Structural highlights
Function
MYCB2_HUMAN E3 ubiquitin-protein ligase which mediates ubiquitination and subsequent proteasomal degradation of TSC2/tuberin. Interacts with the E2 enzymes UBE2D1, UBE2D3 and UBE2L3 (in vitro). May function as a facilitator or regulator of transcriptional activation by MYC. May have a role during synaptogenesis.[1]
Publication Abstract from PubMed
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.
Structural basis for RING-Cys-Relay E3 ligase activity and its role in axon integrity.,Mabbitt PD, Loreto A, Dery MA, Fletcher AJ, Stanley M, Pao KC, Wood NT, Coleman MP, Virdee S Nat Chem Biol. 2020 Nov;16(11):1227-1236. doi: 10.1038/s41589-020-0598-6. Epub, 2020 Aug 3. PMID:32747811[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Han S, Witt RM, Santos TM, Polizzano C, Sabatini BL, Ramesh V. Pam (Protein associated with Myc) functions as an E3 ubiquitin ligase and regulates TSC/mTOR signaling. Cell Signal. 2008 Jun;20(6):1084-91. doi: 10.1016/j.cellsig.2008.01.020. Epub, 2008 Feb 1. PMID:18308511 doi:http://dx.doi.org/10.1016/j.cellsig.2008.01.020
- ↑ Mabbitt PD, Loreto A, Déry MA, Fletcher AJ, Stanley M, Pao KC, Wood NT, Coleman MP, Virdee S. Structural basis for RING-Cys-Relay E3 ligase activity and its role in axon integrity. Nat Chem Biol. 2020 Nov;16(11):1227-1236. PMID:32747811 doi:10.1038/s41589-020-0598-6
