Abstract:

RNF213 is a giant ubiquitin E3 ligase that integrates cellular stress signals to modulate inflammatory signalling. How RNF213 activity is regulated, and how Moyamoya disease (MMD) mutations disrupt this control, has remained unclear. In this talk, I will present cryo-EM structures of RNF213, present in autoinhibited and activated states, and show how ATP binding induces activation of its E3 ligase activity. I will further discuss how redox-active agents, post-translational modifications, and disease mutations converge on the same molecular switch to (dys)regulate RNF213 function during inflammatory signalling.

Bio:

Dr. Tim Clausen is a Senior Group Leader at the Research Institute of Molecular Pathology (IMP) at the Vienna BioCenter, where he has led an independent research group since 2002. Trained as a structural biologist under Nobel Laureate Robert Huber at the Max Planck Institute of Biochemistry, his work is driven by a long-standing fascination for proteins as elegant molecular machines. His research focuses on the mechanisms of protein quality control, exploring how cells recognize and eliminate damaged or harmful molecules. By combining integrative structural biology with a focus to explore unconventional cellular pathways, his lab has uncovered new post-translational modifications, identified bacterial counterparts of the ubiquitin–proteasome system, and developed approaches to dissect massive multi-enzyme assemblies. These discoveries have reshaped our understanding of protein degradation and cellular defence, with implications for cancer, neurodegeneration, and muscle disease. Dr. Clausen has received two ERC Advanced Grants, the Heinz Maier-Leibnitz Prize, and is an Allen Distinguished Investigator.