positive regulation of protein polyubiquitination / F-box domain binding / cellular response to cell-matrix adhesion / : / 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 / positive regulation of ubiquitin protein ligase activity ...positive regulation of protein polyubiquitination / F-box domain binding / cellular response to cell-matrix adhesion / : / 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 / positive regulation of ubiquitin protein ligase activity / cyclin-dependent protein serine/threonine kinase inhibitor activity / Cul7-RING ubiquitin ligase complex / Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 / cellular response to leptin stimulus / maintenance of protein location in nucleus / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling / cyclin-dependent protein serine/threonine kinase activator activity / male pronucleus / female pronucleus / cellular response to cocaine / response to glucagon / cyclin-dependent protein serine/threonine kinase regulator activity / positive regulation of DNA biosynthetic process / SCF ubiquitin ligase complex / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / cellular response to insulin-like growth factor stimulus / positive regulation of intracellular estrogen receptor signaling pathway / ubiquitin ligase complex scaffold activity / cyclin A1-CDK2 complex / cyclin E2-CDK2 complex / 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 / Prolactin receptor signaling / positive regulation of heterochromatin formation / p53-Dependent G1 DNA Damage Response / X chromosome / PTK6 Regulates Cell Cycle / regulation of anaphase-promoting complex-dependent catabolic process / Defective binding of RB1 mutants to E2F1,(E2F2, E2F3) / microtubule organizing center / centriole replication / Regulation of APC/C activators between G1/S and early anaphase / telomere maintenance in response to DNA damage / regulation of DNA replication / cullin family protein binding / centrosome duplication / G0 and Early G1 / cochlea development / Telomere Extension By Telomerase / protein K63-linked ubiquitination / animal organ regeneration / Activation of the pre-replicative complex / 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 / protein K48-linked ubiquitination / Activation of ATR in response to replication stress / positive regulation of double-strand break repair via homologous recombination / Cyclin E associated events during G1/S transition / Cyclin A/B1/B2 associated events during G2/M transition / Cyclin A:Cdk2-associated events at S phase entry / cyclin-dependent protein kinase holoenzyme complex / Nuclear events stimulated by ALK signaling in cancer / Regulation of BACH1 activity / MAP3K8 (TPL2)-dependent MAPK1/3 activation / condensed chromosome / cellular response to platelet-derived growth factor stimulus / regulation of G2/M transition of mitotic cell cycle / mitotic G1 DNA damage checkpoint signaling / positive regulation of smooth muscle cell proliferation / cellular response to nitric oxide / post-translational protein modification / NIK-->noncanonical NF-kB signaling / SCF-beta-TrCP mediated degradation of Emi1 / cyclin binding / regulation of mitotic cell cycle / Vpu mediated degradation of CD4 / molecular function activator activity / Dectin-1 mediated noncanonical NF-kB signaling / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / positive regulation of DNA replication / ubiquitin binding / Iron uptake and transport / Activation of NF-kappaB in B cells / Degradation of GLI1 by the proteasome / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / meiotic cell cycle / Negative regulation of NOTCH4 signaling / male germ cell nucleus / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome 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.