GPIDR · Understanding the genetic encoding of dynamic interactions underlying transcriptional regulation

Transcription factors often serve as key hubs for dynamic protein-protein interactions in eukaryotic cells. Aside from their characteristic DNA binding domains, the vast majority of transcription factors contain activation domains that are often intrinsically disordered. These domains are not well-characterized, but are thought to contain key sequence-distributed features that enable transcription factors to interact with their many binding partners, and have recently been associated with the capacity to form transcriptional condensates through phase separation. Many questions remain about how genotype and phenotype are related in these relatively uncharacterized regions, particularly with respect to their dynamic binding interactions, with important implications for human disease-associated mutations. Here, we propose to help uncover the relationships between sequence, structure, and dynamics of these interactions in vivo, using the power of deep mutational scanning and protein complementation assays in budding yeast.