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首页> 外文期刊>Journal of Molecular Biology >Two cysteine residues in the DNA-binding domain of CREB control binding to CRE and CREB-mediated gene expression
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Two cysteine residues in the DNA-binding domain of CREB control binding to CRE and CREB-mediated gene expression

机译：CREB的DNA结合域中的两个半胱氨酸残基控制与CRE和CREB介导的基因表达的结合

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The cAMP-responsive element-binding protein (CREB) has been implicated in the regulation of numerous physiological functions including those of several hypoxia-responding genes. All CREB transcription-regulated genes harbor the eight base-pair cAMP-responsive element (CRE) or the seven base-pair AP-1 sequence. Utilizing mutational analysis and biochemical assays, we found that reduction of two cysteine residues located in the DNA-binding basic domain of CREB, enhances the binding efficiency of CREB to DNA and regulates CRE-mediated gene expression. Substitution of these residues to serine renders insensitivity to reduction, hypoxia and to the sulfhydryl-specific modifying agent, N-ethylmaleimide. These substitutions enhance the binding of CREB to its cognate DNA sites under oxidative conditions, and of the CREB-dependent gene expression during non-noxia. These findings are supported by results of molecular modeling of the CREB-CRE interactions. We also found that HTLV-1 Tax enhancement of CREB binding to the cellular and the viral DNA sites and activation of the CRE-dependent gene expression are independent of CREB activation exerted by redox conditions. The genetic biochemical and molecular modeling presented in this work indicate that the two cysteine residues in the bZIP domain of CREB regulate the binding efficiency of CREB to its cognate DNA sites and as a consequence the activation of CREB-mediated gene expression.
机译：cAMP反应元件结合蛋白（CREB）已参与许多生理功能的调节，包括几个缺氧反应基因的功能。所有CREB转录调控的基因都包含8个碱基对的cAMP响应元件（CRE）或7个碱基对的AP-1序列。利用突变分析和生化分析，我们发现减少CREB的DNA结合基本域中的两个半胱氨酸残基，提高了CREB与DNA的结合效率并调节CRE介导的基因表达。这些残基被丝氨酸取代对还原，缺氧和巯基特异性修饰剂N-乙基马来酰亚胺不敏感。这些取代增强了在氧化条件下CREB与其同源DNA位点的结合，并增强了非缺氧时CREB依赖性基因的表达。这些发现得到了CREB-CRE相互作用的分子建模结果的支持。我们还发现HTLV-1税收增强CREB结合到细胞和病毒的DNA位点和CRE依赖基因表达的激活与氧化还原条件施加的CREB激活无关。这项工作中提出的遗传生物化学和分子模型表明，CREB的bZIP域中的两个半胱氨酸残基调节了CREB与其同源DNA位点的结合效率，并因此激活了CREB介导的基因表达。

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