登録情報 データベース : EMDB / ID : EMD-27435 ダウンロードとリンクタイトル Active FLCN GAP complex マップデータ 詳細 試料複合体 : Cryo-EM structure of the Active FLCN GAP compex複合体 : Rag-Ragulator複合体 : FLCN:SLC-FNIP2タンパク質・ペプチド : x 1種リガンド : x 3種 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
asparagine transport / L-asparagine transmembrane transporter activity / sterol sensor activity / negative regulation of cell proliferation involved in kidney development / L-arginine transmembrane transport / L-arginine transmembrane transporter activity / negative regulation of post-translational protein modification / cell proliferation involved in kidney development / regulation of cholesterol import / positive regulation of protein localization to lysosome ... asparagine transport / L-asparagine transmembrane transporter activity / sterol sensor activity / negative regulation of cell proliferation involved in kidney development / L-arginine transmembrane transport / L-arginine transmembrane transporter activity / negative regulation of post-translational protein modification / cell proliferation involved in kidney development / regulation of cholesterol import / positive regulation of protein localization to lysosome / regulation of cell-substrate junction organization / glutamine transport / L-glutamine transmembrane transporter activity / Gtr1-Gtr2 GTPase complex / regulation of cholesterol efflux / positive regulation of RNA polymerase II regulatory region sequence-specific DNA binding / L-amino acid transmembrane transporter activity / FNIP-folliculin RagC/D GAP / Ragulator complex / negative regulation of brown fat cell differentiation / regulation of Ras protein signal transduction / L-leucine transmembrane transporter activity / amino acid transmembrane transport / protein localization to cell junction / regulation of TORC1 signaling / negative regulation of lysosome organization / regulation of pro-B cell differentiation / amino acid transmembrane transporter activity / protein localization to lysosome / TORC1 signaling / regulation of TOR signaling / endosome organization / ATPase inhibitor activity / MTOR signalling / Amino acids regulate mTORC1 / fibroblast migration / lysosome localization / Energy dependent regulation of mTOR by LKB1-AMPK / protein localization to membrane / kinase activator activity / enzyme-substrate adaptor activity / negative regulation of glycolytic process / enzyme inhibitor activity / negative regulation of TOR signaling / arginine binding / cell-cell junction assembly / negative regulation of cold-induced thermogenesis / negative regulation of Rho protein signal transduction / azurophil granule membrane / endosomal transport / regulation of cell size / Macroautophagy / small GTPase-mediated signal transduction / lysosome organization / cholesterol binding / positive regulation of transforming growth factor beta receptor signaling pathway / RHOJ GTPase cycle / RHOQ GTPase cycle / mTORC1-mediated signalling / cellular response to nutrient levels / tertiary granule membrane / CDC42 GTPase cycle / glutathione transferase / RHOH GTPase cycle / hemopoiesis / ficolin-1-rich granule membrane / centriolar satellite / glutathione transferase activity / RHOG GTPase cycle / positive regulation of TOR signaling / regulation of receptor recycling / TOR signaling / RAC2 GTPase cycle / RAC3 GTPase cycle / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / response to amino acid / positive regulation of autophagy / specific granule membrane / energy homeostasis / positive regulation of intrinsic apoptotic signaling pathway / protein-membrane adaptor activity / positive regulation of TORC1 signaling / tumor necrosis factor-mediated signaling pathway / RAC1 GTPase cycle / ERK1 and ERK2 cascade / cellular response to amino acid starvation / cellular response to starvation / negative regulation of autophagy / viral genome replication / intrinsic apoptotic signaling pathway / RNA splicing / glutathione metabolic process / phosphatidylinositol 3-kinase/protein kinase B signal transduction / GTPase activator activity / transforming growth factor beta receptor signaling pathway / guanyl-nucleotide exchange factor activity / epithelial cell proliferation / Regulation of PTEN gene transcription / positive regulation of interleukin-8 production / cholesterol homeostasis 類似検索 - 分子機能 Amino acid transporter, transmembrane domain / Folliculin / Folliculin, DENN domain / Folliculin, DENN domain, C-terminal superfamily / Transmembrane amino acid transporter protein / Folliculin C-terminal domain / Folliculin-interacting protein family / Folliculin-interacting