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

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Understanding crystal structure for heart health

An EU-funded research team successfully characterised the complex formed by two transcription factors implicated in Holt Oram Syndrome. Advances in this area have the potential to help future heart patients.

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Holt Oram Syndrome (HOS) is a heart and limb syndrome, which manifests itself in 1 in 100,000 live births. The syndrome is connected to mutations in the transcription factor TBX5 gene. Similar symptoms to HOS are observed when mutations in the human transcription factor Nkx2-5 are present. TBX5 and Nkx2-5 play central roles in cardiac development and on interaction synergistically activate the promoters of the cardiac-specific peptide precursor type A (ANF) and connexin (cx40). The goal of the 'Crystallographic and biochemical studies of the human TBX5-Nkx2-5-DNA complex' (TBX5-NKX2) project was to characterise the TBX5-Nkx2-5-DNA complex and determine its crystal structure. The project applied structural biology techniques including cloning, protein expression and purification, protein/DNA interaction studies, crystallisation and crystallography to characterise the complex. Project partners made solid progress and insights into the TBX5 specific promoter recognition were obtained together with significant structural and biophysical data on the complex. The full crystal structure will be published in a leading academic journal in the near future. Knowledge of the crystal structure allows for a comprehensive structural analysis of the interaction mechanisms between TBX5 and Nkx2-5 and their DNA binding sites. It also promises to give a better understanding of the synergistic promoter activation of TBX5 and Nkx2-5 at a molecular level. Gaining these insights is of broad interest for cardiovascular biology because this knowledge can be used for influencing cardiac growth and in cardiac regeneration in patients.

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