登録情報 データベース : EMDB / ID : EMD-41816 ダウンロードとリンクタイトル Cryo-EM structure of the RAF1-HSP90-CDC37 complex in the closed state マップデータSharpened Map 詳細 試料複合体 : Complex of RAF1-HSP90-CDC37複合体 : Heat shock protein 90タンパク質・ペプチド : Heat shock protein 83複合体 : RAF1 & HSP90 co-chaperone CDC37タンパク質・ペプチド : RAF proto-oncogene serine/threonine-protein kinaseタンパク質・ペプチド : Hsp90 co-chaperone Cdc37, N-terminally processedリガンド : ADENOSINE-5'-TRIPHOSPHATEリガンド : MAGNESIUM ION 詳細 キーワード CRAF / RAF1 / HSP90 / CDC37 / SIGNALING PROTEIN-CHAPERONE complex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
regulation of type II interferon-mediated signaling pathway / HSP90-CDC37 chaperone complex / death-inducing signaling complex assembly / positive regulation of mitophagy in response to mitochondrial depolarization / intermediate filament cytoskeleton organization / type B pancreatic cell proliferation / regulation of Rho protein signal transduction / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / Rap1 signalling ... regulation of type II interferon-mediated signaling pathway / HSP90-CDC37 chaperone complex / death-inducing signaling complex assembly / positive regulation of mitophagy in response to mitochondrial depolarization / intermediate filament cytoskeleton organization / type B pancreatic cell proliferation / regulation of Rho protein signal transduction / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / Rap1 signalling / regulation of cell motility / insulin secretion involved in cellular response to glucose stimulus / protein kinase regulator activity / protein folding chaperone complex / Negative feedback regulation of MAPK pathway / post-transcriptional regulation of gene expression / GP1b-IX-V activation signalling / IFNG signaling activates MAPKs / regulation of cyclin-dependent protein serine/threonine kinase activity / Drug-mediated inhibition of ERBB2 signaling / Resistance of ERBB2 KD mutants to trastuzumab / Resistance of ERBB2 KD mutants to sapitinib / Resistance of ERBB2 KD mutants to tesevatinib / Resistance of ERBB2 KD mutants to neratinib / Resistance of ERBB2 KD mutants to osimertinib / Resistance of ERBB2 KD mutants to afatinib / Resistance of ERBB2 KD mutants to AEE788 / Resistance of ERBB2 KD mutants to lapatinib / Drug resistance in ERBB2 TMD/JMD mutants / ERBB2-ERBB3 signaling pathway / regulation of cell differentiation / face development / pseudopodium / somatic stem cell population maintenance / regulation of type I interferon-mediated signaling pathway / thyroid gland development / neurotrophin TRK receptor signaling pathway / extrinsic apoptotic signaling pathway via death domain receptors / MAP kinase kinase kinase activity / protein targeting / negative regulation of protein-containing complex assembly / RHOBTB2 GTPase cycle / Schwann cell development / type II interferon-mediated signaling pathway / activation of adenylate cyclase activity / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / Signaling by ERBB2 / heat shock protein binding / response to muscle stretch / myelination / CD209 (DC-SIGN) signaling / Constitutive Signaling by Overexpressed ERBB2 / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / insulin-like growth factor receptor signaling pathway / thymus development / ATP-dependent protein folding chaperone / Signaling by ERBB2 TMD/JMD mutants / RAF activation / wound healing / Constitutive Signaling by EGFRvIII / Signaling by high-kinase activity BRAF mutants / Hsp90 protein binding / Signaling by ERBB2 ECD mutants / MAP2K and MAPK activation / Signaling by ERBB2 KD Mutants / Regulation of necroptotic cell death / Stimuli-sensing channels / Downregulation of ERBB2 signaling / kinase binding / 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 / disordered domain specific binding / MAPK cascade / Signaling by BRAF and RAF1 fusions / unfolded protein binding / protein folding / insulin receptor signaling pathway / positive regulation of peptidyl-serine phosphorylation / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / protein-folding chaperone binding / cellular response to heat / scaffold