Intermolecular Interactions of Cardiac Transcription Factors NKX2.5 and TBX5

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 the...

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Veröffentlicht in:Biochemistry (Easton) 2016-03, Vol.55 (12), p.1702-1710
Hauptverfasser: Pradhan, Lagnajeet, Gopal, Sunil, Li, Shichang, Ashur, Shayan, Suryanarayanan, Saai, Kasahara, Hideko, Nam, Hyun-Joo
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container_end_page 1710
container_issue 12
container_start_page 1702
container_title Biochemistry (Easton)
container_volume 55
creator Pradhan, Lagnajeet
Gopal, Sunil
Li, Shichang
Ashur, Shayan
Suryanarayanan, Saai
Kasahara, Hideko
Nam, Hyun-Joo
description 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.
doi_str_mv 10.1021/acs.biochem.6b00171
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subjects Amino Acid Sequence
Crystallography, X-Ray
Heart
Homeobox Protein Nkx-2.5
Homeodomain Proteins - chemistry
Homeodomain Proteins - genetics
Homeodomain Proteins - metabolism
Humans
Molecular Sequence Data
Protein Binding - physiology
Protein Structure, Secondary
Protein Structure, Tertiary
T-Box Domain Proteins - chemistry
T-Box Domain Proteins - genetics
T-Box Domain Proteins - metabolism
Transcription Factors - chemistry
Transcription Factors - genetics
Transcription Factors - metabolism
title Intermolecular Interactions of Cardiac Transcription Factors NKX2.5 and TBX5
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