登録情報 データベース : EMDB / ID : EMD-34084 ダウンロードとリンクタイトル Cryo-EM Structure of FGF23-FGFR4-aKlotho-HS Quaternary Complex マップデータ 詳細 試料複合体 : 1:2:1:1 FGF23-FGFR4-aKlotho-HS Quaternary Complex複合体 : FGFR4-aKlotho-HSタンパク質・ペプチド : Fibroblast growth factor receptor 4タンパク質・ペプチド : Klotho複合体 : FGF23タンパク質・ペプチド : Fibroblast growth factor 23リガンド : COPPER (II) IONリガンド : ZINC ION 詳細 キーワード FGF hormones / FGF Receptor / Klotho Co-Receptor / Heparan Sulfate Glycosaminoglycans / SIGNALING PROTEIN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
type 1 fibroblast growth factor receptor binding / FGFRL1 modulation of FGFR1 signaling / norepinephrine biosynthetic process / FGFR4 mutant receptor activation / betaKlotho-mediated ligand binding / positive regulation of vitamin D 24-hydroxylase activity / beta-glucuronidase / negative regulation of hormone secretion / FGFR1c and Klotho ligand binding and activation / beta-glucuronidase activity ... type 1 fibroblast growth factor receptor binding / FGFRL1 modulation of FGFR1 signaling / norepinephrine biosynthetic process / FGFR4 mutant receptor activation / betaKlotho-mediated ligand binding / positive regulation of vitamin D 24-hydroxylase activity / beta-glucuronidase / negative regulation of hormone secretion / FGFR1c and Klotho ligand binding and activation / beta-glucuronidase activity / regulation of phosphate transport / positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway / regulation of extracellular matrix disassembly / intracellular phosphate ion homeostasis / vitamin D catabolic process / response to sodium phosphate / phosphate ion homeostasis / negative regulation of bone mineralization / Signaling by activated point mutants of FGFR3 / FGFR3c ligand binding and activation / Phospholipase C-mediated cascade; FGFR3 / regulation of bile acid biosynthetic process / fibroblast growth factor receptor binding / cellular response to vitamin D / FGFR2c ligand binding and activation / Activated point mutants of FGFR2 / vitamin D binding / Phospholipase C-mediated cascade; FGFR2 / FGFR4 ligand binding and activation / energy reserve metabolic process / fibroblast growth factor receptor activity / Phospholipase C-mediated cascade; FGFR4 / Signaling by activated point mutants of FGFR1 / FGFR1c ligand binding and activation / Downstream signaling of activated FGFR1 / Phospholipase C-mediated cascade: FGFR1 / response to vitamin D / cellular response to leptin stimulus / cellular response to interleukin-6 / negative regulation of systemic arterial blood pressure / response to angiotensin / cellular response to parathyroid hormone stimulus / positive regulation of DNA biosynthetic process / PI-3K cascade:FGFR3 / beta-glucosidase activity / positive regulation of catalytic activity / fibroblast growth factor binding / PI-3K cascade:FGFR2 / PI-3K cascade:FGFR4 / PI-3K cascade:FGFR1 / response to magnesium ion / positive regulation of proteolysis / regulation of lipid metabolic process / PI3K Cascade / fibroblast growth factor receptor signaling pathway / negative regulation of osteoblast differentiation / calcium ion homeostasis / positive regulation of bone mineralization / SHC-mediated cascade:FGFR3 / SHC-mediated cascade:FGFR2 / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / SHC-mediated cascade:FGFR1 / FRS-mediated FGFR3 signaling / transport vesicle / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / FRS-mediated FGFR1 signaling / regulation of cell migration / Signaling by FGFR2 in disease / ERK1 and ERK2 cascade / Signaling by FGFR1 in disease / response to activity / cholesterol homeostasis / determination of adult lifespan / Negative regulation of FGFR3 signaling / Negative regulation of FGFR2 signaling / Negative regulation of FGFR4 signaling / animal organ morphogenesis / Post-translational protein phosphorylation / Negative regulation of FGFR1 signaling / growth factor activity / hormone activity / receptor protein-tyrosine kinase / Golgi lumen / peptidyl-tyrosine