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

通过这一奖项，化学部门的生命过程化学项目将资助来自德克萨斯农工大学的Tatyana Igumenova博士研究细胞膜表面钙依赖性信号过程的分子途径。细胞的寿命取决于它们对环境的反应。细胞需要获取有关环境的信息并对其作出反应。这种信息的传递是通过细胞膜通过所谓的信号传递过程进行的。这些信号传导过程是由一组结合钙的特殊蛋白质辅助的。钙介导的蛋白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，利用非天然（非天然）金属离子与蛋白质的结合，了解一类蛋白质（即C2结构域）的结构和动力学。这项研究的目的是深入了解蛋白质和金属离子之间以及蛋白质和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的传递。Igumenova教授通过与一所标题1高中的教育合作伙伴关系，为来自弱势群体和弱势群体的高中生组织了为期两天的暑期讲习班，其中90%以上的学生是少数民族，64%的学生有资格成为经济弱势群体。在这次经历中，高中生们通过讲座、使用Igumenova博士和她的学生们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。本项目的重点是C2结构域，一类Ca2+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Synaptotagmin I。该实验方法结合了核磁共振和EPR光谱以及量子化学计算，应用于C2结构域与异种（即非天然）金属离子的配合物，以研究Synaptotagmin I的Ca2+感应区域的构象偏好。蛋白质动力学在C2与金属离子相互作用中的作用，以及金属离子依赖性C2结构域向脂质膜募集的结构基础。所提出的工作的影响超出了所研究的两种蛋白质系统，因为在100多种信号蛋白中发现了C2结构域。除了揭示信号转导的机制外，本研究的信息还为外源金属离子的生物化学提供了新的见解。该奖项反映了美国国家科学基金会的法定使命，并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，被认为值得支持。

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.