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- PDB-7ysw: Cryo-EM Structure of FGF23-FGFR4-aKlotho-HS Quaternary Complex -

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Basic information

Entry
Database: PDB / ID: 7ysw
TitleCryo-EM Structure of FGF23-FGFR4-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


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 / regulation of phosphate transport / FGFR1c and Klotho ligand binding and activation / 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 / FGFR4 mutant receptor activation / betaKlotho-mediated ligand binding / positive regulation of vitamin D 24-hydroxylase activity / beta-glucuronidase / regulation of phosphate transport / FGFR1c and Klotho ligand binding and activation / positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway / negative regulation of hormone secretion / beta-glucuronidase activity / regulation of extracellular matrix disassembly / vitamin D catabolic process / response to sodium phosphate / intracellular phosphate ion homeostasis / 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 / 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 / Phospholipase C-mediated cascade; FGFR2 / FGFR4 ligand binding and activation / vitamin D binding / 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 / energy reserve metabolic process / response to vitamin D / cellular response to leptin stimulus / cellular response to interleukin-6 / positive regulation of catalytic activity / negative regulation of systemic arterial blood pressure / response to angiotensin / cellular response to parathyroid hormone stimulus / beta-glucosidase activity / positive regulation of DNA biosynthetic process / PI-3K cascade:FGFR3 / PI-3K cascade:FGFR2 / PI-3K cascade:FGFR4 / PI-3K cascade:FGFR1 / fibroblast growth factor binding / positive regulation of proteolysis / regulation of lipid metabolic process / response to magnesium ion / PI3K Cascade / negative regulation of osteoblast differentiation / fibroblast growth factor receptor signaling pathway / SHC-mediated cascade:FGFR3 / positive regulation of bone mineralization / SHC-mediated cascade:FGFR2 / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / calcium ion homeostasis / 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 / Signaling by FGFR2 in disease / Signaling by FGFR1 in disease / regulation of cell migration / ERK1 and ERK2 cascade / cholesterol homeostasis / response to activity / determination of adult lifespan / animal organ morphogenesis / Negative regulation of FGFR3 signaling / Post-translational protein phosphorylation / Negative regulation of FGFR2 signaling / Negative regulation of FGFR4 signaling / Negative regulation of FGFR1 signaling / growth factor activity / receptor protein-tyrosine kinase / hormone activity / 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 / positive regulation of MAPK cascade / carbohydrate metabolic process / positive regulation of ERK1 and ERK2 cascade / cell differentiation
Similarity search - Function
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 / 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 / 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
Similarity search - Domain/homology
COPPER (II) ION / Fibroblast growth factor receptor 4 / Fibroblast growth factor 23 / Klotho
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.03 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 13, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 14, 2023Provider: repository / Type: Initial release
Revision 1.1Jun 21, 2023Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jul 5, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Oct 16, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
C: Fibroblast growth factor receptor 4
E: Fibroblast growth factor receptor 4
A: Klotho
B: Fibroblast growth factor 23
hetero molecules


Theoretical massNumber of molelcules
Total (without water)179,1957
Polymers176,1604
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

#1: Protein Fibroblast growth factor receptor 4 / FGFR-4


Mass: 23652.729 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FGFR4, JTK2, TKF / Cell line (production host): HEK293 / Production host: Homo sapiens (human)
References: UniProt: P22455, 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

#2: 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): HEK293 / 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-AltpA2SO3]{[(4+1)][a-D-GlcpNSO36SO3]{[(4+1)][a-L-IdopA2SO3]{[(4+1)][a-D-GalpNSO36SO3]{[(4+1)][a-L-AltpA2SO3]{[(4+1)][a-D-GlcpNSO36SO3]{[(4+1)][a-L-AltpA2SO3]{[(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-CU / COPPER (II) ION


Mass: 63.546 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cu
#6: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn

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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-FGFR4-aKlotho-HS Quaternary ComplexCOMPLEX#1-#30RECOMBINANT
2FGFR4-aKlotho-HSCOMPLEX#1-#21RECOMBINANT
3FGF23COMPLEX#31RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Escherichia 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: 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: 2800 nm / Nominal defocus min: 700 nm
Image recordingElectron dose: 53.84 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 3.03 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 856877 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00312781
ELECTRON MICROSCOPYf_angle_d0.54417430
ELECTRON MICROSCOPYf_dihedral_angle_d4.4781696
ELECTRON MICROSCOPYf_chiral_restr0.0411842
ELECTRON MICROSCOPYf_plane_restr0.0042228

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