| Structural highlights
Function
[ARI2_HUMAN] E3 ubiquitin-protein ligase, which catalyzes ubiquitination of target proteins together with ubiquitin-conjugating enzyme E2 UBE2L3 (PubMed:16118314, PubMed:17646546, PubMed:19340006, PubMed:24076655). Acts as an atypical E3 ubiquitin-protein ligase by working together with cullin-5-RING ubiquitin ligase complex (ECS complex, also named CRL5 complex) and initiating ubiquitination of ECS substrates: associates with ECS complex and specifically mediates addition of the first ubiquitin on ECS targets (By similarity). The initial ubiquitin is then elongated (By similarity). E3 ubiquitin-protein ligase activity is activated upon binding to neddylated form of the ECS complex (PubMed:24076655). Mediates 'Lys-6', 'Lys-48'- and 'Lys-63'-linked polyubiquitination (PubMed:16118314, PubMed:17646546, PubMed:19340006). May play a role in myelopoiesis (PubMed:19340006).[UniProtKB:Q9Y4X5][1] [2] [3] [4]
Publication Abstract from PubMed
An emerging mechanism of ubiquitylation involves partnering of two distinct E3 ligases. In the best-characterized E3-E3 pathways, ARIH-family RING-between-RING (RBR) E3s ligate ubiquitin to substrates of neddylated cullin-RING E3s. The E3 ARIH2 has been implicated in ubiquitylation of substrates of neddylated CUL5-RBX2-based E3s, including APOBEC3-family substrates of the host E3 hijacked by HIV-1 virion infectivity factor (Vif). However, the structural mechanisms remained elusive. Here structural and biochemical analyses reveal distinctive ARIH2 autoinhibition, and activation on assembly with neddylated CUL5-RBX2. Comparison to structures of E3-E3 assemblies comprising ARIH1 and neddylated CUL1-RBX1-based E3s shows cullin-specific regulation by NEDD8. Whereas CUL1-linked NEDD8 directly recruits ARIH1, CUL5-linked NEDD8 does not bind ARIH2. Instead, the data reveal an allosteric mechanism. NEDD8 uniquely contacts covalently linked CUL5, and elicits structural rearrangements that unveil cryptic ARIH2-binding sites. The data reveal how a ubiquitin-like protein induces protein-protein interactions indirectly, through allostery. Allosteric specificity of ubiquitin-like protein modifications may offer opportunities for therapeutic targeting.
CUL5-ARIH2 E3-E3 ubiquitin ligase structure reveals cullin-specific NEDD8 activation.,Kostrhon S, Prabu JR, Baek K, Horn-Ghetko D, von Gronau S, Klugel M, Basquin J, Alpi AF, Schulman BA Nat Chem Biol. 2021 Oct;17(10):1075-1083. doi: 10.1038/s41589-021-00858-8. Epub, 2021 Sep 13. PMID:34518685[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Marteijn JA, van Emst L, Erpelinck-Verschueren CA, Nikoloski G, Menke A, de Witte T, Lowenberg B, Jansen JH, van der Reijden BA. The E3 ubiquitin-protein ligase Triad1 inhibits clonogenic growth of primary myeloid progenitor cells. Blood. 2005 Dec 15;106(13):4114-23. doi: 10.1182/blood-2005-04-1450. Epub 2005, Aug 23. PMID:16118314 doi:http://dx.doi.org/10.1182/blood-2005-04-1450
- ↑ Marteijn JA, van der Meer LT, van Emst L, van Reijmersdal S, Wissink W, de Witte T, Jansen JH, Van der Reijden BA. Gfi1 ubiquitination and proteasomal degradation is inhibited by the ubiquitin ligase Triad1. Blood. 2007 Nov 1;110(9):3128-35. doi: 10.1182/blood-2006-11-058602. Epub 2007, Jul 23. PMID:17646546 doi:http://dx.doi.org/10.1182/blood-2006-11-058602
- ↑ Marteijn JA, van der Meer LT, Smit JJ, Noordermeer SM, Wissink W, Jansen P, Swarts HG, Hibbert RG, de Witte T, Sixma TK, Jansen JH, van der Reijden BA. The ubiquitin ligase Triad1 inhibits myelopoiesis through UbcH7 and Ubc13 interacting domains. Leukemia. 2009 Aug;23(8):1480-9. Epub 2009 Apr 2. PMID:19340006 doi:leu200957
- ↑ Kelsall IR, Duda DM, Olszewski JL, Hofmann K, Knebel A, Langevin F, Wood N, Wightman M, Schulman BA, Alpi AF. TRIAD1 and HHARI bind to and are activated by distinct neddylated Cullin-RING ligase complexes. EMBO J. 2013 Oct 30;32(21):2848-60. doi: 10.1038/emboj.2013.209. Epub 2013 Sep, 27. PMID:24076655 doi:http://dx.doi.org/10.1038/emboj.2013.209
- ↑ Kostrhon S, Prabu JR, Baek K, Horn-Ghetko D, von Gronau S, Klugel M, Basquin J, Alpi AF, Schulman BA. CUL5-ARIH2 E3-E3 ubiquitin ligase structure reveals cullin-specific NEDD8 activation. Nat Chem Biol. 2021 Oct;17(10):1075-1083. doi: 10.1038/s41589-021-00858-8. Epub, 2021 Sep 13. PMID:34518685 doi:http://dx.doi.org/10.1038/s41589-021-00858-8
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