Structural investigations of transcription factors bound to specific DNA

In the cell this regulatory code is determined by transcription factors (TFs) that recognise specific DNA sequence motifs. TFs commonly work together to form TF-TF complexes on DNA. Even though individual interactions between TFs are often weak, the complexes formed on DNA can still be highly specific, both in terms of the TF-TF pairing, and the spacing between the individual motifs. The molecular basis of this specificity is, however, unclear. This project aims to determine the structural basis of cooperative binding of multiple transcription factors to free DNA. As models, we will use homeodomain proteins that have diverse biological roles despite binding to the same motif on free DNA. The homeodomains differ, however, in choice of TF partners such as basic helix-loop-helix (bHLH) proteins. The specific aims of this research program are to: determine the molecular basis of partner choice of canonical homeodomain proteins and to understand the structural basis of spacing preferences.