登録情報 データベース : EMDB / ID : EMD-20551 構造の表示 ダウンロードとリンクタイトル Structure of a MAPK pathway complex マップデータStructure of a MAPK pathway complex 詳細 試料複合体 : ERK pathway complexタンパク質・ペプチド : Serine/threonine-protein kinase B-rafタンパク質・ペプチド : 14-3-3 protein zeta/delta 詳細機能・相同性 機能・相同性情報分子機能 ドメイン・相同性 構成要素
Golgi reassembly / synaptic target recognition / respiratory system process / NOTCH4 Activation and Transmission of Signal to the Nucleus / regulation of synapse maturation / CD4-positive, alpha-beta T cell differentiation / trehalose metabolism in response to stress / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / establishment of Golgi localization / negative regulation of synaptic vesicle exocytosis ... Golgi reassembly / synaptic target recognition / respiratory system process / NOTCH4 Activation and Transmission of Signal to the Nucleus / regulation of synapse maturation / CD4-positive, alpha-beta T cell differentiation / trehalose metabolism in response to stress / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / establishment of Golgi localization / negative regulation of synaptic vesicle exocytosis / Signalling to p38 via RIT and RIN / head morphogenesis / myeloid progenitor cell differentiation / tube formation / ARMS-mediated activation / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / endothelial cell apoptotic process / Rap1 signalling / negative regulation of fibroblast migration / positive regulation of glucose transmembrane transport / establishment of protein localization to membrane / negative regulation of protein localization to nucleus / mitogen-activated protein kinase kinase binding / regulation of T cell differentiation / Negative feedback regulation of MAPK pathway / KSRP (KHSRP) binds and destabilizes mRNA / positive regulation of axonogenesis / Frs2-mediated activation / GP1b-IX-V activation signalling / stress fiber assembly / positive regulation of axon regeneration / face development / synaptic vesicle exocytosis / somatic stem cell population maintenance / MAP kinase kinase activity / thyroid gland development / Regulation of localization of FOXO transcription factors / Interleukin-3, Interleukin-5 and GM-CSF signaling / phosphoserine residue binding / MAP kinase kinase kinase activity / Activation of BAD and translocation to mitochondria / protein targeting / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / cellular response to glucose starvation / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / negative regulation of endothelial cell apoptotic process / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / positive regulation of substrate adhesion-dependent cell spreading / RHO GTPases activate PKNs / positive regulation of stress fiber assembly / negative regulation of TORC1 signaling / response to cAMP / protein sequestering activity / cellular response to calcium ion / ERK1 and ERK2 cascade / negative regulation of innate immune response / hippocampal mossy fiber to CA3 synapse / substrate adhesion-dependent cell spreading / regulation of ERK1 and ERK2 cascade / cellular response to nerve growth factor stimulus / thymus development / Translocation of SLC2A4 (GLUT4) to the plasma membrane / Deactivation of the beta-catenin transactivating complex / long-term synaptic potentiation / TP53 Regulates Metabolic Genes / animal organ morphogenesis / Negative regulation of NOTCH4 signaling / RAF activation / Spry regulation of FGF signaling / lung development / Signaling by high-kinase activity BRAF mutants / visual learning / MAP2K and MAPK activation / regulation of protein stability / epidermal growth factor receptor signaling pathway / response to peptide hormone / Negative regulation of MAPK pathway / Signaling by RAF1 mutants / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / MAPK cascade / Signaling by BRAF and RAF1 fusions / melanosome / cellular response to xenobiotic stimulus / presynapse / positive regulation of peptidyl-serine phosphorylation / T cell receptor signaling pathway / regulation of cell population proliferation / cell body / T cell differentiation in thymus / scaffold protein binding / angiogenesis / DNA-binding transcription factor binding / vesicle / transmembrane transporter binding / negative regulation of neuron apoptotic process / Ras protein signal transduction / positive regulation of ERK1 and ERK2 cascade 類似検索 - 分子機能 Raf-like Ras-binding domain / Raf-like Ras-binding / Ras-binding domain (RBD) profile. / Raf-like Ras-binding domain / Diacylglycerol/phorbol-ester binding / Phorbol esters/diacylglycerol binding domain (C1 domain) / Zinc finger phorbol-ester/DAG-type signature. / Zinc finger phorbol-ester/DAG-type profile. / Protein kinase C conserved region 1 (C1) domains (Cysteine-rich domains) / Protein kinase C-like, phorbol ester/diacylglycerol-binding domain ... Raf-like Ras-binding domain / Raf-like Ras-binding / Ras-binding domain (RBD) profile. / Raf-like Ras-binding domain / Diacylglycerol/phorbol-ester binding / Phorbol esters/diacylglycerol binding domain (C1 domain) / Zinc finger phorbol-ester/DAG-type signature. / Zinc finger phorbol-ester/DAG-type profile. / Protein kinase C conserved region 1 (C1) domains (Cysteine-rich domains) / Protein kinase C-like, phorbol ester/diacylglycerol-binding domain / C1-like domain superfamily / 14-3-3 proteins signature 2. / 14-3-3 protein, conserved site / 14-3-3 proteins signature 1. / 14-3-3 protein / 14-3-3 homologues / 14-3-3 domain / 14-3-3 domain superfamily / 14-3-3 protein / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Ubiquitin-like domain superfamily / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily 類似検索 - ドメイン・相同性 Serine/threonine-protein kinase B-raf / 14-3-3 protein zeta/delta 類似検索 - 構成要素生物種 Homo sapiens (ヒト) / Human (ヒト)手法 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度 : 6.8 Å 詳細 データ登録者Park E / Rawson S / Jeon H / Eck MJ 資金援助 米国, 2件 詳細 詳細を隠すOrganization Grant number 国 National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI) P50CA165962 米国 National Institutes of Health/National Cancer Institute (NIH/NCI) R50CA221830 米国
引用ジャーナル : Nature / 年 : 2019タイトル : Architecture of autoinhibited and active BRAF-MEK1-14-3-3 complexes.著者 : Eunyoung Park / Shaun Rawson / Kunhua Li / Byeong-Won Kim / Scott B Ficarro / Gonzalo Gonzalez-Del Pino / Humayun Sharif / Jarrod A Marto / Hyesung Jeon / Michael J Eck / 要旨 : RAF family kinases are RAS-activated switches that initiate signalling through the MAP kinase cascade to control cellular proliferation, differentiation and survival. RAF activity is tightly ... RAF family kinases are RAS-activated switches that initiate signalling through the MAP kinase cascade to control cellular proliferation, differentiation and survival. RAF activity is tightly regulated and inappropriate activation is a frequent cause of cancer; however, the structural basis for RAF regulation is poorly understood at present. Here we use cryo-electron microscopy to determine autoinhibited and active-state structures of full-length BRAF in complexes with MEK1 and a 14-3-3 dimer. The reconstruction reveals an inactive BRAF-MEK1 complex restrained in a cradle formed by the 14-3-3 dimer, which binds the phosphorylated S365 and S729 sites that flank the BRAF kinase domain. The BRAF cysteine-rich domain occupies a central position that stabilizes this assembly, but the adjacent RAS-binding domain is poorly ordered and peripheral. The 14-3-3 cradle maintains autoinhibition by sequestering the membrane-binding cysteine-rich domain and blocking dimerization of the BRAF kinase domain. In the active state, these inhibitory interactions are released and a single 14-3-3 dimer rearranges to bridge the C-terminal pS729 binding sites of two BRAFs, which drives the formation of an active, back-to-back BRAF dimer. Our structural snapshots provide a foundation for understanding normal RAF regulation and its mutational disruption in cancer and developmental syndromes. 履歴 登録 2019年8月1日 - ヘッダ(付随情報) 公開 2019年10月2日 - マップ公開 2019年10月9日 - 更新 2020年4月22日 - 現状 2020年4月22日 処理サイト : RCSB / 状態 : 公開
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