Abstract / Summary
RNF213 is a giant AAA+ ubiquitin ligase that serves as a central hub of innate immunity, responding to diverse stress signals with broad reactivity. This versatility demands tight regulation, and its failure causes disease, such as Moyamoya angiopathy and cancer progression. How the mega-enzyme is restrained and how mutations override this control is unknown. Here, we show that RNF213 activity is regulated by a dimeric switch - a constitutive dimer that alternates between auto-inhibited and activation-competent states. In the closed dimer, intermolecular contacts bury the E3 machinery, whereas ATP binding remodels the AAA+ core to open the dimer and prime ubiquitination. Dimer conversion is tuned by ubiquitination factors, redox conditions and post-translational modifications, allowing multiple stress signals to act through the same activation mechanism. Moyamoya mutations subvert the same open-closed transition, destabilizing the auto-inhibited dimer in a graded manner that tracks with clinical severity. Structural, biochemical and cellular data reveal how disease mutations allosterically disrupt the dimer interface and bypass ATP-dependent control to drive NF-{kappa}B activation and caspase-dependent apoptosis. Together, our findings reveal a tuneable dimeric switch that converts diverse stressors into graded inflammatory signalling and provide a mechanistic link between genetic predisposition, environmental triggers and Moyamoya disease.