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

Abstract

RNF213 is a giant AAA+ ubiquitin ligase that serves as a central hub of innate immunity, responding to diverse stress signals with broad reactivity1-6. This versatility demands tight regulation, and its failure causes disease, such as Moyamoya angiopathy7-10 and cancer progression11-13. 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-{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.

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BibTeX RIS

BibTeX

@misc{bell2026tuneable,
  title = {{A tuneable structural switch controls RNF213 activity and is bypassed in Moyamoya disease}},
  author = {L. E. Bell and V. Faas and D. B. Grabarczyk and M. H. Wallnöfer and E. Kohoutkova and L. Deszcz and T. L. Williams and A. Meinhart and H. Scott and F. Riant and C. Aloui and M. Kossorotoff and L. Lacan and F. Godart and E. Tournier-Lasserve and A. J. Fletcher and T. Clausen},
  howpublished = {medRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.07.26364583},
  url = {https://www.medrxiv.org/content/10.64898/2026.10.07.26364583v1},
  note = {CC BY},
}

RIS

TY  - UNPB
TI  - A tuneable structural switch controls RNF213 activity and is bypassed in Moyamoya disease
AU  - L. E. Bell
AU  - V. Faas
AU  - D. B. Grabarczyk
AU  - M. H. Wallnöfer
AU  - E. Kohoutkova
AU  - L. Deszcz
AU  - T. L. Williams
AU  - A. Meinhart
AU  - H. Scott
AU  - F. Riant
AU  - C. Aloui
AU  - M. Kossorotoff
AU  - L. Lacan
AU  - F. Godart
AU  - E. Tournier-Lasserve
AU  - A. J. Fletcher
AU  - T. Clausen
PY  - 2026
DA  - 2026/10/07
PB  - medRxiv
DO  - 10.64898/2026.10.07.26364583
UR  - https://www.medrxiv.org/content/10.64898/2026.10.07.26364583v1
AB  - RNF213 is a giant AAA+ ubiquitin ligase that serves as a central hub of innate immunity, responding to diverse stress signals with broad reactivity1-6. This versatility demands tight regulation, and its failure causes disease, such as Moyamoya angiopathy7-10 and cancer progression11-13. 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-{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.
ER  -

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