phosphorylation / Constitutive Signaling by Aberrant PI3K in Cancer / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / cell migration / PIP3 activates AKT signaling / glucose homeostasis / heparin binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / protein autophosphorylation / carbohydrate metabolic process / cell differentiation / positive regulation of ERK1 and ERK2 cascade / receptor complex 類似検索 - 分子機能 Fibroblast growth factor family / Fibroblast growth factor / Acidic and basic fibroblast growth factor family. / Fibroblast growth factor receptor family / Glycosyl hydrolases family 1, N-terminal conserved site / Glycosyl hydrolases family 1 N-terminal signature. / Cytokine IL1/FGF / Glycosyl hydrolase family 1 / Glycoside hydrolase family 1 / Immunoglobulin domain ... Fibroblast growth factor family / Fibroblast growth factor / Acidic and basic fibroblast growth factor family. / Fibroblast growth factor receptor family / Glycosyl hydrolases family 1, N-terminal conserved site / Glycosyl hydrolases family 1 N-terminal signature. / Cytokine IL1/FGF / Glycosyl hydrolase family 1 / Glycoside hydrolase family 1 / Immunoglobulin domain / Immunoglobulin I-set / Immunoglobulin I-set domain / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Immunoglobulin subtype / Immunoglobulin / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Glycoside hydrolase superfamily / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Immunoglobulin-like fold / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily 類似検索 - ドメイン・相同性 Fibroblast growth factor receptor 4 / Fibroblast growth factor 23 / Klotho 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 : 3.03 Å 詳細 データ登録者Mohammadi M / Chen L 資金援助 中国, 1件 詳細 詳細を隠すOrganization Grant number 国 National Natural Science Foundation of China (NSFC) OJQD2022007 中国
引用ジャーナル : Nature / 年 : 2023タイトル : Structural basis for FGF hormone signalling.著者 : Lingfeng Chen / Lili Fu / Jingchuan Sun / Zhiqiang Huang / Mingzhen Fang / Allen Zinkle / Xin Liu / Junliang Lu / Zixiang Pan / Yang Wang / Guang Liang / Xiaokun Li / Gaozhi Chen / Moosa Mohammadi / 要旨 : α/βKlotho coreceptors simultaneously engage fibroblast growth factor (FGF) hormones (FGF19, FGF21 and FGF23) and their cognate cell-surface FGF receptors (FGFR1-4) thereby stabilizing the endocrine ... α/βKlotho coreceptors simultaneously engage fibroblast growth factor (FGF) hormones (FGF19, FGF21 and FGF23) and their cognate cell-surface FGF receptors (FGFR1-4) thereby stabilizing the endocrine FGF-FGFR complex. However, these hormones still require heparan sulfate (HS) proteoglycan as an additional coreceptor to induce FGFR dimerization/activation and hence elicit their essential metabolic activities. To reveal the molecular mechanism underpinning the coreceptor role of HS, we solved cryo-electron microscopy structures of three distinct 1:2:1:1 FGF23-FGFR-αKlotho-HS quaternary complexes featuring the 'c' splice isoforms of FGFR1 (FGFR1c), FGFR3 (FGFR3c) or FGFR4 as the receptor component. These structures, supported by cell-based receptor complementation and heterodimerization experiments, reveal that a single HS chain enables FGF23 and its primary FGFR within a 1:1:1 FGF23-FGFR-αKlotho ternary complex to jointly recruit a lone secondary FGFR molecule leading to asymmetric receptor dimerization and activation. However, αKlotho does not directly participate in recruiting the secondary receptor/dimerization. We also show that the asymmetric mode of receptor dimerization is applicable to paracrine FGFs that signal solely in an HS-dependent fashion. Our structural and biochemical data overturn the current symmetric FGFR dimerization paradigm and provide blueprints for rational discovery of modulators of FGF signalling as therapeutics for human metabolic diseases and cancer. 履歴 登録 2022年8月13日 - ヘッダ(付随情報) 公開 2023年6月14日 - マップ公開 2023年6月14日 - 更新 2023年7月5日 - 現状 2023年7月5日 処理サイト : PDBj / 状態 : 公開
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