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X-ray structure of TRIM21 RING E3 ligase in complex with E2 enzyme Ube2WX-ray structure of TRIM21 RING E3 ligase in complex with E2 enzyme Ube2W
Structural highlights
FunctionUBE2W_HUMAN Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. Catalyzes monoubiquitination. Involved in degradation of misfolded chaperone substrates by mediating monoubiquitination of STUB1/CHIP, leading to recruitment of ATXN3 to monoubiquitinated STUB1/CHIP, and restriction of the length of ubiquitin chain attached to STUB1/CHIP substrates by ATXN3. After UV irradiation, but not after mitomycin-C (MMC) treatment, acts as a specific E2 ubiquitin-conjugating enzyme for the Fanconi anemia complex by associating with E3 ubiquitin-protein ligase FANCL and catalyzing monoubiquitination of FANCD2, a key step in the DNA damage pathway. In vitro catalyzes 'Lys-11'-linked polyubiquitination. Transfers ubiquitin in complex with RING/U-box type E3s that do not have active site cysteine residues to form thioester bonds with ubiquitin, and preferentially ubiquitinates the N-terminus of substrates, such as ATXN3, STUB1 and SUMO2.[1] [2] [3] [4] [5] Publication Abstract from PubMedTRIM proteins are the largest family of E3 ligases in mammals. They include the intracellular antibody receptor TRIM21, which is responsible for mediating targeted protein degradation during Trim-Away. Despite their importance, the ubiquitination mechanism of TRIM ligases has remained elusive. Here we show that while Trim-Away activation results in ubiquitination of both ligase and substrate, ligase ubiquitination is not required for substrate degradation. N-terminal TRIM21 RING ubiquitination by the E2 Ube2W can be inhibited by N-terminal acetylation, but this doesn't prevent substrate ubiquitination nor degradation. Instead, uncoupling ligase and substrate degradation prevents ligase recycling and extends functional persistence in cells. Further, Trim-Away degrades substrates irrespective of whether they contain lysines or are N-terminally acetylated, which may explain the ability of TRIM21 to counteract fast-evolving pathogens and degrade diverse substrates. Trim-Away ubiquitinates and degrades lysine-less and N-terminally acetylated substrates.,Kiss L, Rhinesmith T, Luptak J, Dickson CF, Weidenhausen J, Smyly S, Yang JC, Maslen SL, Sinning I, Neuhaus D, Clift D, James LC Nat Commun. 2023 Apr 15;14(1):2160. doi: 10.1038/s41467-023-37504-x. PMID:37061529[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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