Mechanisms of Nickel-Responsive Proteins

我的研究计划将检查负责镍稳态的蛋白质的化学性质和金属响应活动。 镍是许多生命形式的必需营养素，但它也可能有毒。 因此，使用镍的生物体必须严格和具体地控制可用镍的量及其分布方式。 这是通过关键蛋白质来实现的，这些蛋白质将镍离子运送到细胞内外，将镍离子运送到需要的地方，并调节关键因子的产生。 对这些蛋白质的一个主要化学挑战是它们的功能由镍结合控制，镍结合激活或抑制生物化学活性。 金属结合如何控制蛋白质功能是一个有趣的基本问题，推进我们在这一领域的知识需要检查的金属络合物的生物无机化学，蛋白质的活性和结构的分析，以及这些系统的广泛背景知识。 该提案描述了揭示镍结合如何激活关键镍稳态蛋白的功能反应的实验。迄今为止，我们的研究提供了有关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有关这些系统的镍依赖活动机制的基础问题的令人兴奋的阶段。为了实现这一目标，我们将使用跨学科的方法，从蛋白质化学，无机光谱学和结构生物学中汲取，为学员提供丰富的教育环境。具体目标包括描绘金属离子配位和DNA结合的镍响应转录因子之间的关系，并确定这种活动是如何连接到pH依赖性调节。 此外，我们将建立金属络合物的结合是如何连接到金属选择性运输的一个关键镍膜进口商。 金属调节活性是管理不同类型金属离子的蛋白质的基本特性，而不仅仅是镍，因此该计划将帮助我们实现我们的最终目标，即了解在分子水平上管理细胞内过渡金属稳态的化学机制。 了解生命的这一基本方面将对生物技术和环境修复等领域产生重大影响。 最后，这个多学科计划是在包容，支持和尊重的环境中进行的，并提供研究，分析和沟通方面的优秀培训。 这种教育为高技能的年轻科学家在包括制药，生物技术，生物医学以及相关领域在内的各种行业的未来职业做好准备。

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.