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Open data
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Basic information
Entry | Database: PDB / ID: 7ysu | ||||||
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Title | Cryo-EM Structure of FGF23-FGFR3c-aKlotho-HS Quaternary Complex | ||||||
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![]() | SIGNALING PROTEIN / FGF hormones / FGF Receptor / Klotho Co-Receptor / Heparan Sulfate Glycosaminoglycans | ||||||
Function / homology | ![]() fibroblast growth factor receptor apoptotic signaling pathway / t(4;14) translocations of FGFR3 / negative regulation of developmental growth / Signaling by FGFR3 fusions in cancer / type 1 fibroblast growth factor receptor binding / bone maturation / FGFRL1 modulation of FGFR1 signaling / norepinephrine biosynthetic process / positive regulation of vitamin D 24-hydroxylase activity / beta-glucuronidase ...fibroblast growth factor receptor apoptotic signaling pathway / t(4;14) translocations of FGFR3 / negative regulation of developmental growth / Signaling by FGFR3 fusions in cancer / type 1 fibroblast growth factor receptor binding / bone maturation / FGFRL1 modulation of FGFR1 signaling / norepinephrine biosynthetic process / positive regulation of vitamin D 24-hydroxylase activity / beta-glucuronidase / chondrocyte proliferation / negative regulation of hormone secretion / FGFR1c and Klotho ligand binding and activation / beta-glucuronidase activity / regulation of phosphate transport / endochondral bone growth / positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway / intracellular phosphate ion homeostasis / vitamin D catabolic process / FGFR3b ligand binding and activation / response to sodium phosphate / negative regulation of bone mineralization / phosphate ion homeostasis / 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 / Phospholipase C-mediated cascade; FGFR2 / vitamin D binding / FGFR4 ligand binding and activation / fibroblast growth factor receptor activity / endochondral ossification / Phospholipase C-mediated cascade; FGFR4 / Signaling by activated point mutants of FGFR1 / FGFR1c ligand binding and activation / energy reserve metabolic process / Downstream signaling of activated FGFR1 / Phospholipase C-mediated cascade: FGFR1 / positive regulation of phospholipase activity / response to vitamin D / cellular response to leptin stimulus / cellular response to interleukin-6 / negative regulation of systemic arterial blood pressure / response to angiotensin / bone morphogenesis / cellular response to parathyroid hormone stimulus / beta-glucosidase activity / negative regulation of osteoblast differentiation / PI-3K cascade:FGFR3 / PI-3K cascade:FGFR2 / bone mineralization / fibroblast growth factor binding / PI-3K cascade:FGFR4 / PI-3K cascade:FGFR1 / cell surface receptor signaling pathway via JAK-STAT / response to magnesium ion / PI3K Cascade / fibroblast growth factor receptor signaling pathway / chondrocyte differentiation / positive regulation of bone mineralization / SHC-mediated cascade:FGFR3 / SHC-mediated cascade:FGFR2 / calcium ion homeostasis / SHC-mediated cascade:FGFR4 / SHC-mediated cascade:FGFR1 / FRS-mediated FGFR3 signaling / positive regulation of tyrosine phosphorylation of STAT protein / FRS-mediated FGFR2 signaling / transport vesicle / Signaling by FGFR3 in disease / FRS-mediated FGFR4 signaling / FRS-mediated FGFR1 signaling / Signaling by FGFR2 in disease / ERK1 and ERK2 cascade / Signaling by FGFR1 in disease / regulation of cell migration / response to activity / skeletal system development / determination of adult lifespan / receptor protein-tyrosine kinase / Negative regulation of FGFR3 signaling / animal organ morphogenesis / Negative regulation of FGFR2 signaling / Post-translational protein phosphorylation / Negative regulation of FGFR4 signaling / Negative regulation of FGFR1 signaling / growth factor activity / hormone activity / Constitutive Signaling by Aberrant PI3K in Cancer / Golgi lumen / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / MAPK cascade / PIP3 activates AKT signaling / cell-cell signaling / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / protein tyrosine kinase activity Similarity search - Function | ||||||
Biological species | ![]() | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å | ||||||
![]() | Mohammadi, M. / Chen, L. | ||||||
Funding support | ![]()
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![]() | ![]() Title: Structural basis for FGF hormone signalling. Authors: 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 / ![]() ![]() Abstract: 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. | ||||||
History |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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PDBx/mmCIF format | ![]() | 316.7 KB | Display | ![]() |
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PDB format | ![]() | 255.1 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
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-Related structure data
Related structure data | ![]() 34082MC ![]() 7yshC ![]() 7yswC M: map data used to model this data C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
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Assembly
Deposited unit | ![]()
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Components
-Fibroblast growth factor ... , 2 types, 3 molecules CEB
#2: Protein | Mass: 23358.441 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() References: UniProt: P22607, receptor protein-tyrosine kinase #3: Protein | | Mass: 20450.064 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
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-Protein / Sugars , 2 types, 2 molecules A
#1: Protein | Mass: 108404.914 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
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#4: Polysaccharide | 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-(1-4)-2-O-sulfo-alpha-L-idopyranuronic acid Type: oligosaccharide / Mass: 2905.368 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source |
-Non-polymers , 2 types, 2 molecules ![](data/chem/img/ZN.gif)
![](data/chem/img/CU.gif)
![](data/chem/img/CU.gif)
#5: Chemical | ChemComp-ZN / |
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#6: Chemical | ChemComp-CU / |
-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
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Sample preparation
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Buffer solution | pH: 7.5 | ||||||||||||||||||||||||
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | ||||||||||||||||||||||||
Vitrification | Cryogen name: ETHANE |
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Electron microscopy imaging
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2800 nm / Nominal defocus min: 600 nm |
Image recording | Electron dose: 72.44 e/Å2 / Film or detector model: GATAN K2 BASE (4k x 4k) |
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Processing
Software | Name: PHENIX / Version: 1.20.1_4487: / Classification: refinement | ||||||||||||||||||||||||
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CTF correction | Type: NONE | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 291540 / Symmetry type: POINT | ||||||||||||||||||||||||
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