6TAY

Mouse RNF213 mutant R4753K modeling the Moyamoya-disease-related Human variant R4810K

Summary for 6TAY

• Entry DOI: 10.2210/pdb6tay/pdb
• Related: 6TAX
• EMDB information: 10430
• Descriptor: RNF213,E3 ubiquitin-protein ligase RNF213,E3 ubiquitin-protein ligase RNF213, ADENOSINE-5'-TRIPHOSPHATE, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: rnf213, e3 ligase, aaa-protein, signaling protein
• Biological source: Mus musculus (House mouse); More
• Total number of polymer chains: 1
• Total formula weight: 528312.62

Authors

Ahel, J.,Meinhart, A.,Haselbach, D.,Clausen, T. (deposition date: 2019-10-31, release date: 2020-07-01, Last modification date: 2024-11-13)

Primary citation

Ahel, J.,Lehner, A.,Vogel, A.,Schleiffer, A.,Meinhart, A.,Haselbach, D.,Clausen, T.
Moyamoya disease factor RNF213 is a giant E3 ligase with a dynein-like core and a distinct ubiquitin-transfer mechanism.
Elife, 9:-, 2020

PubMed Abstract: 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.

PubMed: 32573437
DOI: 10.7554/eLife.56185

Experimental method

ELECTRON MICROSCOPY (3.2 Å)