gp78-MPQC hub · Defining the Mechanisms of gp78 as a Master Regulator of Ubiquitin E3 Ligase in Membrane Protein Quality Control.

The ubiquitin-proteasome system (UPS) is responsible for the degradation of approximately 80% of proteins, enabling precise control of protein quality and maintaining protein homeostasis within the cell. Over the past four decades, a comprehensive understanding of the regulatory mechanisms governing the UPS, particularly concerning various cytosolic and nuclear proteins has been developed. However, there remains significant knowledge gaps regarding how membrane proteins, which account for one-third of human proteins and serve as targets for 70% of FDA-approved drugs, are regulated by the UPS. The specificity of the UPS is dictated by E3 ligases, which bind to substrates and execute ubiquitination. gp78 is the master regulatory ubiquitin E3 ligase for membrane proteins, enabling rigorous control of membrane protein quality and participating in various pathways. gp78 not only works with the biogenesis factors to form a detection center responsible for targeting misfolded proteins but also cooperates with the E2 enzyme and several quality control factors to promote recognition and ubiquitination of a wide range of important substrates, leading to their degradation via the proteasome. Yet remaining questions abound: How does gp78 detect misfolded proteins? What are gp78's substrates and their biological functions? What structural mechanisms underlie the recognition and ubiquitination of membrane substrates by gp78?This proposal aims to combine state-of-the-art approaches in structural biology and biochemistry, cell biology, and chemical biology to systematically dissect the underlying molecular mechanisms by which the gp78 membrane protein quality control hub, mediates substrate detection, recognition, and ubiquitination.The project will advance our understanding of how cells perform the difficult task of membrane protein quality control and pave the way for pharmacological studies targeting membrane protein degradation.