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首页> 外文期刊>Journal of Molecular Biology >Steric mechanism of auto-inhibitory regulation of specific and non-specific DNA binding by the ETS transcriptional repressor ETV6.
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Steric mechanism of auto-inhibitory regulation of specific and non-specific DNA binding by the ETS transcriptional repressor ETV6.

机译：ETS转录阻遏物ETV6自动抑制特异性和非特异性DNA结合的立体机制。

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摘要

DNA binding by the ETS transcriptional repressor ETV6 (or TEL) is auto-inhibited ~50-fold due to an α-helix that sterically blocks its ETS domain binding interface. Using NMR spectroscopy, we demonstrate that this marginally stable helix is unfolded, and not displaced to a non-inhibitory position, when ETV6 is bound to DNA containing a consensus (5')GGAA(3') recognition site. Although significantly lower in affinity, binding to non-specific DNA is auto-inhibited ~5-fold and is also accompanied by helix unfolding. Based on NMR chemical shift perturbations, both specific and non-specific DNA are bound via the same canonical ETS domain interface. However, spectral perturbations are smaller for the non-specific complex, suggesting weaker and less well-defined interactions than in the specific complex. In parallel, the crystal structure of ETV6 bound to a specific DNA duplex was determined. The structure of this complex reveals that a non-conserved histidine residue in the ETS domain recognition helix helps establish the specificity of ETV6 for DNA-binding sites containing (5')GGAA(3')versus(5')GGAT(3'). These studies provide a unified steric mechanism for attenuating ETV6 binding to both specific and non-specific DNA and expand the repertoire of characterized auto-inhibitory strategies utilized to regulate ETS factors.
机译：ETS转录阻遏物ETV6（或TEL）与DNA的结合被自动抑制了约50倍，这是由于α-螺旋在空间上阻断了其ETS结构域结合界面。使用NMR光谱，我们证明当ETV6与包含共有（5'）GGAA（3'）识别位点的DNA结合时，此边缘稳定的螺旋结构将展开，并且不会移位到非抑制位置。尽管亲和力大大降低，但与非特异性DNA的结合却被自动抑制了约5倍，并且还伴随着螺旋展开。基于NMR化学位移扰动，特异性和非特异性DNA均通过相同的规范ETS结构域界面结合。但是，非特定复合物的光谱扰动较小，这表明与特定复合物相比，相互作用较弱且定义不清。平行地，确定了结合至特定DNA双链体的ETV6的晶体结构。该复合物的结构表明，ETS结构域识别螺旋中的非保守组氨酸残基有助于确定ETV6对包含（5'）GGAA（3'）对（5'）GGAT（3'）的DNA结合位点的特异性。这些研究为减弱ETV6与特异和非特异DNA的结合提供了统一的空间机制，并扩大了用于调节ETS因子的特征性自抑制策略的范围。

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