 Transcription factors (TFs) interact with DNA via the DNA binding domain (DBD, blue triangle) and to their interaction partners (grey) via their transactivation domains (TAD, green rectangle). The enrichment for negatively charged residues leads to a local extended conformation of the TAD via intra-chain repulsions, providing the appropriate context for aromatic residues to be exposed and to bind to their interaction partners in hydrophobic binding pocket (circular inset). The aromatic residues could fit the pocket in a stochastic manner, binding in different configurations. This would result in the formation of a "fuzzy" complex. In this case, the negative charges could furthermore contribute to the affinity of binding given that the TAD-interaction surfaces often expose positively charged patches. The absence of positively charged residues, compositional bias and particular spacing of negatively charged and aromatic residues could hence be considered as giving rise to a collection of short mini motifs that collectively contributes to TAD functionality 