Focused map- CyclinA-CDK2-class. Ubiquitin ligation to F-box protein substrates by SCF-RBR E3-E3 super-assembly: CUL1-RBX1-SKP1-SKP2-CKSHS1-Cyclin A-CDK2-p27. Transition State 1
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複合体: NEDD8-CUL1-RBX1-SKP1-SKP2-CKSHS1-Cyclin A-CDK2-p27-UBE2L3~Ub~ARIH1. Transition State 1 composite map.
cyclin-dependent protein kinase regulator activity / regulation of lens fiber cell differentiation / negative regulation of cyclin-dependent protein kinase activity / negative regulation of cardiac muscle tissue regeneration / negative regulation of kinase activity / positive regulation of protein polyubiquitination / autophagic cell death / FOXO-mediated transcription of cell cycle genes / Parkin-FBXW7-Cul1 ubiquitin ligase complex / negative regulation of epithelial cell proliferation involved in prostate gland development ...cyclin-dependent protein kinase regulator activity / regulation of lens fiber cell differentiation / negative regulation of cyclin-dependent protein kinase activity / negative regulation of cardiac muscle tissue regeneration / negative regulation of kinase activity / positive regulation of protein polyubiquitination / autophagic cell death / FOXO-mediated transcription of cell cycle genes / Parkin-FBXW7-Cul1 ubiquitin ligase complex / negative regulation of epithelial cell proliferation involved in prostate gland development / F-box domain binding / negative regulation of cyclin-dependent protein serine/threonine kinase activity / cellular response to cell-matrix adhesion / : / cyclin A2-CDK1 complex / Aberrant regulation of mitotic exit in cancer due to RB1 defects / regulation of cell cycle G1/S phase transition / cell cycle G1/S phase transition / PcG protein complex / cellular response to luteinizing hormone stimulus / regulation of exit from mitosis / negative regulation of epithelial cell apoptotic process / cullin-RING ubiquitin ligase complex / epithelial cell proliferation involved in prostate gland development / positive regulation of ubiquitin protein ligase activity / ubiquitin ligase activator activity / Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 / cyclin-dependent protein serine/threonine kinase inhibitor activity / Cul7-RING ubiquitin ligase complex / cellular response to leptin stimulus / maintenance of protein location in nucleus / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling / RHO GTPases activate CIT / regulation of cyclin-dependent protein serine/threonine kinase activity / cyclin-dependent protein serine/threonine kinase activator activity / male pronucleus / nuclear export / female pronucleus / negative regulation of mitotic cell cycle / cellular response to cocaine / AKT phosphorylates targets in the cytosol / response to glucagon / epithelial cell apoptotic process / cyclin-dependent protein serine/threonine kinase regulator activity / positive regulation of DNA biosynthetic process / SCF ubiquitin ligase complex / cellular response to antibiotic / Cul4A-RING E3 ubiquitin ligase complex / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / molecular function inhibitor activity / cellular response to insulin-like growth factor stimulus / cellular response to lithium ion / positive regulation of intracellular estrogen receptor signaling pathway / cyclin A1-CDK2 complex / cyclin E2-CDK2 complex / ubiquitin ligase complex scaffold activity / cyclin E1-CDK2 complex / cyclin A2-CDK2 complex / positive regulation of DNA-templated DNA replication initiation / cyclin-dependent protein kinase activity / G2 Phase / Y chromosome / Phosphorylation of proteins involved in G1/S transition by active Cyclin E:Cdk2 complexes / positive regulation of heterochromatin formation / p53-Dependent G1 DNA Damage Response / Prolactin receptor signaling / X chromosome / protein kinase inhibitor activity / PTK6 Regulates Cell Cycle / Constitutive Signaling by AKT1 E17K in Cancer / regulation of anaphase-promoting complex-dependent catabolic process / Defective binding of RB1 mutants to E2F1,(E2F2, E2F3) / microtubule organizing center / inner ear development / centriole replication / Regulation of APC/C activators between G1/S and early anaphase / telomere maintenance in response to DNA damage / regulation of DNA replication / regulation of G1/S transition of mitotic cell cycle / negative regulation of vascular associated smooth muscle cell proliferation / centrosome duplication / cullin family protein binding / G0 and Early G1 / cochlea development / Telomere Extension By Telomerase / protein K63-linked ubiquitination / animal organ regeneration / Activation of the pre-replicative complex / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / protein monoubiquitination / cyclin-dependent kinase / cyclin-dependent protein serine/threonine kinase activity / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / ubiquitin-like ligase-substrate adaptor activity / Regulation of MITF-M-dependent genes involved in cell cycle and proliferation / Cajal body / positive regulation of double-strand break repair via homologous recombination / Activation of ATR in response to replication stress / Cyclin E associated events during G1/S transition / protein K48-linked ubiquitination 類似検索 - 分子機能
ジャーナル: Nature / 年: 2021 タイトル: Ubiquitin ligation to F-box protein targets by SCF-RBR E3-E3 super-assembly. 著者: Daniel Horn-Ghetko / David T Krist / J Rajan Prabu / Kheewoong Baek / Monique P C Mulder / Maren Klügel / Daniel C Scott / Huib Ovaa / Gary Kleiger / Brenda A Schulman / 要旨: E3 ligases are typically classified by hallmark domains such as RING and RBR, which are thought to specify unique catalytic mechanisms of ubiquitin transfer to recruited substrates. However, rather ...E3 ligases are typically classified by hallmark domains such as RING and RBR, which are thought to specify unique catalytic mechanisms of ubiquitin transfer to recruited substrates. However, rather than functioning individually, many neddylated cullin-RING E3 ligases (CRLs) and RBR-type E3 ligases in the ARIH family-which together account for nearly half of all ubiquitin ligases in humans-form E3-E3 super-assemblies. Here, by studying CRLs in the SKP1-CUL1-F-box (SCF) family, we show how neddylated SCF ligases and ARIH1 (an RBR-type E3 ligase) co-evolved to ubiquitylate diverse substrates presented on various F-box proteins. We developed activity-based chemical probes that enabled cryo-electron microscopy visualization of steps in E3-E3 ubiquitylation, initiating with ubiquitin linked to the E2 enzyme UBE2L3, then transferred to the catalytic cysteine of ARIH1, and culminating in ubiquitin linkage to a substrate bound to the SCF E3 ligase. The E3-E3 mechanism places the ubiquitin-linked active site of ARIH1 adjacent to substrates bound to F-box proteins (for example, substrates with folded structures or limited length) that are incompatible with previously described conventional RING E3-only mechanisms. The versatile E3-E3 super-assembly may therefore underlie widespread ubiquitylation.