| Autor: |
Mabbitt PD; MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, UK., Loreto A; John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK., Déry MA; MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, UK., Fletcher AJ; MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, UK., Stanley M; Division of Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dundee, UK., Pao KC; MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, UK., Wood NT; MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, UK., Coleman MP; John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK.; The Babraham Institute, Babraham Research Campus, Cambridge, UK., Virdee S; MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, UK. s.s.virdee@dundee.ac.uk. |
| Abstrakt: |
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. |
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