Histidine switch controlling pH-dependent protein folding and DNA binding in a transcription factor at the core of synthetic network devices.
Histidine switch controlling pH-dependent protein folding and DNA binding in a transcription factor at the core of synthetic network devices.
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DOI：
10.1039/c6mb00304d
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发表时间：
2016-07-19
影响因子：
--
通讯作者：
Grove A
中科院分区：
文献类型：
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作者：
Deochand DK;Perera IC;Crochet RB;Gilbert NC;Newcomer ME;Grove A
据报道，治疗策略依赖于合成网络装置，其中尿酸感应转录调节器检测尿酸的病理水平并触发尿酸氧化酶的产生或释放。所涉及的转录因子 HucR 是多重抗生素耐药性 (MarR) 蛋白家族的成员。我们发现，形成二聚体界面支架的长螺旋枢轴点处堆叠的组氨酸残基的质子化导致可逆形成熔球状态，并显着减弱生理温度下的 DNA 结合。我们还表明，尿酸盐与每个蛋白质叶中对称位点的结合是通过二聚体界面进行传递的。这是首次证明 MarR 家族转录因子通过熔球和紧凑折叠状态之间的 pH 依赖性相互转化进行调节。我们的数据进一步表明，HucR 可用于依赖于 pH 变化检测的合成装置。
Therapeutic strategies have been reported that depend on synthetic network devices in which a urate-sensing transcriptional regulator detects pathological levels of urate and triggers production or release of urate oxidase. The transcription factor involved, HucR, is a member of the multiple antibiotic resistance (MarR) protein family. We show that protonation of stacked histidine residues at the pivot point of long helices that form the scaffold of the dimer interface leads to reversible formation of a molten globule state and significantly attenuated DNA binding at physiological temperatures. We also show that binding of urate to symmetrical sites in each protein lobe is communicated via the dimer interface. This is the first demonstration of regulation of a MarR family transcription factor by pH-dependent interconversion between a molten globule and a compact folded state. Our data further suggest that HucR may be utilized in synthetic devices that depend on detection of pH changes.