6T7F

RCR E3 ligase E2-Ubiquitin transthiolation intermediate

Summary for 6T7F

• Entry DOI: 10.2210/pdb6t7f/pdb
• Descriptor: E3 ubiquitin-protein ligase MYCBP2, Ubiquitin-conjugating enzyme E2 D3, Polyubiquitin-C, ... (6 entities in total)
• Functional Keywords: ring-cys-relay, rcr, activity based probe, ubiquitination, threonine e3 ligase., ligase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 55222.31

Authors

Mabbitt, P.D.,Virdee, S. (deposition date: 2019-10-21, release date: 2020-08-05, Last modification date: 2024-11-06)

Primary citation

Mabbitt, P.D.,Loreto, A.,Dery, M.A.,Fletcher, A.J.,Stanley, M.,Pao, K.C.,Wood, N.T.,Coleman, M.P.,Virdee, S.
Structural basis for RING-Cys-Relay E3 ligase activity and its role in axon integrity.
Nat.Chem.Biol., 16:1227-1236, 2020

PubMed 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.

PubMed: 32747811
DOI: 10.1038/s41589-020-0598-6

Experimental method

X-RAY DIFFRACTION (2.58 Å)