CCeMMP Seminar Series – Prof. Isabelle Rouiller – Feb 2025

Maintaining cellular homeostasis is crucial for survival, requiring the degradation of damaged proteins and organelles and the regulation of diverse cellular processes. VCP (p97), a conserved ATP-dependent protein remodeler, plays a pivotal role in these processes, including protein degradation, cell cycle regulation, DNA repair, and stress response. Dysfunction in VCP has been linked to various neurodegenerative disorders and has been identified as a therapeutic target for cancer treatment and infectious diseases. In this seminar, Prof. Rouiller will explore the impact of a disease-associated mutation on VCP dynamics. She will introduce a novel cryo-EM-based image analysis method to characterize continuous conformational changes and demonstrate its application in analysing VCP’s substrate-binding domain in both wild-type and mutant forms. Additionally, she will present recent findings on VCP’s interactions with UBX family cofactors, key regulators defined by their Ubiquitin Regulatory X domain that direct VCP to a range of cellular functions. The seminar will conclude with insights into the mycobacterial DNA-Ku Non-Homologous End Joining (NHEJ) synapsis complex. NHEJ serves as the sole mechanism for repairing double-strand breaks (DSBs) in Mycobacterium tuberculosis during dormancy in host macrophages, and this system provides a robust model for studying how VCP homologs disassemble Ku during DNA repair. This research not only deepens our understanding of the molecular mechanisms underlying VCP function but also demonstrates the power of combining structural and biochemical approaches to tackle complex biological questions.

Prof. Isabelle Rouiller

Deputy Director CCeMMP, UoM Node Leader, University of Melbourne, Bio21, Parkville, Australia