Eukaryotic Transcription Factors and Signal Transduction

Our major goal is to decipher the molecular mechanisms by which sequence-specific factors and cofactors regulate transcription. We apply protein biochemistry and biosensor techniques to study transcription factor complex assembly in real time.

Our work focuses on the CCAAT-binding complex (CBC). In A. nidulans and A. fumigatus, the CBC consists of the subunits HapB, HapC and HapE. A multitude of genes has been found to be positively or negatively regulated by the CBC, including genes involved in production of natural products and iron homeostasis. In collaboration with the group of Michael Groll (TU Munich) we solved the crystal structure of the CBC:DNA complex, which revealed a novel mode of sequence-specific DNA binding. 

Structure of the CBC:DNA complex. (A) Ribbon plot of the CBC bound to the CCAAT box in the cycA promoter. (B) Structural superposition of the CBC and the first turn of the nucleosome.
Structure of the CBC:DNA complex. (A) Ribbon plot of the CBC bound to the CCAAT box in the cycA promoter. (B) Structural superposition of the CBC and the first turn of the nucleosome.

Novel molecular mechanisms of iron sensing and homeostasis in filamentous fungi

The bZIP transcription factor HapX mediates adaptation to iron limitation and consequently virulence by repressing iron-consumption and activating iron uptake. HapX activity depends on physical interaction with the CBC. In collaboration with the group of Hubertus Haas (Innsbruck Medical University), we demonstrated that HapX is not only crucial for adaptation to iron starvation but also for iron resistance via activating vacuolar iron storage. A HapX homodimer and the CBC cooperatively bind an evolutionary conserved DNA motif in the promoter of the cccA gene thus explaining the discrimination between CBC and HapX/CBC target genes. Our data uncovered a novel regulatory mechanism mediating both iron resistance and adaptation to iron starvation dependent on the Janus-type transcription factor HapX. 

A) Bipartite DNA motif present in cccA promoters. (B) Surface Plasmon Resonance analysis of the CBC/DNA-HapX ternary complex.
A) Bipartite DNA motif present in cccA promoters. (B) Surface Plasmon Resonance analysis of the CBC/DNA-HapX ternary complex.