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- EMDB-34075: Cryo-EM Structure of FGF23-FGFR1c-aKlotho-HS Quaternary Complex -
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Open data
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Basic information
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Title | Cryo-EM Structure of FGF23-FGFR1c-aKlotho-HS Quaternary Complex | |||||||||
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![]() | FGF hormones / ![]() ![]() | |||||||||
Function / homology | ![]() type 1 fibroblast growth factor receptor binding / FGFRL1 modulation of FGFR1 signaling / norepinephrine biosynthetic process / positive regulation of vitamin D 24-hydroxylase activity / ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() Similarity search - Function | |||||||||
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![]() | Mohammadi M / Chen L | |||||||||
Funding support | ![]()
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![]() | ![]() 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 | ![]() | 59.9 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 17.9 KB 17.9 KB | Display Display | ![]() |
Images | ![]() | 106 KB | ||
Masks | ![]() | 64 MB | ![]() | |
Others | ![]() ![]() | 59.5 MB 59.5 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 7yshMC ![]() 7ysuC ![]() 7yswC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Voxel size | X=Y=Z: 1.096 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Mask #1
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Density Histograms |
-Half map: #1
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Density Histograms |
-Half map: #2
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Density Histograms |
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Sample components
-Entire : 1:2:1:1 FGF23-FGFR1c-aKlotho-HS Quaternary Complex
Entire | Name: 1:2:1:1 FGF23-FGFR1c-aKlotho-HS Quaternary Complex |
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Components |
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-Supramolecule #1: 1:2:1:1 FGF23-FGFR1c-aKlotho-HS Quaternary Complex
Supramolecule | Name: 1:2:1:1 FGF23-FGFR1c-aKlotho-HS Quaternary Complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3 |
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Source (natural) | Organism: ![]() ![]() |
-Macromolecule #1: Klotho
Macromolecule | Name: Klotho / type: protein_or_peptide / ID: 1 / Details: Klotho co-receptor / Number of copies: 1 / Enantiomer: LEVO / EC number: ![]() |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 109.164797 KDa |
Recombinant expression | Organism: ![]() ![]() |
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 CSFFHTRKS |
-Macromolecule #2: Fibroblast growth factor 23
Macromolecule | Name: Fibroblast growth factor 23 / type: protein_or_peptide / ID: 2 / Details: FGF23 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 30.367006 KDa |
Recombinant expression | Organism: ![]() ![]() ![]() |
Sequence | String: MHHHHHHSSG LVPRGSGMKE TAAAKFERQH MDSPDLGTDD DDKAMGYPNA SPLLGSSWGG LIHLYTATAR NSYHLQIHKN GHVDGAPHQ TIYSALMIRS EDAGFVVITG VMSRRYLCMD FRGNIFGSHY FDPENCRFQH QTLENGYDVY HSPQYHFLVS L GRAKRAFL ...String: MHHHHHHSSG LVPRGSGMKE TAAAKFERQH MDSPDLGTDD DDKAMGYPNA SPLLGSSWGG LIHLYTATAR NSYHLQIHKN GHVDGAPHQ TIYSALMIRS EDAGFVVITG VMSRRYLCMD FRGNIFGSHY FDPENCRFQH QTLENGYDVY HSPQYHFLVS L GRAKRAFL PGMNPPPYSQ FLSRRNEIPL IHFNTPIPRQ HTQSAEDDSE RDPLNVLKPR ARMTPAPASC SQELPSAEDN SP MASDPLG VVRGGRVNTH AGGTGPEGCR PFAKFI |
-Macromolecule #3: Isoform 20 of Fibroblast growth factor receptor 1
Macromolecule | Name: Isoform 20 of Fibroblast growth factor receptor 1 / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO / EC number: ![]() |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 26.373006 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: DNTKPNRMPV APYWTSPEKM EKKLHAVPAA KTVKFKCPSS GTPNPTLRWL KNGKEFKPDH RIGGYKVRYA TWSIIMDSVV PSDKGNYTC IVENEYGSIN HTYQLDVVER SPHRPILQAG LPANKTVALG SNVEFMCKVY SDPQPHIQWL KHIEVNGSKI G PDNLPYVQ ...String: DNTKPNRMPV APYWTSPEKM EKKLHAVPAA KTVKFKCPSS GTPNPTLRWL KNGKEFKPDH RIGGYKVRYA TWSIIMDSVV PSDKGNYTC IVENEYGSIN HTYQLDVVER SPHRPILQAG LPANKTVALG SNVEFMCKVY SDPQPHIQWL KHIEVNGSKI G PDNLPYVQ ILKTAGVNTT DKEMEVLHLR NVSFEDAGEY TCLAGNSIGL SHHSAWLTVL EALEERPGTK HHHHHH |
-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 | ![]() |
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Aggregation state | particle |
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Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | FEI TALOS ARCTICA |
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Electron beam | Acceleration voltage: 200 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD![]() |
Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.37 e/Å2 |
Experimental equipment | ![]() Model: Talos Arctica / Image courtesy: FEI Company |
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Image processing
Startup model | Type of model: PDB ENTRY PDB model - PDB ID: |
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Initial angle assignment | Type: NOT APPLICABLE |
Final angle assignment | Type: NOT APPLICABLE |
Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 2.74 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 1497967 |