The proteasome is a molecular machine inside eukaryotic cells that removes unwanted or unneeded proteins by unfolding them, feeding them into a central chamber, and then chopping them up into small pieces that can be recycled. Proteins destined for destruction are tagged with a chain composed of multiple copies of a small protein called ubiquitin. In this project, the principal investigator, together with undergraduate and master's students, will investigate how ubiquitin chains affect the ability of the proteasome to unfold the attached target protein. The proteasome is a central player in many aspects of cellular function, so better understanding of its mechanism, and why some proteins are degraded and others are spared, will benefit many scientists who study these cellular processes. Many undergraduate and master's students will work on this project, and, through their intellectual investment, will increase their critical thinking and scientific inquiry skills, which will serve them well as they go on to careers in medicine, industry, academia or other fields. The PI will work with Villanova's Academic Advancement program to excite underrepresented students about doing research while in college. The PI will also work to disseminate a project-based course for biochemistry majors that gives students a taste of real research.
The proteasome is a macromolecular machine inside every eukaryotic cell that unfolds and degrades proteins destined for disposition. The proteasome therefore, impacts nearly all biological processes by controlling the concentration of hundreds of proteins in a cell, and so is foundational to understanding cellular biology. Despite the proteasome’s centrality, questions remain concerning proteasome function. The overall goal of the research conducted in the principal investigator's laboratory is to understand the molecular determinants of the proteasome's ability to unfold proteins. It is generally thought that if a protein is targeted to the proteasome via polyubiquitination, that protein is degraded. However, sometimes proteins are incompletely degraded, leading to protein fragments with new or even toxic functions. It is not fully understood when or why incomplete degradation occurs. In earlier NSF-funded research, the PI showed that the polyubiquitin chain attached to a substrate protein increases the ability of the proteasome to unfold the substrate protein and that proteasomal ubiquitin receptors mediate this activation. However, the mechanism remains unknown. In this project, the PI will determine (1) how the ubiquitin chain architecture affects the proteasome's ability to unfold a substrate, (2) how proteasome-associated proteins, in combination with ubiquitin receptors, influence the proteasome's unfolding ability and (3) how binding to ubiquitin receptors is communicated to the proteasomal motor proteins.
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.
