positive regulation of protein polyubiquitination / F-box domain binding / Phosphorylation of proteins involved in the G2/M transition by Cyclin A:Cdc2 complexes / cyclin A2-CDK1 complex / Aberrant regulation of mitotic exit in cancer due to RB1 defects / PcG protein complex / cell cycle G1/S phase transition / cellular response to luteinizing hormone stimulus / mitotic cell cycle phase transition / Cul7-RING ubiquitin ligase complex ...positive regulation of protein polyubiquitination / F-box domain binding / Phosphorylation of proteins involved in the G2/M transition by Cyclin A:Cdc2 complexes / cyclin A2-CDK1 complex / Aberrant regulation of mitotic exit in cancer due to RB1 defects / PcG protein complex / cell cycle G1/S phase transition / cellular response to luteinizing hormone stimulus / mitotic cell cycle phase transition / 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 / male pronucleus / cyclin-dependent protein serine/threonine kinase activator activity / female pronucleus / cellular response to cocaine / response to glucagon / positive regulation of intracellular estrogen receptor signaling pathway / cyclin-dependent protein serine/threonine kinase regulator activity / SCF ubiquitin ligase complex / cellular response to insulin-like growth factor stimulus / ubiquitin ligase complex scaffold activity / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / positive regulation of DNA biosynthetic process / cochlea development / 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 / positive regulation of heterochromatin formation / p53-Dependent G1 DNA Damage Response / Prolactin receptor signaling / X chromosome / PTK6 Regulates Cell Cycle / regulation of DNA replication / regulation of anaphase-promoting complex-dependent catabolic process / protein monoubiquitination / Defective binding of RB1 mutants to E2F1,(E2F2, E2F3) / centriole replication / Regulation of APC/C activators between G1/S and early anaphase / cullin family protein binding / centrosome duplication / protein K63-linked ubiquitination / Telomere Extension By Telomerase / G0 and Early G1 / ubiquitin-like ligase-substrate adaptor activity / positive regulation of double-strand break repair via homologous recombination / negative regulation of mitotic cell cycle / Activation of the pre-replicative complex / cellular response to nitric oxide / cyclin-dependent protein kinase holoenzyme complex / cyclin-dependent kinase / animal organ regeneration / protein K48-linked ubiquitination / cyclin-dependent protein serine/threonine kinase activity / Nuclear events stimulated by ALK signaling in cancer / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / Activation of ATR in response to replication stress / Cyclin E associated events during G1/S transition / Cyclin A/B1/B2 associated events during G2/M transition / Cajal body / Cyclin A:Cdk2-associated events at S phase entry / condensed chromosome / mitotic G1 DNA damage checkpoint signaling / regulation of mitotic cell cycle / regulation of G2/M transition of mitotic cell cycle / Regulation of BACH1 activity / MAP3K8 (TPL2)-dependent MAPK1/3 activation / cyclin binding / post-translational protein modification / : / meiotic cell cycle / positive regulation of DNA replication / ubiquitin binding / male germ cell nucleus / SCF-beta-TrCP mediated degradation of Emi1 / NIK-->noncanonical NF-kB signaling / molecular function activator activity / cellular response to estradiol stimulus / Vpu mediated degradation of CD4 / Dectin-1 mediated noncanonical NF-kB signaling / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / Degradation of GLI1 by the proteasome / Activation of NF-kappaB in B cells / Negative regulation of NOTCH4 signaling / Iron uptake and transport / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / FBXL7 down-regulates AURKA during mitotic entry and in early mitosis 類似検索 - 分子機能
ジャーナル: Sci Rep / 年: 2023 タイトル: Cryo-EM structure of SKP1-SKP2-CKS1 in complex with CDK2-cyclin A-p27KIP1. 著者: Rhianna J Rowland / Richard Heath / Daniel Maskell / Rebecca F Thompson / Neil A Ranson / James N Blaza / Jane A Endicott / Martin E M Noble / Marco Salamina / 要旨: p27KIP1 (cyclin-dependent kinase inhibitor 1B, p27) is a member of the CIP/KIP family of CDK (cyclin dependent kinase) regulators that inhibit cell cycle CDKs. p27 phosphorylation by CDK1/2, signals ...p27KIP1 (cyclin-dependent kinase inhibitor 1B, p27) is a member of the CIP/KIP family of CDK (cyclin dependent kinase) regulators that inhibit cell cycle CDKs. p27 phosphorylation by CDK1/2, signals its recruitment to the SCF (S-phase kinase associated protein 1 (SKP1)-cullin-SKP2) E3 ubiquitin ligase complex for proteasomal degradation. The nature of p27 binding to SKP2 and CKS1 was revealed by the SKP1-SKP2-CKS1-p27 phosphopeptide crystal structure. Subsequently, a model for the hexameric CDK2-cyclin A-CKS1-p27-SKP1-SKP2 complex was proposed by overlaying an independently determined CDK2-cyclin A-p27 structure. Here we describe the experimentally determined structure of the isolated CDK2-cyclin A-CKS1-p27-SKP1-SKP2 complex at 3.4 Å global resolution using cryogenic electron microscopy. This structure supports previous analysis in which p27 was found to be structurally dynamic, transitioning from disordered to nascent secondary structure on target binding. We employed 3D variability analysis to further explore the conformational space of the hexameric complex and uncovered a previously unidentified hinge motion centred on CKS1. This flexibility gives rise to open and closed conformations of the hexameric complex that we propose may contribute to p27 regulation by facilitating recognition with SCF. This 3D variability analysis further informed particle subtraction and local refinement approaches to enhance the local resolution of the complex.