The hidden side of selenoprotein S: its binding and reaction partners beyond protein degradation

这项研究旨在获得对利用微量元素硒的蛋白质如何执行其重要细胞功能的基本见解，尽管它明显缺乏稳定的形状。此外，它还将加深我们对硒赋予细胞生命化学的优势的理解。该项目的一个组成部分是对有身体、神经生物学、情感或学习障碍的本科生和研究生进行培训。作为这个项目的积极参与者，残疾学生将获得宝贵的研究经验，否则他们往往被排除在外。支持和指导对他们的成功和职业发展都至关重要，将通过两种途径提供。第一种是通过团队领导和每天与他们一起工作的成员。第二种是通过学生和专业人士的广泛网络，他们面临着类似的挑战，事实证明，这些挑战是支持、机会和鼓励的宝贵、互补的来源。像所有的硒蛋白一样，硒蛋白S含有遗传编码的氨基酸硒半胱氨酸。使用高活性的硒需要严格的、资源密集型的调节，到目前为止所有表征的硒蛋白都利用这种昂贵的氨基酸来实现酶功能。然而，尽管它们的重要性毋庸置疑，但许多硒蛋白的功能仍未确定，还有待于适当的表征。该项目旨在填补这一认识空白，内在无序的硒蛋白S，膜结合多蛋白复合体的一部分。它的功能包括蛋白质质量控制、囊泡运输、脂质合成和信号转导。然而，目前既不知道它的直接蛋白质伙伴，也不知道其反应性硒半胱氨酸的作用。为了了解硒蛋白S的神秘功能，我们将对其相互作用组进行分析，以确定哪些蛋白质是关键的相互作用因子。这将阐明硒蛋白S直接连接哪些功能和途径。然后，选定的相互作用子集将用于交联、结构和蛋白质组学研究，以确定相互作用部位(S)及其详细结构。总之，这项研究将为硒在氧化还原生物学中的使用以及硒蛋白的细胞作用提供基本的见解。该奖项由分子生物物理学(分子和细胞生物科学)和生命过程化学资助。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

This research aims at gaining fundamental insights into how a protein that utilizes the trace element selenium can execute its vital cellular functions despite its apparent lack of a stable shape. Furthermore, it will deepen our understanding of the advantages selenium confers to the chemistry of cellular life. An integral part of this project is its training of undergraduate and graduate students with physical, neurobiological, emotional, or learning disabilities. As active participants in this project, students with disabilities will gain invaluable research experience from which they are otherwise often excluded. Support and mentorship, both critical for their success and career progression, will be provided through two avenues. The first is through the team leader and members that work with them daily. The second is through an extensive network of students and professionals facing similar challenges that have been proven to be an invaluable, complementary source of support, opportunities, and encouragement.Like all selenoproteins, selenoprotein s contains the genetically encoded amino acid selenocysteine. The use of the highly reactive selenium necessitates a tight, resource-intensive regulation, and all selenoproteins characterized so far exploit this costly amino acid for enzymatic function. Yet, despite their undisputed importance, the functions of many selenoproteins remain unidentified and await proper characterization. This project aims to fill this knowledge gap for the intrinsically disordered selenoprotein S, part of membrane-bound multi-protein complexes. Its function spans protein quality control, vesicle trafficking, lipid synthesis, and signaling. However, neither its direct protein partners nor the role of its reactive selenocysteine are currently known. To understand the enigmatic function of selenoprotein s, its interactome will be analyzed to pinpoint which proteins are key interactors. This will illuminate to which functions and pathways selenoprotein s directly connects. Then a selected subset of the identified interactors will be used for crosslinking, structural and proteomics studies to determine the interaction site(s) and its detailed structure. Together, this research will provide fundamental insight into the use of selenium in redox biology and the cellular roles of selenoproteins. The award was funded by Molecular Biophysics (Molecular and Cellular Biosciences) and the Chemistry of Life Processes.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.