Intermolecular Interactions of Cardiac Transcription Factors NKX2.5 and TBX5

Abstract

Heart development in mammalian systems is controlled by combinatorial interactions of master cardiac transcription factors such as TBX5 and NKX2.5. They bind to promoters/enhancers of downstream targets as homo- or heteromultimeric complexes. They physically interact and synergistically regulate their target genes. To elucidate the molecular basis of the intermolecular interactions, a heterodimer and a homodimer of NKX2.5 and TBX5 were studied using X-ray crystallography. Here we report a crystal structure of human NKX2.5 and TBX5 DNA binding domains in a complex with a 19 bp target DNA and a crystal structure of TBX5 homodimer. The ternary complex structure of NKX2.5 and TBX5 with the target DNA shows physical interactions between the two proteins through Lys158 (NKX2.5), Asp140 (TBX5), and Pro142 (TBX5), residues that are highly conserved in TBX and NKX families across species. Extensive homodimeric interactions were observed between the TBX5 proteins in both crystal structures. In particular, in the crystal structure of TBX5 protein that includes the N-terminal and DNA binding domains, intermolecular interactions were mediated by the N-terminal domain of the protein. The N-terminal domain of TBX5 was predicted to be "intrinsically unstructured", and in one of the two molecules in an asymmetric unit, the N-terminal domain assumes a β-strand conformation bridging two β-sheets from the two molecules. The structures reported here may represent general mechanisms for combinatorial interactions among transcription factors regulating developmental processes.

Atrial fibrillation risk loci interact to modulate Ca2+-dependent atrial rhythm homeostasis

“…GATA4 and NKX2-5 physically and genetically interact with TBX5 during cardiac development, and all 3 cardiogenic TFs are strongly expressed in the adult atrium and are genetically linked to AF risk in humans ( Figure 1A and refs. 2,33,35,41,[46][47][48]. We therefore hypothesized that GATA4 and NKX2-5 would genetically interact with TBX5 in adult atrial rhythm control.…”

A Tbx5 Nonsense Mutation in Siblings With Divergent Phenotypes Associated With Isolated Septal Defects

“…Relevant literature was reviewed to check the novelty of the obtained sequence variant. Multiple sequence alignment was carried out using ConSurf [17] whereas, structural analysis and the visualization of protein was also carried out using Protein Data Bank (PDB) file -4 s0H [18].…”

An update on genetic variants of theNKX2‐5

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