protein, N-terminal domain / Folliculin-interacting protein, middle domain / Folliculin-interacting protein, C-terminal domain ... Amino acid transporter, transmembrane domain / Folliculin / Folliculin, DENN domain / Folliculin, DENN domain, C-terminal superfamily / Transmembrane amino acid transporter protein / Folliculin C-terminal domain / Folliculin-interacting protein family / Folliculin-interacting protein, N-terminal domain / Folliculin-interacting protein, middle domain / Folliculin-interacting protein, C-terminal domain / Folliculin-interacting protein N-terminus / Folliculin-interacting protein middle domain / Folliculin-interacting protein C-terminus / Tripartite DENN domain, FNIP1/2-type / Tripartite DENN FNIP1/2-type domain profile. / Folliculin/SMCR8, longin domain / Folliculin/SMCR8, tripartite DENN domain / Vesicle coat protein involved in Golgi to plasma membrane transport / Tripartite DENN FLCN/SMCR8-type domain profile. / LAMTOR1/MEH1 / Late endosomal/lysosomal adaptor and MAPK and MTOR activator / Late endosomal/lysosomal adaptor and MAPK and MTOR activator / Ragulator complex protein LAMTOR4 / Ragulator complex protein LAMTOR3 / Ragulator complex protein LAMTOR5 / RagA/B / Mitogen-activated protein kinase kinase 1 interacting / Ragulator complex protein LAMTOR5 / Mitogen-activated protein kinase kinase 1 interacting / Gtr1/RagA G protein / RagC/D / Gtr1/RagA G protein conserved region / Ragulator complex protein LAMTOR2-like / Roadblock/LAMTOR2 domain / Roadblock/LC7 domain / Roadblock/LC7 domain / Glutathione S-transferase, C-terminal domain / Glutathione S-transferase, N-terminal domain / Glutathione transferase family / Glutathione S-transferase, C-terminal / Soluble glutathione S-transferase N-terminal domain profile. / Glutathione S-transferase, C-terminal-like / Soluble glutathione S-transferase C-terminal domain profile. / Glutathione S-transferase, N-terminal / Glutathione S-transferase, C-terminal domain superfamily / Thioredoxin-like superfamily / P-loop containing nucleoside triphosphate hydrolase 類似検索 - ドメイン・相同性 Ragulator complex protein LAMTOR5 / Glutathione S-transferase class-mu 26 kDa isozyme / Ragulator complex protein LAMTOR4 / Ragulator complex protein LAMTOR1 / Ras-related GTP-binding protein A / Neutral amino acid transporter 9 / Folliculin / Ras-related GTP-binding protein C / Folliculin-interacting protein 2 / Ragulator complex protein LAMTOR3 / Ragulator complex protein LAMTOR2 類似検索 - 構成要素生物種 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 : 3.53 Å 詳細 データ登録者Jansen RM / Hurley JH 資金援助 米国, イタリア, 4件 詳細 詳細を隠すOrganization Grant number 国 National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS) GM111730 米国 National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS) GM130995 米国 National Science Foundation (NSF, United States) 米国 Italian Association for Cancer Research イタリア
引用ジャーナル : Sci Adv / 年 : 2022タイトル : Structural basis for FLCN RagC GAP activation in MiT-TFE substrate-selective mTORC1 regulation.著者 : Rachel M Jansen / Roberta Peruzzo / Simon A Fromm / Adam L Yokom / Roberto Zoncu / James H Hurley / 要旨 : The mechanistic target of rapamycin complex 1 (mTORC1) regulates cell growth and catabolism in response to nutrients through phosphorylation of key substrates. The tumor suppressor folliculin (FLCN) ... The mechanistic target of rapamycin complex 1 (mTORC1) regulates cell growth and catabolism in response to nutrients through phosphorylation of key substrates. The tumor suppressor folliculin (FLCN) is a RagC/D guanosine triphosphatase (GTPase)-activating protein (GAP) that regulates mTORC1 phosphorylation of MiT-TFE transcription factors, controlling lysosome biogenesis and autophagy. We determined the cryo-electron microscopy structure of the active FLCN complex (AFC) containing FLCN, FNIP2, the N-terminal tail of SLC38A9, the RagA:RagC GTPase dimer, and the Ragulator scaffold. Relative to the inactive lysosomal FLCN complex structure, FLCN reorients by 90°, breaks contact with RagA, and makes previously unseen contacts with RagC that position its Arg finger for catalysis. Disruption of the AFC-specific interfaces of FLCN and FNIP2 with RagC eliminated GAP activity and led to nuclear retention of TFE3, with no effect on mTORC1 substrates S6K or 4E-BP1. The structure provides a basis for regulation of an mTORC1 substrate-specific pathway and a roadmap to discover MiT-TFE family selective mTORC1 antagonists. 履歴 登録 2022年6月25日 - ヘッダ(付随情報) 公開 2022年9月28日 - マップ公開 2022年9月28日 - 更新 2022年9月28日 - 現状 2022年9月28日 処理サイト : RCSB / 状態 : 公開
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