A tuneable structural switch controls RNF213 activity and is bypassed in Moyamoya disease

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Abstract
RNF213 is a giant AAA+ ubiquitin ligase that serves as a central hub of innate immunity, responding to diverse stress signals with broad reactivity 1-6 . This versatility demands tight regulation, and its failure causes disease, such as Moyamoya angiopathy 7-10 and cancer progression 11-13 . 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 autoinhibited 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-κB 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.
Funding Information
  • Fondation Leducq (21CVD03)
  • French priority research program on rare diseases
  • Marie Sklodowska-Curie grant (847548)
  • UKRI Future Leaders Fellowship (MR/T043482/1)

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