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

University Of Delaware, Newark DE

Investigators

Abstract

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.