登録情報 データベース : EMDB / ID : EMD-48401 ダウンロードとリンクタイトル Cryo-EM structure of CRAF/MEK1/14-3-3 complex (open monomer conformation, CRAF Y340D/Y341D mutant) マップデータ 詳細 試料複合体 : CRAF/MEK1/14-3-3 complex複合体 : CRAFタンパク質・ペプチド : RAF proto-oncogene serine/threonine-protein kinase複合体 : MEK1タンパク質・ペプチド : Dual specificity mitogen-activated protein kinase kinase 1複合体 : 14-3-3 dimerタンパク質・ペプチド : 14-3-3 protein zetaリガンド : PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTERリガンド : MAGNESIUM IONリガンド : 5-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxyethoxy)imidazo[1,5-a]pyridine-6-carboxamide 詳細 キーワード CRAF-MEK1-14-3-3 complex / MAPK pathway / TRANSFERASE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
death-inducing signaling complex assembly / epithelial cell proliferation involved in lung morphogenesis / positive regulation of endodermal cell differentiation / negative regulation of homotypic cell-cell adhesion / negative regulation of hypoxia-induced intrinsic apoptotic signaling pathway / regulation of vascular associated smooth muscle contraction / intermediate filament cytoskeleton organization / mitogen-activated protein kinase kinase / Golgi inheritance / placenta blood vessel development ... death-inducing signaling complex assembly / epithelial cell proliferation involved in lung morphogenesis / positive regulation of endodermal cell differentiation / negative regulation of homotypic cell-cell adhesion / negative regulation of hypoxia-induced intrinsic apoptotic signaling pathway / regulation of vascular associated smooth muscle contraction / intermediate filament cytoskeleton organization / mitogen-activated protein kinase kinase / Golgi inheritance / placenta blood vessel development / MAP-kinase scaffold activity / positive regulation of muscle contraction / regulation of axon regeneration / cerebellar cortex formation / labyrinthine layer development / regulation of Rho protein signal transduction / melanosome transport / type B pancreatic cell proliferation / Signaling by MAP2K mutants / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / Rap1 signalling / vesicle transport along microtubule / positive regulation of axonogenesis / positive regulation of Ras protein signal transduction / insulin secretion involved in cellular response to glucose stimulus / regulation of Golgi inheritance / mitogen-activated protein kinase kinase kinase binding / central nervous system neuron differentiation / triglyceride homeostasis / trachea formation / Negative feedback regulation of MAPK pathway / regulation of early endosome to late endosome transport / IFNG signaling activates MAPKs / regulation of stress-activated MAPK cascade / Frs2-mediated activation / GP1b-IX-V activation signalling / MAPK3 (ERK1) activation / ERBB2-ERBB3 signaling pathway / neurotrophin TRK receptor signaling pathway / regulation of neurotransmitter receptor localization to postsynaptic specialization membrane / pseudopodium / face development / endodermal cell differentiation / MAP kinase kinase activity / Bergmann glial cell differentiation / positive regulation of ATP biosynthetic process / regulation of cell differentiation / thyroid gland development / Uptake and function of anthrax toxins / positive regulation of protein serine/threonine kinase activity / extrinsic apoptotic signaling pathway via death domain receptors / somatic stem cell population maintenance / protein kinase activator activity / positive regulation of peptidyl-serine phosphorylation / MAP kinase kinase kinase activity / type II interferon-mediated signaling pathway / negative regulation of protein-containing complex assembly / Schwann cell development / response to axon injury / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / keratinocyte differentiation / neuron projection morphogenesis / response to muscle stretch / ERK1 and ERK2 cascade / myelination / positive regulation of autophagy / protein serine/threonine/tyrosine kinase activity / CD209 (DC-SIGN) signaling / dendrite cytoplasm / insulin-like growth factor receptor signaling pathway / response to glucocorticoid / MAP3K8 (TPL2)-dependent MAPK1/3 activation / thymus development / adenylate cyclase activator activity / protein serine/threonine kinase activator activity / Signal transduction by L1 / cell motility / positive regulation of transcription elongation by RNA polymerase II / wound healing / RAF activation / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / small GTPase binding / Stimuli-sensing channels / neuron differentiation / chemotaxis / 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 / Signaling by BRAF and RAF1 fusions / cellular senescence / insulin receptor signaling pathway / late endosome / MAPK cascade / heart development / response to oxidative stress / protein tyrosine kinase activity 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. ... : / 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 / Ubiquitin-like domain superfamily / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / 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 RAF proto-oncogene serine/threonine-protein kinase / Dual specificity mitogen-activated protein kinase kinase 1 / 14-3-3 protein zeta 類似検索 - 構成要素生物種 Homo sapiens (ヒト) / Spodoptera exigua (シロイチモジヨトウ)手法 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度 : 3.9 Å 詳細 データ登録者Jang DM / Jeon H / Eck MJ 資金援助 米国, 1件 詳細 詳細を隠すOrganization Grant number 国 National Institutes of Health/National Cancer Institute (NIH/NCI) R35CA242461-06 米国
引用ジャーナル : Nat Commun / 年 : 2025タイトル : Cryo-EM structures of CRAF/MEK1/14-3-3 complexes in autoinhibited and open-monomer states reveal features of RAF regulation.著者 : Dong Man Jang / Kayla Boxer / Byung Hak Ha / Emre Tkacik / Talya Levitz / Shaun Rawson / Rebecca J Metivier / Anna Schmoker / Hyesung Jeon / Michael J Eck / 要旨 : CRAF (RAF1) is one of three RAF-family kinases that initiate MAP kinase signaling in response to activated RAS and is essential for oncogenic signaling from mutant KRAS. Like BRAF, CRAF is regulated ... CRAF (RAF1) is one of three RAF-family kinases that initiate MAP kinase signaling in response to activated RAS and is essential for oncogenic signaling from mutant KRAS. Like BRAF, CRAF is regulated by 14-3-3 engagement and by intramolecular autoinhibitory interactions of its N-terminal regulatory region. Unlike BRAF, it is thought to require tyrosine phosphorylation in its N-terminal acidic (NtA) motif for full catalytic activation. Here we describe cryo-EM reconstructions of full-length CRAF in complex with MEK1 and a 14-3-3 dimer. These structures reveal a fully autoinhibited conformation analogous to that observed for BRAF and two "open monomer" states in which the inhibitory interactions of the CRD and 14-3-3 dimer are released or rearranged, but the kinase domain remains inactive. Structure-function studies of the NtA motif indicate that phosphorylation or acidic mutations in this segment increase catalytic activity by destabilizing the inactive conformation of the kinase domain. Collectively, these studies provide a structural foundation for understanding the shared and unique regulatory features of CRAF and will inform efforts to selectively block CRAF signaling in cancer. 履歴 登録 2024年12月20日 - ヘッダ(付随情報) 公開 2025年9月10日 - マップ公開 2025年9月10日 - 更新 2025年10月8日 - 現状 2025年10月8日 処理サイト : RCSB / 状態 : 公開
すべて表示 表示を減らす