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Moyamoya disease factor RNF213 is a giant E3 ligase with a dynein-like core and a distinct ubiquitin-transfer mechanism

RNF213 is the major susceptibility factor for Moyamoya disease, a progressive cerebrovascular disorder that often leads to brain stroke in adults and children. Characterization of disease-associated mutations has been complicated by the enormous size of RNF213. Here, we present the cryo-EM structure...

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Autores principales: Ahel, Juraj, Lehner, Anita, Vogel, Antonia, Schleiffer, Alexander, Meinhart, Anton, Haselbach, David, Clausen, Tim
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311170/
https://www.ncbi.nlm.nih.gov/pubmed/32573437
http://dx.doi.org/10.7554/eLife.56185
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author Ahel, Juraj
Lehner, Anita
Vogel, Antonia
Schleiffer, Alexander
Meinhart, Anton
Haselbach, David
Clausen, Tim
author_facet Ahel, Juraj
Lehner, Anita
Vogel, Antonia
Schleiffer, Alexander
Meinhart, Anton
Haselbach, David
Clausen, Tim
author_sort Ahel, Juraj
collection PubMed
description RNF213 is the major susceptibility factor for Moyamoya disease, a progressive cerebrovascular disorder that often leads to brain stroke in adults and children. Characterization of disease-associated mutations has been complicated by the enormous size of RNF213. Here, we present the cryo-EM structure of mouse RNF213. The structure reveals the intricate fold of the 584 kDa protein, comprising an N-terminal stalk, a dynein-like core with six ATPase units, and a multidomain E3 module. Collaboration with UbcH7, a cysteine-reactive E2, points to an unexplored ubiquitin-transfer mechanism that proceeds in a RING-independent manner. Moreover, we show that pathologic MMD mutations cluster in the composite E3 domain, likely interfering with substrate ubiquitination. In conclusion, the structure of RNF213 uncovers a distinct type of an E3 enzyme, highlighting the growing mechanistic diversity in ubiquitination cascades. Our results also provide the molecular framework for investigating the emerging role of RNF213 in lipid metabolism, hypoxia, and angiogenesis.
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spelling pubmed-73111702020-06-24 Moyamoya disease factor RNF213 is a giant E3 ligase with a dynein-like core and a distinct ubiquitin-transfer mechanism Ahel, Juraj Lehner, Anita Vogel, Antonia Schleiffer, Alexander Meinhart, Anton Haselbach, David Clausen, Tim eLife Biochemistry and Chemical Biology RNF213 is the major susceptibility factor for Moyamoya disease, a progressive cerebrovascular disorder that often leads to brain stroke in adults and children. Characterization of disease-associated mutations has been complicated by the enormous size of RNF213. Here, we present the cryo-EM structure of mouse RNF213. The structure reveals the intricate fold of the 584 kDa protein, comprising an N-terminal stalk, a dynein-like core with six ATPase units, and a multidomain E3 module. Collaboration with UbcH7, a cysteine-reactive E2, points to an unexplored ubiquitin-transfer mechanism that proceeds in a RING-independent manner. Moreover, we show that pathologic MMD mutations cluster in the composite E3 domain, likely interfering with substrate ubiquitination. In conclusion, the structure of RNF213 uncovers a distinct type of an E3 enzyme, highlighting the growing mechanistic diversity in ubiquitination cascades. Our results also provide the molecular framework for investigating the emerging role of RNF213 in lipid metabolism, hypoxia, and angiogenesis. eLife Sciences Publications, Ltd 2020-06-23 /pmc/articles/PMC7311170/ /pubmed/32573437 http://dx.doi.org/10.7554/eLife.56185 Text en © 2020, Ahel et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Biochemistry and Chemical Biology
Ahel, Juraj
Lehner, Anita
Vogel, Antonia
Schleiffer, Alexander
Meinhart, Anton
Haselbach, David
Clausen, Tim
Moyamoya disease factor RNF213 is a giant E3 ligase with a dynein-like core and a distinct ubiquitin-transfer mechanism
title Moyamoya disease factor RNF213 is a giant E3 ligase with a dynein-like core and a distinct ubiquitin-transfer mechanism
title_full Moyamoya disease factor RNF213 is a giant E3 ligase with a dynein-like core and a distinct ubiquitin-transfer mechanism
title_fullStr Moyamoya disease factor RNF213 is a giant E3 ligase with a dynein-like core and a distinct ubiquitin-transfer mechanism
title_full_unstemmed Moyamoya disease factor RNF213 is a giant E3 ligase with a dynein-like core and a distinct ubiquitin-transfer mechanism
title_short Moyamoya disease factor RNF213 is a giant E3 ligase with a dynein-like core and a distinct ubiquitin-transfer mechanism
title_sort moyamoya disease factor rnf213 is a giant e3 ligase with a dynein-like core and a distinct ubiquitin-transfer mechanism
topic Biochemistry and Chemical Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311170/
https://www.ncbi.nlm.nih.gov/pubmed/32573437
http://dx.doi.org/10.7554/eLife.56185
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