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- EMDB-34084: Cryo-EM Structure of FGF23-FGFR4-aKlotho-HS Quaternary Complex -

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Basic information

Entry
Database: EMDB / ID: EMD-34084
TitleCryo-EM Structure of FGF23-FGFR4-aKlotho-HS Quaternary Complex
Map data
Sample
  • Complex: 1:2:1:1 FGF23-FGFR4-aKlotho-HS Quaternary Complex
    • Complex: FGFR4-aKlotho-HS
      • Protein or peptide: Fibroblast growth factor receptor 4
      • Protein or peptide: Klotho
    • Complex: FGF23
      • Protein or peptide: Fibroblast growth factor 23
  • Ligand: COPPER (II) ION
  • Ligand: ZINC ION
KeywordsFGF hormones / FGF Receptor / Klotho Co-Receptor / Heparan Sulfate Glycosaminoglycans / SIGNALING PROTEIN
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 / negative regulation of hormone secretion / FGFR1c and Klotho ligand binding and activation / beta-glucuronidase activity ...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 / negative regulation of hormone secretion / FGFR1c and Klotho ligand binding and activation / beta-glucuronidase activity / regulation of phosphate transport / positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway / regulation of extracellular matrix disassembly / 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 / 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 / vitamin D binding / Phospholipase C-mediated cascade; FGFR2 / FGFR4 ligand binding and activation / energy reserve metabolic process / 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 / 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 / positive regulation of DNA biosynthetic process / PI-3K cascade:FGFR3 / beta-glucosidase activity / positive regulation of catalytic activity / fibroblast growth factor binding / PI-3K cascade:FGFR2 / PI-3K cascade:FGFR4 / PI-3K cascade:FGFR1 / response to magnesium ion / positive regulation of proteolysis / regulation of lipid metabolic process / PI3K Cascade / fibroblast growth factor receptor signaling pathway / negative regulation of osteoblast differentiation / calcium ion homeostasis / positive regulation of bone mineralization / SHC-mediated cascade:FGFR3 / SHC-mediated cascade:FGFR2 / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / 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 / regulation of cell migration / Signaling by FGFR2 in disease / ERK1 and ERK2 cascade / Signaling by FGFR1 in disease / response to activity / cholesterol homeostasis / determination of adult lifespan / Negative regulation of FGFR3 signaling / Negative regulation of FGFR2 signaling / Negative regulation of FGFR4 signaling / animal organ morphogenesis / Post-translational protein phosphorylation / Negative regulation of FGFR1 signaling / growth factor activity / hormone activity / receptor protein-tyrosine kinase / 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 / carbohydrate metabolic process / cell differentiation / positive regulation of ERK1 and ERK2 cascade / receptor complex
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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / 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
Fibroblast growth factor receptor 4 / Fibroblast growth factor 23 / Klotho
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.03 Å
AuthorsMohammadi M / Chen L
Funding support China, 1 items
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, 2022-
Header (metadata) releaseJun 14, 2023-
Map releaseJun 14, 2023-
UpdateJul 5, 2023-
Current statusJul 5, 2023Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_34084.png

Downloads & links

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Map

FileDownload / File: emd_34084.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.096 Å
Density
Contour LevelBy AUTHOR: 0.5
Minimum - Maximum-4.266253 - 6.2282715
Average (Standard dev.)-0.00008131034 (±0.06753295)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 438.4 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_34084_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_34084_half_map_1.map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Half map: #1

Fileemd_34084_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : 1:2:1:1 FGF23-FGFR4-aKlotho-HS Quaternary Complex

EntireName: 1:2:1:1 FGF23-FGFR4-aKlotho-HS Quaternary Complex
Components
  • Complex: 1:2:1:1 FGF23-FGFR4-aKlotho-HS Quaternary Complex
    • Complex: FGFR4-aKlotho-HS
      • Protein or peptide: Fibroblast growth factor receptor 4
      • Protein or peptide: Klotho
    • Complex: FGF23
      • Protein or peptide: Fibroblast growth factor 23
  • Ligand: COPPER (II) ION
  • Ligand: ZINC ION

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Supramolecule #1: 1:2:1:1 FGF23-FGFR4-aKlotho-HS Quaternary Complex

SupramoleculeName: 1:2:1:1 FGF23-FGFR4-aKlotho-HS Quaternary Complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #2: FGFR4-aKlotho-HS

SupramoleculeName: FGFR4-aKlotho-HS / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#2

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Supramolecule #3: FGF23

SupramoleculeName: FGF23 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #3

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Macromolecule #1: Fibroblast growth factor receptor 4

