Mechanisms of signal transduction revealed through unique chemistry of xenobiotic metal ions

有了这个奖项，化学部的生命过程化学项目资助德克萨斯州A M大学的Tatyana Igumenova博士研究细胞膜表面钙依赖性信号传导过程的分子途径。 细胞的生命取决于它们对环境的反应。 细胞需要获取环境信息并做出反应，这些信息的传递通过细胞膜进行，称为信号传递过程。 这些信号传导过程由一组结合钙的专门蛋白质辅助。 钙介导的蛋白质与膜结合的许多方面仍然未知。 研究实验的重点是通过一种创新的实验方法来理解一类蛋白质的结构和动力学，即C2结构域，该方法利用了非天然（非天然）金属离子与蛋白质的结合。 该研究的目的是深入了解蛋白质与金属离子之间以及蛋白质与膜之间相互作用的基本生物化学和生物物理学，因为这些相互作用决定了信息向细胞中的传输。 教授Igumenova组织了为期2天的夏季研讨会，通过与标题1高中的教育伙伴关系，学生人数超过90%的少数民族和64%的资格作为经济上处于不利地位的代表性不足和弱势群体的高中生。 在此期间，高中生通过讲座，使用由Igumenova博士和她的学生构建的维基百科网页，以及关于金属离子在生物学中的重要作用以及一些金属离子的毒性的实践活动来学习。 该项目的重点是C2结构域，一类Ca 2+依赖性外周膜蛋白。 本研究选择的C2结构域属于两种在人类生物学中至关重要的蛋白质，蛋白激酶C和突触结合蛋白I。 结合NMR、EPR谱和量子化学计算的实验方法被应用于C2结构域与异生素的复合物（即非天然）金属离子，以研究突触结合蛋白I的Ca2+感应区的构象偏好，蛋白质动力学在C2与金属离子相互作用中的作用，以及C2结构域向脂膜的金属离子依赖性募集的结构基础。 这项工作的影响超出了正在研究的两个蛋白质系统，因为C2结构域存在于100多种信号蛋白中。 除了揭示信号转导的机制外，这项研究的信息还为异生物质金属离子的生物化学提供了新的见解。该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的知识价值和更广泛的影响审查标准进行评估来支持。

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Tatyana Igumenova from Texas A&M University to investigate molecular pathways of calcium-dependent signaling processes at the cell membrane surface. The life of cells depends on their response to their environment. Cells need to get information about the environment and react to it. The communication of this information takes place through the cell membrane by what are called signaling processes. These signaling processes are aided by a specialized set of proteins that bind calcium. Many aspects of the calcium-mediated protein binding to membranes remain unknown. The research experiments focus on the understanding the structure and dynamics of a class of these proteins, namely C2 domains, by an innovative experimental approach that takes advantage of the binding of unnatural (non-native) metal ions to the protein. The objective of the research is to obtain insight into the fundamental biological chemistry and biophysics of the interactions between the protein and metal ions and between the protein and membrane because these interactions determine the transmission of information into the cell. Professor Igumenova organizes a 2-day summer workshop for high-school students from under-represented and under-privileged groups through an educational partnership with a Title 1 high school in which student population is more than 90% minority and 64% qualifies as economically disadvantaged. During this experience, the high school students learn through lectures, use of Wikipedia webpages constructed by Dr. Igumenova and her students, and hands-on activities about the important role of metal ions in biology as well as about the toxicity of some metal ions. This project is focused on C2 domains, a class of Ca2+-dependent peripheral membrane proteins. The C2 domains chosen for this study belong to two proteins that are of paramount importance in human biology, Protein Kinase C and Synaptotagmin I. The experimental approach, which integrates NMR and EPR spectroscopies and quantum chemical calculations, is applied to the complexes of C2 domains with xenobiotic (i.e. non-native) metal ions to investigate the conformational preferences of the Ca2+-sensing region of Synaptotagmin I, the role of protein dynamics in C2 interactions with metal ions, and the structural basis of the metal-ion dependent recruitment of C2 domains to lipid membranes. The impact of the proposed work goes beyond the two protein systems under study because the C2 domains are found in more than 100 signaling proteins. In addition to uncovering the mechanisms of signal transduction, information from this study provides new insight into the biological chemistry of xenobiotic metal ions.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.