Peptide kinase and phosphopeptide phosphatase ribozymes

University Of Missouri-Columbia, Columbia MO

Investigators

Abstract

With this award, the Chemistry of Life Processes Program is supporting the research of Professor Donald Burke of the University of Missouri toward the development of RNA enzymes that catalyze phosphoryl transfer with peptide substrates. Phosphoryl transfer onto the 2'- and 5'-hydroxyls of RNA and DNA is a well-established catalytic capability of nucleic acids. In contrast, there have been no reports of ribozymes that add phosphates to, or remove phosphates from, other substrates, in spite of strong experimental proof-of-principle and sound chemical foundations arguing that such activity should be within reach of ribozyme catalysis. The research plan utilizes an innovative combination of new and established technologies, while building on strong preliminary studies of kinase ribozymes and aptamer-protein interactions. Identification and characterization of a ribozyme that manipulates the phosphorylation state of a peptide would represent a major advance in nucleic acid chemistry and chemical biology. The project further seeks to define the RNA's contribution to both substrate binding and catalysis, and to establish the roles of individual bases/sugars on the RNA in key mechanistic steps, particularly those involving proton transfer. The project has potentially broad scientific impacts, as it seeks to push the limits of nucleic acid catalysis. Expanding RNA catalysis into the realm of peptide substrates would also deepen our understanding of ribozyme-peptide co-evolution during the origins of biological systems. Nucleic acid-based kinases and phosphatases also have potential longer term impacts in chemical and cell biology, particularly in the unraveling and manipulation of phosphorylation-based signaling pathways. This work will also impact the public through newspaper and online publications and via a collaborative project with MU School of Journalism aimed at strengthening communication at the intersection between Life Sciences and communication with the public. Finally, in this project, the PI seeks to train next generation scientists, through the mentoring of both undergraduate and graduate coworkers at the chemistry-biology interface.