METALLOREGULATION BY MERR AND FUR PROTEIN FAMILIES

描述(申请人描述)：金属离子传感机制是 对细胞对必需金属和有毒金属的反应至关重要。新兴 从微生物金属调控系统的研究中得到的一般模型 是理解金属细胞生物学的起点。 人类。MERR和Fur家族的金属调节蛋白控制着 保护真细菌细胞免受物理损伤的一系列基因的表达 以及包括抗生素治疗在内的化学压力。在各种致命的 微生物、毛皮或一种密切相关的铁感受器蛋白控制毒素 表情。一种普遍但有争议的铁反应机制 去抑制已经被提出，但到目前为止还没有得到解决。 对这些汞和铁感受器蛋白的机制研究现已开始。 以提供对锌和铜响应的金属调节的见解。E. ColiZntR蛋白是最近发现的MERR家族成员，是一种 控制锌出口表达的锌特异性金属调控蛋白 机械设备。其对应的Zur蛋白是毛皮家族的成员， 对锌摄取机制的表达进行锌响应控制。 这些基因共同控制锌的吸收和输出，确保细胞 既没有经历锌饥饿，也没有中毒。在这两种情况下，机制 转录控制或金属识别的分子基础不是 但已经确立了。 这项建议侧重于金属识别的能量和结构方面。 金属诱导变构转换机制的构象变化。 MERR以前所未有的方式控制转录：金属-蛋白质 相互作用导致DNA结构的扭曲，使DNA变得更好 转录机器的模板。通过比较阳性对照 对于其他家庭成员的机制，如ZntR，对此进行了全面的测试 DNA扭曲的机制是可能的。积极的控制机制很差 已被理解，但在理解分子方面具有根本的重要性 基因调控的基础。 ZntR、Zur和Fur重金属识别的分子基础 系统将在生物聚合物和配位化学水平上进行探索。这个 对这些新应激反应的结构、功能和能量的洞察 转录因子将提供对分子更深层次的理解 机制与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.