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- PDB-7ysh: Cryo-EM Structure of FGF23-FGFR1c-aKlotho-HS Quaternary Complex -

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Basic information

Entry
Database: PDB / ID: 7ysh
TitleCryo-EM Structure of FGF23-FGFR1c-aKlotho-HS Quaternary Complex
Components
  • Fibroblast growth factor 23
  • Isoform 20 of Fibroblast growth factor receptor 1
  • Klotho
KeywordsSIGNALING PROTEIN / FGF hormones / FGF Receptor / Klotho Co-Receptor / Heparan Sulfate Glycosaminoglycans
Function / homology
Function and homology information


type 1 fibroblast growth factor receptor binding / norepinephrine biosynthetic process / FGFRL1 modulation of FGFR1 signaling / positive regulation of vitamin D 24-hydroxylase activity / beta-glucuronidase / regulation of phosphate transport / FGFR1c and Klotho ligand binding and activation / negative regulation of hormone secretion / positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway / beta-glucuronidase activity ...type 1 fibroblast growth factor receptor binding / norepinephrine biosynthetic process / FGFRL1 modulation of FGFR1 signaling / positive regulation of vitamin D 24-hydroxylase activity / beta-glucuronidase / regulation of phosphate transport / FGFR1c and Klotho ligand binding and activation / negative regulation of hormone secretion / positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway / beta-glucuronidase activity / response to sodium phosphate / vitamin D catabolic process / 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 / intracellular phosphate ion homeostasis / FGFR2c ligand binding and activation / Activated point mutants of FGFR2 / FGFR4 ligand binding and activation / Phospholipase C-mediated cascade; FGFR2 / Phospholipase C-mediated cascade; FGFR4 / cellular response to vitamin D / vitamin D binding / Signaling by activated point mutants of FGFR1 / FGFR1c ligand binding and activation / Downstream signaling of activated FGFR1 / Phospholipase C-mediated cascade: FGFR1 / energy reserve metabolic process / cellular response to leptin stimulus / response to vitamin D / 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 / PI-3K cascade:FGFR2 / PI-3K cascade:FGFR4 / PI-3K cascade:FGFR1 / fibroblast growth factor binding / response to magnesium ion / PI3K Cascade / fibroblast growth factor receptor signaling pathway / negative regulation of osteoblast differentiation / positive regulation of bone mineralization / SHC-mediated cascade:FGFR3 / SHC-mediated cascade:FGFR2 / SHC-mediated cascade:FGFR4 / SHC-mediated cascade:FGFR1 / calcium ion homeostasis / FRS-mediated FGFR3 signaling / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / FRS-mediated FGFR1 signaling / neurogenesis / Signaling by FGFR2 in disease / Signaling by FGFR1 in disease / ERK1 and ERK2 cascade / regulation of cell migration / response to activity / determination of adult lifespan / Post-translational protein phosphorylation / Negative regulation of FGFR3 signaling / growth factor activity / Negative regulation of FGFR2 signaling / Negative regulation of FGFR4 signaling / Negative regulation of FGFR1 signaling / receptor protein-tyrosine kinase / hormone activity / Golgi lumen / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / Constitutive Signaling by Aberrant PI3K in Cancer / PIP3 activates AKT signaling / RAF/MAP kinase cascade / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / carbohydrate metabolic process / positive regulation of ERK1 and ERK2 cascade / positive regulation of MAPK cascade / apical plasma membrane / endoplasmic reticulum lumen / positive regulation of cell population proliferation / positive regulation of DNA-templated transcription / extracellular space / extracellular exosome / extracellular region / membrane / plasma membrane / cytoplasm
Similarity search - Function
Fibroblast growth factor family / Fibroblast growth factor / Acidic and basic fibroblast growth factor 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 / Glycosidases / Glycoside hydrolase superfamily ...Fibroblast growth factor family / Fibroblast growth factor / Acidic and basic fibroblast growth factor 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 / Glycosidases / Glycoside hydrolase superfamily / TIM Barrel / Alpha-Beta Barrel / Alpha Beta
Similarity search - Domain/homology
COPPER (II) ION / Isoform 20 of Fibroblast growth factor receptor 1 / Fibroblast growth factor 23 / Klotho
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.74 Å
AuthorsMohammadi, M. / Chen, L.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)OJQD2022007 China
CitationJournal: Nature / Year: 2023
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
DepositionAug 12, 2022Deposition site: PDBJ / Processing site: PDBJ
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Klotho
B: Fibroblast growth factor 23
D: Isoform 20 of Fibroblast growth factor receptor 1
E: Isoform 20 of Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)195,0567
Polymers192,2784
Non-polymers2,7783
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 3 types, 4 molecules ABDE

#1: Protein Klotho


Mass: 109164.797 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Klotho co-receptor / Source: (gene. exp.) Homo sapiens (human) / Gene: KL / Cell line (production host): HEK293S GnTI- / Production host: Homo sapiens (human) / References: UniProt: Q9UEF7, beta-glucuronidase
#2: Protein Fibroblast growth factor 23 / FGF-23 / Phosphatonin / Tumor-derived hypophosphatemia-inducing factor


Mass: 30367.006 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: FGF23 / Source: (gene. exp.) Homo sapiens (human) / Gene: FGF23, HYPF, UNQ3027/PRO9828 / Cell line (production host): HEK293S GnTI- / Production host: Escherichia coli (E. coli) / References: UniProt: Q9GZV9
#3: Protein Isoform 20 of Fibroblast growth factor receptor 1 / FGFR-1 / Basic fibroblast growth factor receptor 1 / BFGFR / bFGF-R-1 / Fms-like tyrosine kinase 2 ...FGFR-1 / Basic fibroblast growth factor receptor 1 / BFGFR / bFGF-R-1 / Fms-like tyrosine kinase 2 / FLT-2 / N-sam / Proto-oncogene c-Fgr / "c" splice isoform of FGFR1 / FGFR1c


Mass: 26373.006 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FGFR1, BFGFR, CEK, FGFBR, FLG, FLT2, HBGFR / Cell line (production host): HEK293S GnTI- / Production host: Homo sapiens (human)
References: UniProt: P11362-20, receptor protein-tyrosine kinase

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Sugars , 1 types, 1 molecules

#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


Type: oligosaccharide / Mass: 2649.180 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
WURCS=2.0/2,9,8/[a2122h-1a_1-5_2*NSO/3=O/3=O_6*OSO/3=O/3=O][a2121A-1a_1-5_2*OSO/3=O/3=O]/1-2-1-2-1-2-1-2-1/a4-b1_b4-c1_c4-d1_d4-e1_e4-f1_f4-g1_g4-h1_h4-i1WURCSPDB2Glycan 1.1.0
[][a-D-GlcpNSO36SO3]{[(4+1)][a-L-IdopA2SO3]{[(4+1)][a-D-GlcpNSO36SO3]{[(4+1)][a-L-IdopA2SO3]{[(4+1)][a-D-GlcpNSO36SO3]{[(4+1)][a-L-IdopA2SO3]{[(4+1)][a-D-GlcpNSO36SO3]{[(4+1)][a-L-IdopA2SO3]{[(4+1)][a-D-GlcpNSO36SO3]{}}}}}}}}}LINUCSPDB-CARE

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Non-polymers , 2 types, 2 molecules

#5: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-CU / COPPER (II) ION


Mass: 63.546 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cu / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: 1:2:1:1 FGF23-FGFR1c-aKlotho-HS Quaternary Complex / Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 700 nm
Image recordingElectron dose: 50.37 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.14_3260: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: NONE
3D reconstructionResolution: 2.74 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1497967 / Symmetry type: POINT

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