Mechanisms of Nickel-Responsive Proteins

我的研究项目将检查负责镍稳态的蛋白质的化学性质和金属反应活性。镍是许多生命形式所必需的营养物质，但它也可能是有毒的。因此，使用镍的生物体必须严格而具体地控制可用镍的数量及其分配方式。这是通过关键蛋白质实现的，这些蛋白质将镍离子运入和运出细胞，将镍离子运送到需要它们的地方，并调节关键因子的产生。这些蛋白质面临的一个主要化学挑战是，它们的功能受镍结合的控制，镍结合激活或抑制生化活性。金属结合如何控制蛋白质的功能是一个有趣的基本问题，要想提高我们在这一领域的知识，需要检查金属络合物的生物无机化学，分析蛋白质的活性和结构，并了解这些系统的广泛背景。这项提议描述了揭示镍结合如何激活关键镍稳态蛋白中的功能反应的实验。到目前为止，我们的研究已经提供了关于单个蛋白质及其镍结合活性的详细信息。我们现在正处于能够回答关于这些系统依赖镍的活动的机制的基础性问题的令人兴奋的阶段。为了实现这一目标，我们将利用蛋白质化学、无机光谱学和结构生物学的跨学科方法，为学员提供丰富的教育环境。具体目标包括描述金属离子配位和镍反应转录因子与DNA结合之间的关系，以及确定这种活性如何与pH依赖的调节联系起来。此外，我们将通过一个关键的镍膜进口商确定金属络合物结合是如何与金属选择性运输联系在一起的。金属调节活性是管理不同类型金属离子的蛋白质的基本属性，而不仅仅是镍，所以这个项目将帮助我们实现我们的最终目标，即在分子水平上了解控制细胞内过渡金属动态平衡的化学机制。了解生活的这一基本方面将对生物技术和环境补救等领域产生重大影响。最后，这个多学科项目是在包容、支持和尊重的环境中进行的，并在研究、分析和沟通方面提供出色的培训。这种教育为未来在制药、生物技术、生物医学以及相关领域的各种行业的职业生涯培养高技能的年轻科学家。

My research program will examine the chemical properties and metal-responsive activities of proteins responsible for nickel homeostasis. Nickel is an essential nutrient for many forms of life, but it can also be toxic. Thus, organisms that use nickel have to tightly and specifically control the amount of available nickel and how it is distributed. This is achieved by critical proteins that transport nickel ions in and out of cells, traffic nickel ions to where they are needed, and regulate the production of key factors. A major chemical challenge to these proteins is that their functions are controlled by nickel binding, which activates or inhibits the biochemical activities. How metal binding controls protein function is an intriguing fundamental question, and advancing our knowledge in this area requires examination of the bioinorganic chemistry of the metal complexes, analysis of the protein activities and structures, and knowledge of the broad contexts of these systems. This proposal describes experiments to uncover how nickel binding activates a functional response in crucial nickel homeostasis proteins. Our research to date has provided detailed information about the individual proteins and their nickel-binding activities. We are now at the exciting stage of being able to answer foundational questions about the mechanisms of the nickel-dependent activities of these systems. To achieve this goal, we will use an interdisciplinary approach that draws from protein chemistry, inorganic spectroscopy, and structural biology, providing a rich educational environment for trainees. Specific aims include delineating the relationship between metal ion coordination and DNA binding by a nickel responsive transcription factor, and also determining how this activity is connected to pH-dependent regulation. Furthermore, we will establish how metal complex binding is linked to metal-selective transport by a key nickel membrane importer. Metal-regulated activity is an essential property of proteins that manage different types of metal ions, not just nickel, so this program will help us achieve our ultimate objective, which is to learn the chemical mechanisms that govern intracellular transition metal homeostasis at a molecular level. Understanding this fundamental aspect of life will have a significant impact on areas such as biotechnology and environmental remediation. Finally, this multidisciplinary program is performed in an inclusive, supportive, and respectful setting, and provides excellent training in research, analysis, and communication. This education prepares highly skilled young scientists for future careers in a variety of industries including pharmaceutical, biotechnology, biomedical, as well as related areas.