TBX5-NKX2 · Crystallographic and biochemical studies of the human TBX5-Nkx2-5-DNA complex

Holt Oram syndrome (HOS) is a heart and limb syndrome, which manifests itself in 1 of 100000 live births. HOS syndrome is an autosomal-dominant disease, where forelimb and cardiac congenital abnormalities are observed. The syndrome is connected to mutations in the T-box transcription factor TBX5 gene. Similar symptoms are observed when mutations in the homeobox transcription factor human Nkx2-5 are present. TBX5 and Nkx2-5 interact with each other and synergistically activate the promoters of the cardiac-specific natriuretic peptide precursor type A (ANF) and connexin (cx40). The project goal is the biochemical characterization and crystal structure solution of the ternary TBX5-Nkx2-5-DNA complex. The crystal structure of the ternary complex will allow a comprehensive structural analysis of the interaction mechanism between TBX5 and Nkx2-5 and their DNA binding sites and will elucidate the synergistic promoter activation of TBX5 and Nkx2-5 on a molecular level. Such insight is of broad interest for cardiovascular biologist because it opens the ultimate perspective to use this knowledge for influencing cardiac growth and for cardiac regeneration. The results of this project will contribute to the European quality and competitiveness in cardio vascular research. The project uses the full portfolio of structural biological research and requires interdisciplinary knowledge in molecular biology, biochemistry, biophysics, protein crystallography and bioinformatical techniques. Thus, the researcher has the possibility to gain skills in all techniques necessary for doing successful research in structural biology. In addition, the multidisciplinary environment at the EMBL will give the researcher the possibility to interact and communicate with scientists in fields other than crystallography. All mentioned points will allow the scientist to gain professional maturity and to develop an independent research career.