Structural and Functional Studies of Molecular Machines Involved in Chemical Modifications of Macromolecules

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PROJECT SUMMARY / ABSTRACT Our lab focuses on structural and functional studies of molecular machines involved in chemical modifications of macromolecules. Naturally occurring chemical modifications of macromolecules play essential roles in all aspects of molecular biology, from transcriptional and translational regulation to functional modulation of various proteins. Misregulation of the chemical modifications is involved in many human diseases such as cancers and neurodegenerative diseases. Although many have been described and characterized, there are still significant amounts of chemical modification systems that are poorly understood. Our long term goal is to elucidate the structure and function of molecular machines involved in various chemical modification systems and develop new tools and strategies to modulate their activity against the relevant diseases based on what we have learned. In the next five years, we will be focusing on two systems, the p97 related ubiquitination system and the Vault related ADP-ribosylation system. More than thirty mutations of human p97 have been identified, which are associated with a number of neurodegenerative diseases. The molecular mechanism, however, remains elusive. Through structural biology approaches and protein engineering, we will address 1) how p97 processes ubiquitin chains of different topologies through the cofactors; 2) the structural and functional consequences of disease mutations; 3) the mechanism of inhibitors of p97 and its cofactors. Our efforts promise unprecedented insights into the function of p97, a central hub of cellular protein homeostasis. Vault is the largest ribonucleoprotein in eukaryotic cells with a unique structure. The function of Vault has been linked to drug resistance in cancer and innate immune response. Recently, major vault protein (MVP) was identified as one of the 9 marker genes that can predict influenza vaccination responses. Given the importance of vaccine development during this COVID-19 pandemic, a deep understanding of Vault’s molecular mechanism is critical. We are going to focus on PARP4, the only enzyme in the Vault complex catalyzing ADP-ribosylation. Elucidating the function of PARP4 and how it interacts with Vault particle is the key to understand the molecular function of Vault.