METALLOREGULATION BY MERR AND FUR PROTEIN FAMILIES

描述（申请人描述）：金属离子感觉机制是 对于细胞对必需金属和有毒金属的反应至关重要。新兴 从微生物金属调节系统的研究是一般模型， 作为理解金属细胞生物学的起点， 人类金属调节蛋白的MerR和Fur家族控制着 一系列基因的表达，这些基因保护真细菌细胞免受物理损伤。 和化学应激包括抗生素治疗。在各种有毒的 毛或一种密切相关的铁传感器蛋白控制毒素 表情一种普遍但有争议的铁反应机制 已经提出了去抑制，但至今尚未解决。 这些汞和铁传感器蛋白的机制研究现在开始 提供对锌和铜响应的金属调节的见解。急诊 大肠杆菌ZntR蛋白是最近发现的MerR家族成员， 控制锌输出表达的锌特异性金属调节蛋白 机械.其对应物Zur蛋白是Fur家族的一员， 对锌吸收机制的表达发挥锌响应控制。 这些基因共同控制锌的吸收和输出，确保细胞 既不经历锌饥饿也不经历毒性。在这两种情况下， 转录控制或金属识别的分子基础， 尚未建立。 这项建议的重点是能量和结构方面的金属识别 和金属诱导的构象变化的变构转换机制。 MerR以前所未有的方式控制转录：金属蛋白 相互作用引起DNA结构的扭曲，使DNA更好地 转录机器的模板。通过比较阳性对照 其他家族成员如ZntR的机制，这是一个全面的测试， DNA畸变机制是可能的。积极的控制机制很差 理解，但在理解分子的基本重要性， 基因调控的基础。 ZntR、Zur和Fur识别重金属的分子基础 系统将在生物聚合物和配位化学水平上进行探测。的 结构，功能，以及这些新的压力响应的充满活力的见解 转录因子将提供更深入的了解分子 机制和过渡金属细胞生物学。

DESCRIPTION (applicant's description): Metal ion sensory mechanisms are critical for cellular responses to essential and toxic metals alike. Emerging from studies of microbial metalloregulatory systems are general models that serve as starting points for understanding the cell biology of metals in humans. The MerR and Fur families of metalloregulatory proteins control the expression of an array of genes that protect the eubacterial cell from physical and chemical stresses including antibiotic treatments. In a variety of virulent microbes, Fur or a closely related iron-sensor protein controls toxin expression. A general but controversial mechanism for iron-responsive derepression has been proposed but is as of yet unresolved. Mechanistic studies of these mercury and iron sensor proteins are now beginning to provide insights into zinc and copper-responsive metalloregulation. The E. coli ZntR protein, a recently discovered member of the MerR family, is a zinc-specific metalloregulatory protein that controls expression of zinc export machinery. Its counterpart, the Zur protein, is a member of the Fur family that exerts zinc-responsive control over the expression of zinc uptake machinery. Together these genes govern zinc uptake and export, ensuring that cells experience neither zinc starvation nor toxicity. In both cases the mechanisms of transcriptional control or the molecular basis of metal recognition are not yet established. This proposal focuses on energetic and structural aspects of metal recognition and metal-induced conformation changes in the allosteric switching mechanism. MerR controls transcription in an unprecedented manner: metal-protein interactions induce distortions in DNA structure that make the DNA a better template for the transcription machinery. By comparing the positive control mechanism for other family members such as ZntR, a comprehensive test of this DNA distortion mechanism is possible. Positive control mechanisms are poorly understood and yet are of fundamental importance in understanding the molecular basis of genetic regulation. The molecular basis of heavy metal recognition in the ZntR, Zur, and Fur systems will be probed at the biopolymer and coordination chemistry levels. The structure, function, and energetic insights of these new stress-responsive transcription factors will provide a deeper understanding of molecular mechanisms and transition metal cell biology.