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首页> 外文期刊>Journal of Molecular Biology >Autoinhibition of ETV6 (TEL) DNA binding: Appended helices sterically block the ETS domain
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Autoinhibition of ETV6 (TEL) DNA binding: Appended helices sterically block the ETS domain

机译：ETV6（TEL）DNA结合的自动抑制：附加的螺旋在空间上阻断ETS结构域

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摘要

ETV6 (or TEL), a transcriptional repressor belonging to the ETS family, is frequently involved in chromosomal translocations linked with human cancers. It displays a DNA-binding mode distinct from other ETS proteins due to the presence of a self-associating PNT domain. In this study, we used NMR spectroscopy to dissect the structural and dynamic bases for the autoinhibition of ETV6 DNA binding by sequences C-terminal to its ETS domain. The C-terminal inhibitory domain (CID) contains two helices, H4 and H5, which sterically block the DNA-binding interface of the ETS domain. Importantly, these appended helices are only marginally stable as revealed by amide hydrogen exchange and 15N relaxation measurements. The CID is thus poised to undergo a facile conformational change as required for DNA binding. The CID also dampens millisecond timescale motions of the ETS domain hypothesized to be critical for the recognition of specific ETS target sequences. This work illustrates the use of appended sequences on conserved structural domains to generate biological diversity and complements previous studies of the allosteric mechanism of ETS1 autoinhibition to reveal both common and divergent features underlying the regulation of DNA binding by ETS transcription factors.
机译：ETV6（或TEL）是ETS家族的转录阻遏物，经常参与与人类癌症相关的染色体易位。由于存在自相关的PNT结构域，它显示了不同于其他ETS蛋白的DNA结合模式。在这项研究中，我们使用NMR光谱来剖析ETV6 DNA结合的E端结构域C端序列自抑制的结构和动态碱基。 C端抑制域（CID）包含两个螺旋H4和H5，它们在空间上阻断ETS域的DNA结合界面。重要的是，这些附加的螺旋仅在边缘上是稳定的，如酰胺氢交换和15N弛豫测量所揭示的。因此，CID准备好进行DNA结合所需的构象变化。 CID还抑制了被认为对识别特定ETS目标序列至关重要的ETS域的毫秒级时标运动。这项工作说明了在保守的结构域上使用附加序列来产生生物多样性，并对ETS1自抑制的变构机制的先前研究进行了补充，以揭示由ETS转录因子调控DNA结合的共同和不同特征。

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