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基本情報
登録情報 | データベース: PDB / ID: 7ysh | ||||||
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タイトル | Cryo-EM Structure of FGF23-FGFR1c-aKlotho-HS Quaternary Complex | ||||||
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![]() | SIGNALING PROTEIN / FGF hormones / FGF Receptor / Klotho Co-Receptor / Heparan Sulfate Glycosaminoglycans | ||||||
機能・相同性 | ![]() type 1 fibroblast growth factor receptor binding / FGFRL1 modulation of FGFR1 signaling / norepinephrine biosynthetic process / positive regulation of vitamin D 24-hydroxylase activity / beta-glucuronidase / negative regulation of hormone secretion / beta-glucuronidase activity / FGFR1c and Klotho ligand binding and activation / regulation of phosphate transport / positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway ...type 1 fibroblast growth factor receptor binding / FGFRL1 modulation of FGFR1 signaling / norepinephrine biosynthetic process / positive regulation of vitamin D 24-hydroxylase activity / beta-glucuronidase / negative regulation of hormone secretion / beta-glucuronidase activity / FGFR1c and Klotho ligand binding and activation / regulation of phosphate transport / positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway / 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 / 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 / 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 / PI-3K cascade:FGFR3 / beta-glucosidase activity / fibroblast growth factor binding / PI-3K cascade:FGFR2 / PI-3K cascade:FGFR4 / PI-3K cascade:FGFR1 / response to magnesium ion / PI3K Cascade / negative regulation of osteoblast differentiation / fibroblast growth factor receptor signaling pathway / calcium ion homeostasis / positive regulation of bone mineralization / SHC-mediated cascade:FGFR3 / SHC-mediated cascade:FGFR2 / SHC-mediated cascade:FGFR4 / SHC-mediated cascade:FGFR1 / FRS-mediated FGFR3 signaling / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / regulation of cell migration / Signaling by FGFR3 in disease / FRS-mediated FGFR1 signaling / Signaling by FGFR2 in disease / ERK1 and ERK2 cascade / Signaling by FGFR1 in disease / response to activity / determination of adult lifespan / Negative regulation of FGFR3 signaling / Negative regulation of FGFR2 signaling / Negative regulation of FGFR4 signaling / animal organ morphogenesis / Negative regulation of FGFR1 signaling / Post-translational protein phosphorylation / growth factor activity / hormone activity / receptor protein-tyrosine kinase / Golgi lumen / 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) / PIP3 activates AKT signaling / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / carbohydrate metabolic process / positive regulation of ERK1 and ERK2 cascade / cell differentiation / positive regulation of protein phosphorylation / apical plasma membrane / endoplasmic reticulum lumen / positive regulation of cell population proliferation / positive regulation of gene expression / positive regulation of DNA-templated transcription / extracellular space / extracellular exosome / extracellular region / membrane / plasma membrane / cytoplasm 類似検索 - 分子機能 | ||||||
生物種 | ![]() | ||||||
手法 | 電子顕微鏡法 / 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 2.74 Å | ||||||
![]() | Mohammadi, M. / Chen, L. | ||||||
資金援助 | ![]()
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![]() | ![]() 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. | ||||||
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構造の表示
構造ビューア | 分子: ![]() ![]() |
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ダウンロードとリンク
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ダウンロード
PDBx/mmCIF形式 | ![]() | 286.7 KB | 表示 | ![]() |
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PDB形式 | ![]() | 230.3 KB | 表示 | ![]() |
PDBx/mmJSON形式 | ![]() | ツリー表示 | ![]() | |
その他 | ![]() |
-検証レポート
文書・要旨 | ![]() | 1.2 MB | 表示 | ![]() |
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文書・詳細版 | ![]() | 1.3 MB | 表示 | |
XML形式データ | ![]() | 52.3 KB | 表示 | |
CIF形式データ | ![]() | 78.1 KB | 表示 | |
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
-関連構造データ
関連構造データ | ![]() 34075MC ![]() 7ysuC ![]() 7yswC M: このデータのモデリングに利用したマップデータ C: 同じ文献を引用 ( |
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類似構造データ | 類似検索 - 機能・相同性 ![]() |
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リンク
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集合体
登録構造単位 | ![]()
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要素
-タンパク質 , 3種, 4分子 ABDE
#1: タンパク質 | 分子量: 109164.797 Da / 分子数: 1 / 由来タイプ: 組換発現 / 詳細: Klotho co-receptor / 由来: (組換発現) ![]() ![]() |
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#2: タンパク質 | 分子量: 30367.006 Da / 分子数: 1 / 由来タイプ: 組換発現 / 詳細: FGF23 / 由来: (組換発現) ![]() ![]() ![]() |
#3: タンパク質 | 分子量: 26373.006 Da / 分子数: 2 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() 参照: UniProt: P11362-20, receptor protein-tyrosine kinase |
-糖 , 1種, 1分子
#4: 多糖 | 2-deoxy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranose-(1-4)-2-O-sulfo-alpha-L-idopyranuronic acid- ...2-deoxy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranose-(1-4)-2-O-sulfo-alpha-L-idopyranuronic acid-(1-4)-2-deoxy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranose-(1-4)-2-O-sulfo-alpha-L-idopyranuronic acid-(1-4)-2-deoxy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranose-(1-4)-2-O-sulfo-alpha-L-idopyranuronic acid-(1-4)-2-deoxy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranose-(1-4)-2-O-sulfo-alpha-L-idopyranuronic acid-(1-4)-2-deoxy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranose タイプ: oligosaccharide / 分子量: 2649.180 Da / 分子数: 1 / 由来タイプ: 組換発現 |
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-非ポリマー , 2種, 2分子 ![](data/chem/img/ZN.gif)
![](data/chem/img/CU.gif)
![](data/chem/img/CU.gif)
#5: 化合物 | ChemComp-ZN / |
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#6: 化合物 | ChemComp-CU / |
-詳細
研究の焦点であるリガンドがあるか | Y |
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-実験情報
-実験
実験 | 手法: 電子顕微鏡法 |
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EM実験 | 試料の集合状態: PARTICLE / 3次元再構成法: 単粒子再構成法 |
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試料調製
構成要素 | 名称: 1:2:1:1 FGF23-FGFR1c-aKlotho-HS Quaternary Complex / タイプ: COMPLEX / Entity ID: #1-#3 / 由来: RECOMBINANT |
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由来(天然) | 生物種: ![]() |
由来(組換発現) | 生物種: ![]() |
緩衝液 | pH: 7.5 |
試料 | 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES |
急速凍結 | 凍結剤: ETHANE |
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電子顕微鏡撮影
実験機器 | ![]() モデル: Talos Arctica / 画像提供: FEI Company |
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顕微鏡 | モデル: FEI TALOS ARCTICA |
電子銃 | 電子線源: ![]() |
電子レンズ | モード: BRIGHT FIELD / 最大 デフォーカス(公称値): 2200 nm / 最小 デフォーカス(公称値): 700 nm |
撮影 | 電子線照射量: 50.37 e/Å2 / フィルム・検出器のモデル: GATAN K3 (6k x 4k) |
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解析
ソフトウェア | 名称: PHENIX / バージョン: 1.14_3260: / 分類: 精密化 |
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CTF補正 | タイプ: NONE |
3次元再構成 | 解像度: 2.74 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 1497967 / 対称性のタイプ: POINT |