Metalloregulation by MerR and Fur Protein Families

MerR 和毛皮蛋白家族的金属调节

• 批准号: 7777795
• 负责人: THOMAS V O'HALLORAN
• 金额: $ 33.33万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-07-01 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7777795
• 关键词: Affinity; Antibiotic Resistance; Aromatic Hydrocarbons; Binding; Biochemical; Biopolymers; Cations; Cells; Cellular biology; Chemicals; Chemistry; Complex; Copper; DNA; DNA Binding; DNA Structure; Discrimination; Drug Metabolic Detoxication; E coli ZntR protein; Ensure; Escherichia coli; Family; Family member; Genes; Genetic; Genetic Transcription; Goals; Growth; Heart; Heavy Metals; Homeostasis; Homologous Gene; Human; In Vitro; Inorganic Chemistry; Ions; Iron; Kinetics; Lead; Maps; Measures; Mediating; Mercury; Metal Binding Site; Metals; Methods; Microbe; Modeling; Molecular; Molecular Conformation; Molecular Probes; Monitor; Operon; Physiological; Play; Protein Family; Proteins; Publishing; Regulation; Reporter; Repression; Resistance; Role; Site; Specificity; Starvation; Stress; Structure; System; Testing; Thermodynamics; Toxic effect; Toxin; Transcriptional Regulation; Transition Elements; Virulent; Zinc; base; biological adaptation to stress; derepression; experience; falls; in vitro testing; in vivo; member; metalloregulatory protein; microbial; prevent; receptor; response; sensor; sensory mechanism; toxic metal; transcription factor; uptake

Metal ion sensory mechanisms are critical for cellularresponses 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 antibiotictreatments. 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 beginningto provide insightsinto 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 interactionsinduce distortions in DNA structure that make the DNA a better templatefor 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 insightsof these new stress- responsive transcription factors will provide a deeper understanding of molecular mechanisms and transition metal cell biology.

金属离子感觉机制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，作为出发点， 了解人体内金属的细胞生物学。金属调节蛋白的MerR和Fur家族 控制保护真细菌细胞免受物理和化学胁迫的一系列基因的表达 包括抗肿瘤治疗。在多种有毒微生物中，Fur或一种密切相关的铁传感蛋白 控制毒素表达。铁反应性去抑制的一个普遍但有争议的机制是 已提出，但尚未解决。 这些汞和铁传感器蛋白的机制研究现在正在努力提供对锌的见解 和铜反应性金属调节。急诊大肠杆菌ZntR蛋白，最近发现的MerR的成员 家族，是一种锌特异性金属调节蛋白，控制锌输出机制的表达。其 对应物Zur蛋白是Fur家族的成员，其对表达施加锌响应控制。 吸收锌的机器这些基因共同控制锌的吸收和输出，确保细胞经历 无锌饥饿或毒性。在这两种情况下，转录控制机制或分子基础 金属识别尚未建立。 该建议侧重于金属识别和金属诱导的能量和结构方面 在变构转换机制的构象变化。MerR以前所未有的方式控制转录， 方式：金属-蛋白质相互作用导致DNA结构的扭曲，使DNA成为更好的模板。 转录机器通过比较其他家族成员如ZntR的阳性控制机制， 这种DNA扭曲机制的全面测试是可能的。积极的控制机制很差 然而，它们在理解遗传调控的分子基础方面具有根本的重要性。 在ZntR，Zur和Fur系统中重金属识别的分子基础将在 生物聚合物和配位化学水平。The structure结构，function功能，and energetic活力insights洞察of these new新stress应力- 响应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

项目成果

Acute cytokine-mediated downregulation of the zinc transporter ZnT8 alters pancreatic beta-cell function.

• DOI: 10.1677/joe-09-0420
• 发表时间: 2010-08
• 期刊: The Journal of endocrinology
• 作者: El Muayed M;Billings LK;Raja MR;Zhang X;Park PJ;Newman MV;Kaufman DB;O'Halloran TV;Lowe WL Jr
• 通讯作者: Lowe WL Jr

Accumulation of cadmium in insulin-producing β cells.

镉在产生胰岛素的β细胞中的积累。

• DOI: 10.4161/isl.23101
• 发表时间: 2012-11
• 期刊: Islets
• 影响因子: 2.2
• 作者: El Muayed M;Raja MR;Zhang X;MacRenaris KW;Bhatt S;Chen X;Urbanek M;O'Halloran TV;Lowe WL Jr
• 通讯作者: Lowe WL Jr