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- PDB-7ysu: Cryo-EM Structure of FGF23-FGFR3c-aKlotho-HS Quaternary Complex -

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Basic information

Entry
Database: PDB / ID: 7ysu
TitleCryo-EM Structure of FGF23-FGFR3c-aKlotho-HS Quaternary Complex
Components
  • (Fibroblast growth factor ...) x 2
  • Klotho
KeywordsSIGNALING PROTEIN / FGF hormones / FGF Receptor / Klotho Co-Receptor / Heparan Sulfate Glycosaminoglycans
Function / homology
Function and homology information


: / t(4;14) translocations of FGFR3 / negative regulation of developmental growth / fibroblast growth factor receptor apoptotic signaling pathway / Signaling by FGFR3 fusions in cancer / bone maturation / type 1 fibroblast growth factor receptor binding / FGFRL1 modulation of FGFR1 signaling / norepinephrine biosynthetic process / beta-glucuronidase ...: / t(4;14) translocations of FGFR3 / negative regulation of developmental growth / fibroblast growth factor receptor apoptotic signaling pathway / Signaling by FGFR3 fusions in cancer / bone maturation / type 1 fibroblast growth factor receptor binding / FGFRL1 modulation of FGFR1 signaling / norepinephrine biosynthetic process / beta-glucuronidase / chondrocyte proliferation / regulation of phosphate transport / FGFR1c and Klotho ligand binding and activation / negative regulation of hormone secretion / endochondral bone growth / positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway / beta-glucuronidase activity / FGFR3b ligand binding and activation / vitamin D catabolic process / response to sodium phosphate / negative regulation of bone mineralization / positive regulation of phospholipase activity / Signaling by activated point mutants of FGFR3 / FGFR3c ligand binding and activation / phosphate ion homeostasis / Phospholipase C-mediated cascade; FGFR3 / fibroblast growth factor receptor binding / FGFR2c ligand binding and activation / Activated point mutants of FGFR2 / FGFR4 ligand binding and activation / Phospholipase C-mediated cascade; FGFR2 / endochondral ossification / Phospholipase C-mediated cascade; FGFR4 / vitamin D binding / Signaling by activated point mutants of FGFR1 / fibroblast growth factor receptor activity / cellular response to vitamin D / FGFR1c ligand binding and activation / intracellular phosphate ion homeostasis / energy reserve metabolic process / Downstream signaling of activated FGFR1 / Phospholipase C-mediated cascade: FGFR1 / response to angiotensin / cellular response to leptin stimulus / negative regulation of systemic arterial blood pressure / bone morphogenesis / cellular response to interleukin-6 / response to vitamin D / positive regulation of tyrosine phosphorylation of STAT protein / 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 / bone mineralization / fibroblast growth factor binding / response to magnesium ion / PI3K Cascade / fibroblast growth factor receptor signaling pathway / cell surface receptor signaling pathway via JAK-STAT / negative regulation of osteoblast differentiation / 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 / transport vesicle / FRS-mediated FGFR3 signaling / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / FRS-mediated FGFR1 signaling / Signaling by FGFR3 in disease / neurogenesis / ERK1 and ERK2 cascade / Signaling by FGFR2 in disease / Signaling by FGFR1 in disease / regulation of cell migration / response to activity / skeletal system development / 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 / cell-cell signaling / PIP3 activates AKT signaling / MAPK cascade / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / protein tyrosine kinase activity
Similarity search - Function
Fibroblast growth factor receptor 3 transmembrane 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 ...Fibroblast growth factor receptor 3 transmembrane 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 / Glycosidases / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Immunoglobulin subtype / Immunoglobulin / Tyrosine-protein kinase, active site / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Glycoside hydrolase superfamily / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / TIM Barrel / Alpha-Beta Barrel / 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 / Alpha Beta
Similarity search - Domain/homology
COPPER (II) ION / Fibroblast growth factor receptor 3 / Fibroblast growth factor 23 / Klotho
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 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
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Klotho
C: Fibroblast growth factor receptor 3
E: Fibroblast growth factor receptor 3
B: Fibroblast growth factor 23
hetero molecules


Theoretical massNumber of molelcules
Total (without water)178,6067
Polymers175,5724
Non-polymers3,0343
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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Fibroblast growth factor ... , 2 types, 3 molecules CEB

#2: Protein Fibroblast growth factor receptor 3 / FGFR-3


Mass: 23358.441 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FGFR3, JTK4 / Cell line (production host): HEK293S GnTI- / Production host: Homo sapiens (human)
References: UniProt: P22607, receptor protein-tyrosine kinase
#3: Protein Fibroblast growth factor 23 / FGF-23 / Phosphatonin / Tumor-derived hypophosphatemia-inducing factor


Mass: 20450.064 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FGF23, HYPF, UNQ3027/PRO9828 / Production host: Escherichia coli (E. coli) / References: UniProt: Q9GZV9

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Protein / Sugars , 2 types, 2 molecules A

#1: Protein Klotho


Mass: 108404.914 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KL / Cell line (production host): HEK293S GnTI- / Production host: Homo sapiens (human) / References: UniProt: Q9UEF7, beta-glucuronidase
#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
DescriptorTypeProgram
WURCS=2.0/2,10,9/[a2121A-1a_1-5_2*OSO/3=O/3=O][a2122h-1a_1-5_2*NSO/3=O/3=O_6*OSO/3=O/3=O]/1-2-1-2-1-2-1-2-1-2/a4-b1_b4-c1_c4-d1_d4-e1_e4-f1_f4-g1_g4-h1_h4-i1_i4-j1WURCSPDB2Glycan 1.1.0
[][a-L-IdopA2SO3]{[(4+1)][a-D-GlcpNSO36SO3]{[(4+1)][a-L-IdopA2SO3]{[(4+1)][a-D-GalpNSO36SO3]{[(4+1)][a-L-AltpA2SO3]{[(4+1)][a-D-GalpNSO36SO3]{[(4+1)][a-L-AltpA2SO3]{[(4+1)][a-D-GalpNSO36SO3]{[(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
#6: Chemical ChemComp-CU / COPPER (II) ION


Mass: 63.546 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cu

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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

Component
IDNameTypeEntity IDParent-IDSource
11:2:1:1 FGF23-FGFR3c-aKlotho-HS Quaternary ComplexCOMPLEX#1-#30RECOMBINANT
2aKlotho,FGFR3COMPLEX#1-#21RECOMBINANT
3FGF23COMPLEX#31RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Escherichia coli (E. coli)562
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: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2800 nm / Nominal defocus min: 600 nm
Image recordingElectron dose: 72.44 e/Å2 / Film or detector model: GATAN K2 BASE (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.20.1_4487: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 291540 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00312803
ELECTRON MICROSCOPYf_angle_d0.57717451
ELECTRON MICROSCOPYf_dihedral_angle_d5.4161695
ELECTRON MICROSCOPYf_chiral_restr0.0421845
ELECTRON MICROSCOPYf_plane_restr0.0052233

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