4s0h
From Proteopedia
TBX5 DB, NKX2.5 HD, ANF DNA Complex
Structural highlights
DiseaseTBX5_HUMAN Holt-Oram syndrome. The disease is caused by mutations affecting the gene represented in this entry. Defects in TBX5 are associated with susceptibility to dilated cardiomyopathy (DCM). A disorder characterized by ventricular and impaired systolic function, resulting in heart failure and arrhythmia. Patient are at risk of premature death.[1] [2] FunctionTBX5_HUMAN DNA-binding protein that regulates the transcription of several genes and is involved in heart development and limb pattern formation.[3] [4] [5] Publication Abstract from PubMedHeart 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 beta-strand conformation bridging two beta-sheets from the two molecules. The structures reported here may represent general mechanisms for combinatorial interactions among transcription factors regulating developmental processes. Intermolecular Interactions of Cardiac Transcription Factors NKX2.5 and TBX5.,Pradhan L, Gopal S, Li S, Ashur S, Suryanarayanan S, Kasahara H, Nam HJ Biochemistry. 2016 Mar 29;55(12):1702-10. doi: 10.1021/acs.biochem.6b00171. Epub , 2016 Mar 9. PMID:26926761[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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