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

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

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