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 / F-box domain binding ...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 / F-box domain binding / negative regulation of epithelial cell proliferation involved in prostate gland development / cellular response to cell-matrix adhesion / negative regulation of cyclin-dependent protein serine/threonine kinase activity / : / cyclin A2-CDK1 complex / Aberrant regulation of mitotic exit in cancer due to RB1 defects / regulation of cell cycle G1/S phase transition / PcG protein complex / cell cycle G1/S phase transition / cellular response to luteinizing hormone stimulus / regulation of exit from mitosis / negative regulation of epithelial cell apoptotic process / epithelial cell proliferation involved in prostate gland development / cullin-RING ubiquitin ligase complex / positive regulation of ubiquitin protein ligase activity / cyclin-dependent protein serine/threonine kinase inhibitor activity / Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 / Cul7-RING ubiquitin ligase complex / cellular response to leptin stimulus / maintenance of protein location in nucleus / ubiquitin ligase activator activity / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling / regulation of cyclin-dependent protein serine/threonine kinase activity / RHO GTPases activate CIT / male pronucleus / cyclin-dependent protein serine/threonine kinase activator activity / nuclear export / female pronucleus / negative regulation of mitotic cell cycle / cellular response to cocaine / AKT phosphorylates targets in the cytosol / epithelial cell apoptotic process / response to glucagon / positive regulation of DNA biosynthetic process / cellular response to antibiotic / cyclin-dependent protein serine/threonine kinase regulator activity / SCF ubiquitin ligase complex / molecular function inhibitor activity / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / cellular response to lithium ion / positive regulation of intracellular estrogen receptor signaling pathway / cellular response to insulin-like growth factor stimulus / Cul4A-RING E3 ubiquitin ligase complex / cyclin A1-CDK2 complex / cyclin E2-CDK2 complex / cyclin E1-CDK2 complex / cyclin A2-CDK2 complex / positive regulation of DNA-templated DNA replication initiation / G2 Phase / Y chromosome / cyclin-dependent protein kinase activity / Phosphorylation of proteins involved in G1/S transition by active Cyclin E:Cdk2 complexes / Prolactin receptor signaling / positive regulation of heterochromatin formation / p53-Dependent G1 DNA Damage Response / X chromosome / ubiquitin ligase complex scaffold activity / Constitutive Signaling by AKT1 E17K in Cancer / PTK6 Regulates Cell Cycle / regulation of anaphase-promoting complex-dependent catabolic process / Defective binding of RB1 mutants to E2F1,(E2F2, E2F3) / protein kinase inhibitor activity / inner ear development / centriole replication / Regulation of APC/C activators between G1/S and early anaphase / regulation of DNA replication / telomere maintenance in response to DNA damage / microtubule organizing center / centrosome duplication / negative regulation of vascular associated smooth muscle cell proliferation / regulation of G1/S transition of mitotic cell cycle / cullin family protein binding / G0 and Early G1 / cochlea development / protein K63-linked ubiquitination / Telomere Extension By Telomerase / 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 / Activation of ATR in response to replication stress / Regulation of MITF-M-dependent genes involved in cell cycle and proliferation / ubiquitin-like ligase-substrate adaptor activity / Cajal body / protein K48-linked ubiquitination / Cyclin E associated events during G1/S transition / Cyclin A:Cdk2-associated events at S phase entry 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.