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Yorodumi- EMDB-34082: Cryo-EM Structure of FGF23-FGFR3c-aKlotho-HS Quaternary Complex -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-34082 | |||||||||
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Title | Cryo-EM Structure of FGF23-FGFR3c-aKlotho-HS Quaternary Complex | |||||||||
Map data | ||||||||||
Sample |
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Keywords | FGF hormones / FGF Receptor / Klotho Co-Receptor / Heparan Sulfate Glycosaminoglycans / SIGNALING PROTEIN | |||||||||
Function / homology | Function and homology information 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 / beta-glucuronidase activity / FGFR1c and Klotho ligand binding and activation / regulation of phosphate transport / positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway / endochondral bone growth / intracellular phosphate ion homeostasis / vitamin D catabolic process / FGFR3b ligand binding and activation / 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 / 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 / endochondral ossification / Signaling by activated point mutants of FGFR1 / FGFR1c ligand binding and activation / 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 / PI-3K cascade:FGFR3 / beta-glucosidase activity / fibroblast growth factor binding / PI-3K cascade:FGFR2 / bone mineralization / PI-3K cascade:FGFR4 / PI-3K cascade:FGFR1 / cell surface receptor signaling pathway via JAK-STAT / response to magnesium ion / PI3K Cascade / negative regulation of osteoblast differentiation / fibroblast growth factor receptor signaling pathway / calcium ion homeostasis / chondrocyte differentiation / positive regulation of bone mineralization / SHC-mediated cascade:FGFR3 / SHC-mediated cascade:FGFR2 / SHC-mediated cascade:FGFR4 / SHC-mediated cascade:FGFR1 / FRS-mediated FGFR3 signaling / positive regulation of tyrosine phosphorylation of STAT protein / transport vesicle / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / regulation of cell migration / Signaling by FGFR3 in disease / FRS-mediated FGFR1 signaling / Signaling by FGFR2 in disease / ERK1 and ERK2 cascade / Signaling by FGFR1 in disease / response to activity / skeletal system development / determination of adult lifespan / Negative regulation of FGFR3 signaling / Negative regulation of FGFR2 signaling / Negative regulation of FGFR4 signaling / animal organ morphogenesis / Negative regulation of FGFR1 signaling / Post-translational protein phosphorylation / growth factor activity / hormone activity / receptor protein-tyrosine kinase / Golgi lumen / 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) / 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 | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.2 Å | |||||||||
Authors | Mohammadi M / Chen L | |||||||||
Funding support | China, 1 items
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Citation | Journal: 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
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_34082.map.gz | 59.8 MB | EMDB map data format | |
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Header (meta data) | emd-34082-v30.xml emd-34082.xml | 18.7 KB 18.7 KB | Display Display | EMDB header |
Images | emd_34082.png | 92.5 KB | ||
Masks | emd_34082_msk_1.map | 64 MB | Mask map | |
Others | emd_34082_half_map_1.map.gz emd_34082_half_map_2.map.gz | 59.4 MB 59.4 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-34082 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-34082 | HTTPS FTP |
-Validation report
Summary document | emd_34082_validation.pdf.gz | 874.9 KB | Display | EMDB validaton report |
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Full document | emd_34082_full_validation.pdf.gz | 874.4 KB | Display | |
Data in XML | emd_34082_validation.xml.gz | 12.4 KB | Display | |
Data in CIF | emd_34082_validation.cif.gz | 14.6 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-34082 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-34082 | HTTPS FTP |
-Related structure data
Related structure data | 7ysuMC 7yshC 7yswC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_34082.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Voxel size | X=Y=Z: 1.048 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Mask #1
File | emd_34082_msk_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #2
File | emd_34082_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_34082_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : 1:2:1:1 FGF23-FGFR3c-aKlotho-HS Quaternary Complex
Entire | Name: 1:2:1:1 FGF23-FGFR3c-aKlotho-HS Quaternary Complex |
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Components |
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-Supramolecule #1: 1:2:1:1 FGF23-FGFR3c-aKlotho-HS Quaternary Complex
Supramolecule | Name: 1:2:1:1 FGF23-FGFR3c-aKlotho-HS Quaternary Complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3 |
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-Supramolecule #2: aKlotho,FGFR3
Supramolecule | Name: aKlotho,FGFR3 / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#2 |
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Source (natural) | Organism: Homo sapiens (human) |
-Supramolecule #3: FGF23
Supramolecule | Name: FGF23 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #3 |
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Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: Klotho
Macromolecule | Name: Klotho / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: beta-glucuronidase |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 108.404914 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: 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 |
-Macromolecule #2: Fibroblast growth factor receptor 3
Macromolecule | Name: Fibroblast growth factor receptor 3 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 23.358441 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: TGAPYWTRPE RMDKKLLAVP AANTVRFRCP AAGNPTPSIS WLKNGREFRG EHRIGGIKLR HQQWSLVMES VVPSDRGNYT CVVENKFGS IRQTYTLDVL ERSPHRPILQ AGLPANQTAV LGSDVEFHCK VYSDAQPHIQ WLKHVEVNGS KVGPDGTPYV T VLKTAGAN ...String: TGAPYWTRPE RMDKKLLAVP AANTVRFRCP AAGNPTPSIS WLKNGREFRG EHRIGGIKLR HQQWSLVMES VVPSDRGNYT CVVENKFGS IRQTYTLDVL ERSPHRPILQ AGLPANQTAV LGSDVEFHCK VYSDAQPHIQ WLKHVEVNGS KVGPDGTPYV T VLKTAGAN TTDKELEVLS LHNVTFEDAG EYTCLAGNSI GFSHHSAWLV VLP |
-Macromolecule #3: Fibroblast growth factor 23
Macromolecule | Name: Fibroblast growth factor 23 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 20.450064 KDa |
Recombinant expression | Organism: Escherichia coli (E. coli) |
Sequence | String: YPNASPLLGS SWGGLIHLYT ATARNSYHLQ IHKNGHVDGA PHQTIYSALM IRSEDAGFVV ITGVMSRRYL CMDFRGNIFG SHYFDPENC RFQHQTLENG YDVYHSPQYH FLVSLGRAKR AFLPGMNPPP YSQFLSRRNE IPLIHFNTPI PRQHTQSAED D SERDPLNV LKPRARMTPA P |
-Macromolecule #5: ZINC ION
Macromolecule | Name: ZINC ION / type: ligand / ID: 5 / Number of copies: 1 / Formula: ZN |
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Molecular weight | Theoretical: 65.409 Da |
-Macromolecule #6: COPPER (II) ION
Macromolecule | Name: COPPER (II) ION / type: ligand / ID: 6 / Number of copies: 1 / Formula: CU |
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Molecular weight | Theoretical: 63.546 Da |
Chemical component information | ChemComp-CU: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K2 BASE (4k x 4k) / Average electron dose: 72.44 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.8000000000000003 µm / Nominal defocus min: 0.6 µm |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Startup model | Type of model: PDB ENTRY PDB model - PDB ID: |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 291540 |
Initial angle assignment | Type: NOT APPLICABLE |
Final angle assignment | Type: NOT APPLICABLE |