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 activating kinase regulator activity / regulation of lens fiber cell differentiation / negative regulation of cardiac muscle tissue regeneration / negative regulation of cyclin-dependent protein kinase activity / positive regulation of protein polyubiquitination / autophagic cell death / Parkin-FBXW7-Cul1 ubiquitin ligase complex / FOXO-mediated transcription of cell cycle genes / negative regulation of epithelial cell proliferation involved in prostate gland development / F-box domain binding ...cyclin-dependent protein kinase activating kinase regulator activity / regulation of lens fiber cell differentiation / negative regulation of cardiac muscle tissue regeneration / negative regulation of cyclin-dependent protein kinase activity / positive regulation of protein polyubiquitination / autophagic cell death / Parkin-FBXW7-Cul1 ubiquitin ligase complex / FOXO-mediated transcription of cell cycle genes / negative regulation of epithelial cell proliferation involved in prostate gland development / F-box domain binding / Phosphorylation of proteins involved in the G2/M transition by Cyclin A:Cdc2 complexes / cyclin A2-CDK1 complex / PcG protein complex / Aberrant regulation of mitotic exit in cancer due to RB1 defects / cell cycle G1/S phase transition / cellular response to luteinizing hormone stimulus / regulation of cell cycle G1/S phase transition / regulation of exit from mitosis / mitotic cell cycle phase transition / epithelial cell proliferation involved in prostate gland development / cullin-RING ubiquitin ligase complex / negative regulation of epithelial cell apoptotic process / negative regulation of cyclin-dependent protein serine/threonine kinase activity / ubiquitin ligase activator activity / negative regulation of phosphorylation / Cul7-RING ubiquitin ligase complex / Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 / positive regulation of ubiquitin protein ligase activity / cyclin-dependent protein serine/threonine kinase inhibitor activity / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling / maintenance of protein location in nucleus / cellular response to leptin stimulus / RHO GTPases activate CIT / male pronucleus / nuclear export / female pronucleus / cyclin-dependent protein serine/threonine kinase activator activity / response to glucagon / cellular response to cocaine / AKT phosphorylates targets in the cytosol / positive regulation of intracellular estrogen receptor signaling pathway / cyclin-dependent protein serine/threonine kinase regulator activity / Cul4A-RING E3 ubiquitin ligase complex / epithelial cell apoptotic process / SCF ubiquitin ligase complex / cellular response to insulin-like growth factor stimulus / cellular response to antibiotic / ubiquitin ligase complex scaffold activity / negative regulation of kinase activity / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / positive regulation of DNA biosynthetic process / regulation of cyclin-dependent protein serine/threonine kinase activity / molecular function inhibitor activity / cochlea development / cellular response to lithium ion / cyclin A1-CDK2 complex / cyclin E2-CDK2 complex / cyclin E1-CDK2 complex / cellular response to platelet-derived growth factor stimulus / cyclin A2-CDK2 complex / positive regulation of DNA-templated DNA replication initiation / G2 Phase / cyclin-dependent protein kinase activity / Y chromosome / Phosphorylation of proteins involved in G1/S transition by active Cyclin E:Cdk2 complexes / protein kinase inhibitor activity / positive regulation of heterochromatin formation / p53-Dependent G1 DNA Damage Response / Prolactin receptor signaling / X chromosome / PTK6 Regulates Cell Cycle / regulation of DNA replication / Constitutive Signaling by AKT1 E17K in Cancer / regulation of anaphase-promoting complex-dependent catabolic process / telomere maintenance in response to DNA damage / regulation of G1/S transition of mitotic cell cycle / protein monoubiquitination / Defective binding of RB1 mutants to E2F1,(E2F2, E2F3) / cullin family protein binding / negative regulation of vascular associated smooth muscle cell proliferation / centriole replication / Regulation of APC/C activators between G1/S and early anaphase / centrosome duplication / inner ear development / Regulation of MITF-M-dependent genes involved in cell cycle and proliferation / protein K63-linked ubiquitination / cellular response to organic cyclic compound / G0 and Early G1 / Telomere Extension By Telomerase / ubiquitin-like ligase-substrate adaptor activity / negative regulation of mitotic cell cycle / localization / positive regulation of double-strand break repair via homologous recombination / Activation of the pre-replicative complex / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / cellular response to nitric oxide / response to amino acid / cyclin-dependent kinase / animal organ regeneration / 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.