MacromoleculeName: Fibroblast growth factor receptor 4 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.652729 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: YPQQAPYWTH PQRMEKKLHA VPAGNTVKFR CPAAGNPTPT IRWLKDGQAF HGENRIGGIR LRHQHWSLVM ESVVPSDRGT YTCLVENAV GSIRYNYLLD VLERSPHRPI LQAGLPANTT AVVGSDVELL CKVYSDAQPH IQWLKHIVIN GSSFGADGFP Y VQVLKTAD ...String:
YPQQAPYWTH PQRMEKKLHA VPAGNTVKFR CPAAGNPTPT IRWLKDGQAF HGENRIGGIR LRHQHWSLVM ESVVPSDRGT YTCLVENAV GSIRYNYLLD VLERSPHRPI LQAGLPANTT AVVGSDVELL CKVYSDAQPH IQWLKHIVIN GSSFGADGFP Y VQVLKTAD INSSEVEVLY LRNVSAEDAG EYTCLAGNSI GLSYQSAWLT VLPEE

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Macromolecule #2: Klotho

MacromoleculeName: Klotho / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO / EC number: beta-glucuronidase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 108.404914 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EPGDGAQTWA RFSRPPAPEA AGLFQGTFPD GFLWAVGSAA YQTEGGWQQH GKGASIWDTF THHPLAPPGD SRNASLPLGA PSPLQPATG DVASDSYNNV FRDTEALREL GVTHYRFSIS WARVLPNGSA GVPNREGLRY YRRLLERLRE LGVQPVVTLY H WDLPQRLQ ...String:
EPGDGAQTWA RFSRPPAPEA AGLFQGTFPD GFLWAVGSAA YQTEGGWQQH GKGASIWDTF THHPLAPPGD SRNASLPLGA PSPLQPATG DVASDSYNNV FRDTEALREL GVTHYRFSIS WARVLPNGSA GVPNREGLRY YRRLLERLRE LGVQPVVTLY H WDLPQRLQ DAYGGWANRA LADHFRDYAE LCFRHFGGQV KYWITIDNPY VVAWHGYATG RLAPGIRGSP RLGYLVAHNL LL AHAKVWH LYNTSFRPTQ GGQVSIALSS HWINPRRMTD HSIKECQKSL DFVLGWFAKP VFIDGDYPES MKNNLSSILP DFT ESEKKF IKGTADFFAL CFGPTLSFQL LDPHMKFRQL ESPNLRQLLS WIDLEFNHPQ IFIVENGWFV SGTTKRDDAK YMYY LKKFI METLKAIKLD GVDVIGYTAW SLMDGFEWHR GYSIRRGLFY VDFLSQDKML LPKSSALFYQ KLIEKNGFPP LPENQ PLEG TFPCDFAWGV VDNYIQVDTT LSQFTDLNVY LWDVHHSKRL IKVDGVVTKK RKSYCVDFAA IQPQIALLQE MHVTHF RFS LDWALILPLG NQSQVNHTIL QYYRCMASEL VRVNITPVVA LWQPMAPNQG LPRLLARQGA WENPYTALAF AEYARLC FQ ELGHHVKLWI TMNEPYTRNM TYSAGHNLLK AHALAWHVYN EKFRHAQNGK ISIALQADWI EPACPFSQKD KEVAERVL E FDIGWLAEPI FGSGDYPWVM RDWLNQRNNF LLPYFTEDEK KLIQGTFDFL ALSHYTTILV DSEKEDPIKY NDYLEVQEM TDITWLNSPS QVAVVPWGLR KVLNWLKFKY GDLPMYIISN GIDDGLHAED DQLRVYYMQN YINEALKAHI LDGINLCGYF AYSFNDRTA PRFGLYRYAA DQFEPKASMK HYRKIIDSNG FPGPETLERF CPEEFTVCTE CSF

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Macromolecule #3: Fibroblast growth factor 23

MacromoleculeName: Fibroblast growth factor 23 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 20.450064 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
YPNASPLLGS SWGGLIHLYT ATARNSYHLQ IHKNGHVDGA PHQTIYSALM IRSEDAGFVV ITGVMSRRYL CMDFRGNIFG SHYFDPENC RFQHQTLENG YDVYHSPQYH FLVSLGRAKR AFLPGMNPPP YSQFLSRRNE IPLIHFNTPI PRQHTQSAED D SERDPLNV LKPRARMTPA P

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Macromolecule #5: COPPER (II) ION

MacromoleculeName: COPPER (II) ION / type: ligand / ID: 5 / Number of copies: 1 / Formula: CU
Molecular weightTheoretical: 63.546 Da
Chemical component information

ChemComp-CU:
COPPER (II) ION

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Macromolecule #6: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 6 / Number of copies: 1 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 53.84 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.8000000000000003 µm / Nominal defocus min: 0.7000000000000001 µm
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

5w21

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.03 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 856877
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE

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