Structural basis for RING-Cys-Relay E3 ligase activity and its role in axon integrity

Peter D. Mabbitt, Andrea Loreto, Marc-André Déry, Adam J. Fletcher, Mathew Stanley, Kuan-Chuan Pao, Nicola T. Wood, Michael P. Coleman, Satpal Virdee (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)
17 Downloads (Pure)

Abstract

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.

Original languageEnglish
Pages (from-to)1227-1236
Number of pages10
JournalNature Chemical Biology
Volume16
Issue number11
Early online date3 Aug 2020
DOIs
Publication statusPublished - 1 Nov 2020

Keywords

  • Chemical tools
  • Enzyme mechanisms
  • Molecular neuroscience
  • Post-translational modifications
  • X-ray crystallography

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