Compared to DNA-binding domains, activation domains are poorly understood because they are poorly conserved, intrinsically disordered, and difficult to predict from protein sequences. This review, organized around commonly asked questions, describes recent progress that the field has made in understanding the sequence features that control activation domains and predicting them from sequence.

Keywords: Activation domain; Coactivator; Convolutional neural network; Intrinsically disordered protein; Protein function prediction; Protein-protein interactions (PPIs); RNA polymerase II; Transactivation domain; Transcription; Transcription factor; Transcriptional activation domain.

Figure 1:

Among annotated activation domains, the traditional classes are highly overlapping. Acidic activation domains have a net charge < −3, P-rich have >15% proline, and S-rich have >15% serine.

Figure 2:

In our acidic exposure model, disordered activation domains rapidly transition between collapsed and expanded states. The collapsed state is inactive. The expanded state is competent to bind coactivators because the W,F,Y,L residues are exposed to solvent. The W,F,Y,L residues make critical contacts with hydrophobic surfaces on the coactivator. Many activation domains experience coupled folding and binding, but folding is not essential. Electrostatic interactions between the activation domain and coactivator can contribute to binding or steering, but these interactions are of low affinity and not always necessary.