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首页> 外文期刊>Biochemistry >Intermolecular Interactions of Cardiac Transcription Factors NKX2.5 and TBX5
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Intermolecular Interactions of Cardiac Transcription Factors NKX2.5 and TBX5

机译：心脏转录因子NKX2.5和TBX5的分子间相互作用

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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 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.
机译：哺乳动物系统中的心脏发育受主要心脏转录因子（例如TBX5和NKX2.5）的组合相互作用控制。它们与下游靶标的启动子/增强子结合为同型或异型多聚体复合物。它们在物理上相互作用并协同调节其靶基因。为了阐明分子间相互作用的分子基础，使用X射线晶体学研究了NKX2.5和TBX5的异二聚体和同二聚体。在这里，我们报告了人类NKX2.5和TBX5 DNA结合结构域的晶体结构，该结构具有19 bp的靶DNA和TBX5同型二聚体的晶体结构。 NKX2.5和TBX5与目标DNA的三元复合结构显示了通过Lys158（NKX2.5），Asp140（TBX5）和Pro142（TBX5）这两种蛋白质之间的物理相互作用，这些残基在TBX和NKX家族中高度保守跨物种。两种晶体结构中的TBX5蛋白之间都观察到广泛的同二聚体相互作用。特别地，在包括N端和DNA结合结构域的TBX5蛋白的晶体结构中，分子间的相互作用由该蛋白的N端结构域介导。 TBX5的N末端结构域被预测为“本征上是非结构化的”，并且在不对称单元的两个分子之一中，N末端结构域呈现一个桥接两个分子的两个β折叠的β链构象。本文报道的结构可能代表调控发育过程的转录因子之间组合相互作用的一般机制。

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