Structural basis for RING-Cys-Relay E3 ligase activity and its role in axon integrity
| Autor: | Peter D. Mabbitt, Michael P. Coleman, Satpal Virdee, Marc-André Déry, Mathew Stanley, Adam J. Fletcher, Andrea Loreto, Nicola T. Wood, Kuan-Chuan Pao |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0303 health sciences
biology Chemistry 030302 biochemistry & molecular biology Signal transducing adaptor protein Cell Biology Molecular neuroscience Plasma protein binding Ubiquitin ligase Cell biology 03 medical and health sciences medicine.anatomical_structure Protein structure Ubiquitin biology.protein medicine Binding site Axon Molecular Biology 030304 developmental biology |
| Zdroj: | Nature Chemical Biology. 16:1227-1236 |
| ISSN: | 1552-4469 1552-4450 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink