Structural basis for RING-Cys-Relay E3 ligase activity and its role in axon integrity
Copyright policy )Structural basis for RING-Cys-Relay E3 ligase activity and its role in axon integrity
MYCBP2 is a ubiquitin (Ub) E3 ligase (E3) that is essential for neurodevelopment and regulates axon maintenance. MYCBP2 transfers Ub to nonlysine substrates via a newly discovered RING-Cys-Relay (RCR) mechanism, where Ub is relayed from an upstream cysteine to a downstream substrate esterification site. The molecular bases for E2-E3 Ub transfer and Ub relay are unknown. Whether these activities are linked to the neural phenotypes is also unclear. We describe the crystal structure of a covalently trapped E2~Ub:MYCBP2 transfer intermediate revealing key structural rearrangements upon E2-E3 Ub transfer and Ub relay. Our data suggest that transfer to the dynamic upstream cysteine, whilst mitigating lysine activity, requires a closed-like E2~Ub conjugate with tempered reactivity, and Ub relay is facilitated by a helix-coil transition. Furthermore, neurodevelopmental defects and delayed injury-induced degeneration in RCR-defective knock-in mice suggest its requirement, and that of substrate esterification activity, for normal neural development and programmed axon degeneration.
- Medical Research Council United Kingdom
- University of Dundee United Kingdom
- UNIVERSITY OF CAMBRIDGE
- UNIVERSITY OF CAMBRIDGE
- University of Cambridge
Models, Molecular, 570, /dk/atira/pure/subjectarea/asjc/1300/1312, Protein Conformation, Ubiquitin-Protein Ligases, Molecular Conformation, Mice, Transgenic, Molecular neuroscience, Article, name=Cell Biology, Mice, Structure-Activity Relationship, Animals, Humans, Cysteine, Gene Knock-In Techniques, X-ray crystallography, Adaptor Proteins, Signal Transducing, Binding Sites, Ubiquitin, Lysine, Ubiquitination, 500, name=Molecular Biology, Axons, Mice, Inbred C57BL, Enzyme mechanisms, Ubiquitin-Conjugating Enzymes, Female, Chemical tools, RING Finger Domains, /dk/atira/pure/subjectarea/asjc/1300/1307, Post-translational modifications, Protein Binding, Signal Transduction
Models, Molecular, 570, /dk/atira/pure/subjectarea/asjc/1300/1312, Protein Conformation, Ubiquitin-Protein Ligases, Molecular Conformation, Mice, Transgenic, Molecular neuroscience, Article, name=Cell Biology, Mice, Structure-Activity Relationship, Animals, Humans, Cysteine, Gene Knock-In Techniques, X-ray crystallography, Adaptor Proteins, Signal Transducing, Binding Sites, Ubiquitin, Lysine, Ubiquitination, 500, name=Molecular Biology, Axons, Mice, Inbred C57BL, Enzyme mechanisms, Ubiquitin-Conjugating Enzymes, Female, Chemical tools, RING Finger Domains, /dk/atira/pure/subjectarea/asjc/1300/1307, Post-translational modifications, Protein Binding, Signal Transduction
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