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From Proteopedia
RNF216/E2-Ub/Ub transthiolation complex
Structural highlights
DiseaseRN216_HUMAN Cerebellar ataxia-hypogonadism syndrome. The disease is caused by variants affecting the gene represented in this entry. FunctionRN216_HUMAN Isoform 1 acts as an E3 ubiquitin ligase, which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and then transfers it to substrates promoting their degradation by the proteasome. Promotes degradation of TRAF3, TLR4 and TLR9. Contributes to the regulation of antiviral responses. Down-regulates activation of NF-kappa-B, IRF3 activation and IFNB production. Isoform 3 inhibits TNF and IL-1 mediated activation of NF-kappa-B. Promotes TNF and RIP mediated apoptosis.[1] [2] Publication Abstract from PubMedThe RING-between-RING (RBR) E3 ubiquitin ligase family in humans comprises 14 members and is defined by a two-step catalytic mechanism in which ubiquitin is first transferred from an E2 ubiquitin-conjugating enzyme to the RBR active site and then to the substrate. To define the core features of this catalytic mechanism, we here structurally and biochemically characterise the two RBRs HOIL-1 and RNF216. Crystal structures of both enzymes in their RBR/E2-Ub/Ub transthiolation complexes capturing the first catalytic step, together with complementary functional experiments, reveal the defining features of the RBR catalytic mechanism. RBRs catalyse ubiquitination via a conserved transthiolation complex structure that enables efficient E2-to-RBR ubiquitin transfer. Our data also highlight a conserved RBR allosteric activation mechanism by distinct ubiquitin linkages that suggests RBRs employ a feed-forward mechanism. We finally identify that the HOIL-1 RING2 domain contains an unusual Zn2/Cys6 binuclear cluster that is required for catalytic activity and substrate ubiquitination. The unifying catalytic mechanism of the RING-between-RING E3 ubiquitin ligase family.,Wang XS, Cotton TR, Trevelyan SJ, Richardson LW, Lee WT, Silke J, Lechtenberg BC Nat Commun. 2023 Jan 11;14(1):168. doi: 10.1038/s41467-023-35871-z. PMID:36631489[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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