Structural basis for RING-Cys-Relay E3 ligase activity and its role in axon integrity
| Autor: | Peter D, Mabbitt, Andrea, Loreto, Marc-André, Déry, Adam J, Fletcher, Mathew, Stanley, Kuan-Chuan, Pao, Nicola T, Wood, Michael P, Coleman, Satpal, Virdee |
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| Rok vydání: | 2019 |
| Předmět: |
Models
Molecular Binding Sites Protein Conformation Ubiquitin Lysine Ubiquitin-Protein Ligases Molecular Conformation Ubiquitination Mice Transgenic Axons Mice Inbred C57BL Mice Structure-Activity Relationship Ubiquitin-Conjugating Enzymes Animals Humans Female Cysteine Gene Knock-In Techniques RING Finger Domains Adaptor Proteins Signal Transducing Protein Binding Signal Transduction |
| Zdroj: | Nature chemical biology. 16(11) |
| ISSN: | 1552-4469 |
| 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 |
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