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Structural Basis for p53 Lys120-Acetylation-Dependent DNA-Binding Mode

机译：p53 Lys120乙酰化依赖的DNA结合模式的结构基础。

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摘要

Normal cellular homeostasis depends on tight regulation of gene expression, which requires the modulation of transcription factors' DNA-binding specificity. That said, the mechanisms that allow transcription factors to distinguish between closely related response elements following different cellular signals are not fully understood. In the tumor suppressor protein p53, acetylation of loop L1 residue Lys120 within the DNA-binding domain has been shown to promote the transcription of proapoptotic genes such as bax. Here, we report the crystal structures of Lys120-acetylated p53 DNA-binding domain in complex with a consensus response element and with the natural BAX response element. Our structural analyses reveal that Lys120 acetylation expands the conformational space of loop L1 in the DNA-bound state. Loop L1 flexibility is known to increase p53's DNA-binding specificity, and Lys120-acetylation-dependent conformational changes in loop L1 enable the formation of sequence-dependent DNA-binding modes for p53. Furthermore, binding to the natural BAX response element is accompanied by global conformational changes, deformation of the DNA helical structure, and formation of an asymmetric tetrameric complex. Based on these findings, we suggest a model for p53's Lys120 acetylation-dependent DNA-binding mode. (C) 2016 Elsevier Ltd. All rights reserved.
机译：正常的细胞稳态取决于基因表达的严格调节，这需要调节转录因子的DNA结合特异性。也就是说，尚未完全理解允许转录因子区分遵循不同细胞信号的密切相关的应答元件的机制。在肿瘤抑制蛋白p53中，已显示DNA结合域中环L1残基Lys120的乙酰化可促进促凋亡基因（如bax）的转录。在这里，我们报告了Lys120乙酰化的p53 DNA结合结构域的晶体结构，该结构具有共有应答元件和天然BAX应答元件。我们的结构分析表明，Lys120乙酰化可扩大DNA结合状态下环L1的构象空间。已知环L1的柔性增加了p53的DNA结合特异性，并且环L1中Lys120-乙酰化依赖性的构象变化使得能够形成p53的序列依赖性DNA结合模式。此外，与天然BAX反应元件的结合伴随着整体构象变化，DNA螺旋结构的变形以及不对称四聚体复合物的形成。基于这些发现，我们建议建立p53的Lys120乙酰化依赖性DNA结合模式的模型。 （C）2016 Elsevier Ltd.保留所有权利。

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