8q7h
From Proteopedia
Structure of CUL9-RBX1 ubiquitin E3 ligase complex in unneddylated and neddylated conformation - focused cullin dimer
Structural highlights
FunctionCUL9_HUMAN Core component of a Cul9-RING ubiquitin-protein ligase complex, a complex that mediates ubiquitination and subsequent degradation of BIRC5 and is required to maintain microtubule dynamics and genome integrity. Acts downstream of the 3M complex, which inhibits CUL9 activity, leading to prevent ubiquitination of BIRC5 (PubMed:24793696). Cytoplasmic anchor protein in p53/TP53-associated protein complex. Regulates the subcellular localization of p53/TP53 and subsequent function (PubMed:12526791, PubMed:17332328).[1] [2] [3] Publication Abstract from PubMedUbiquitin ligation is typically executed by hallmark E3 catalytic domains. Two such domains, 'cullin-RING' and 'RBR', are individually found in several hundred human E3 ligases, and collaborate with E2 enzymes to catalyze ubiquitylation. However, the vertebrate-specific CUL9 complex with RBX1 (also called ROC1), of interest due to its tumor suppressive interaction with TP53, uniquely encompasses both cullin-RING and RBR domains. Here, cryo-EM, biochemistry and cellular assays elucidate a 1.8-MDa hexameric human CUL9-RBX1 assembly. Within one dimeric subcomplex, an E2-bound RBR domain is activated by neddylation of its own cullin domain and positioning from the adjacent CUL9-RBX1 in trans. Our data show CUL9 as unique among RBX1-bound cullins in dependence on the metazoan-specific UBE2F neddylation enzyme, while the RBR domain protects it from deneddylation. Substrates are recruited to various upstream domains, while ubiquitylation relies on both CUL9's neddylated cullin and RBR domains achieving self-assembled and chimeric cullin-RING/RBR E3 ligase activity. Noncanonical assembly, neddylation and chimeric cullin-RING/RBR ubiquitylation by the 1.8 MDa CUL9 E3 ligase complex.,Horn-Ghetko D, Hopf LVM, Tripathi-Giesgen I, Du J, Kostrhon S, Vu DT, Beier V, Steigenberger B, Prabu JR, Stier L, Bruss EM, Mann M, Xiong Y, Schulman BA Nat Struct Mol Biol. 2024 Jul;31(7):1083-1094. doi: 10.1038/s41594-024-01257-y. , Epub 2024 Apr 11. PMID:38605244[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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