protein binding / regulation of apoptotic process / mitochondrial outer membrane / positive regulation of MAPK cascade / protein stabilization / non-specific serine/threonine protein kinase / protein kinase activity / negative regulation of cell population proliferation / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / negative regulation of apoptotic process / apoptotic process / protein kinase binding / perinuclear region of cytoplasm / Golgi apparatus 類似検索 - 分子機能 Cdc37, C-terminal / Cdc37, Hsp90 binding / Cdc37, Hsp90-binding domain superfamily / Cdc37 C terminal domain / Cdc37 Hsp90 binding domain / Cdc37 C terminal domain / Cdc37 Hsp90 binding domain / Cdc37 N terminal kinase binding / Cdc37 / Cdc37, N-terminal domain ... Cdc37, C-terminal / Cdc37, Hsp90 binding / Cdc37, Hsp90-binding domain superfamily / Cdc37 C terminal domain / Cdc37 Hsp90 binding domain / Cdc37 C terminal domain / Cdc37 Hsp90 binding domain / Cdc37 N terminal kinase binding / Cdc37 / Cdc37, N-terminal domain / Cdc37 N terminal kinase binding / 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 / Heat shock protein Hsp90, conserved site / Heat shock hsp90 proteins family signature. / C1-like domain superfamily / HSP90, C-terminal domain / Heat shock protein Hsp90, N-terminal / Heat shock protein Hsp90 family / Hsp90 protein / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / Histidine kinase-like ATPases / Histidine kinase/HSP90-like ATPase / Histidine kinase/HSP90-like ATPase superfamily / Ubiquitin-like domain superfamily / Ribosomal protein S5 domain 2-type fold / 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 Heat shock protein 83 / RAF proto-oncogene serine/threonine-protein kinase / Hsp90 co-chaperone Cdc37 類似検索 - 構成要素生物種 Trichoplusia ni (イラクサキンウワバ) / Homo sapiens (ヒト)手法 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度 : 3.7 Å 詳細 データ登録者Finci LI / Simanshu DK 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) HHSN261200800001E 米国
引用ジャーナル : Commun Biol / 年 : 2024タイトル : Structural dynamics of RAF1-HSP90-CDC37 and HSP90 complexes reveal asymmetric client interactions and key structural elements.著者 : Lorenzo I Finci / Mayukh Chakrabarti / Gulcin Gulten / Joseph Finney / Carissa Grose / Tara Fox / Renbin Yang / Dwight V Nissley / Frank McCormick / Dominic Esposito / Trent E Balius / Dhirendra K Simanshu / 要旨 : RAF kinases are integral to the RAS-MAPK signaling pathway, and proper RAF1 folding relies on its interaction with the chaperone HSP90 and the cochaperone CDC37. Understanding the intricate molecular ... RAF kinases are integral to the RAS-MAPK signaling pathway, and proper RAF1 folding relies on its interaction with the chaperone HSP90 and the cochaperone CDC37. Understanding the intricate molecular interactions governing RAF1 folding is crucial for comprehending this process. Here, we present a cryo-EM structure of the closed-state RAF1-HSP90-CDC37 complex, where the C-lobe of the RAF1 kinase domain binds to one side of the HSP90 dimer, and an unfolded N-lobe segment of the RAF1 kinase domain threads through the center of the HSP90 dimer. CDC37 binds to the kinase C-lobe, mimicking the N-lobe with its HxNI motif. We also describe structures of HSP90 dimers without RAF1 and CDC37, displaying only N-terminal and middle domains, which we term the semi-open state. Employing 1 μs atomistic simulations, energetic decomposition, and comparative structural analysis, we elucidate the dynamics and interactions within these complexes. Our quantitative analysis reveals that CDC37 bridges the HSP90-RAF1 interaction, RAF1 binds HSP90 asymmetrically, and that HSP90 structural elements engage RAF1's unfolded region. Additionally, N- and C-terminal interactions stabilize HSP90 dimers, and molecular interactions in HSP90 dimers rearrange between the closed and semi-open states. Our findings provide valuable insight into the contributions of HSP90 and CDC37 in mediating client folding. 履歴 登録 2023年9月1日 - ヘッダ(付随情報) 公開 2024年3月13日 - マップ公開 2024年3月13日 - 更新 2024年3月13日 - 現状 2024年3月13日 処理サイト : RCSB / 状態 : 公開
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