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- EMDB-41452: Cryo-EM structure of monomeric alpha-Klotho -

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Basic information

Entry
Database: EMDB / ID: EMD-41452
TitleCryo-EM structure of monomeric alpha-Klotho
Map datafull map
Sample
  • Complex: Human aKlotho
    • Protein or peptide: Klotho
KeywordsSIGNALING PROTEIN
Function / homology
Function and homology information


norepinephrine biosynthetic process / beta-glucuronidase / FGFR1c and Klotho ligand binding and activation / positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway / beta-glucuronidase activity / fibroblast growth factor receptor binding / vitamin D binding / Downstream signaling of activated FGFR1 / Phospholipase C-mediated cascade: FGFR1 / energy reserve metabolic process ...norepinephrine biosynthetic process / beta-glucuronidase / FGFR1c and Klotho ligand binding and activation / positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway / beta-glucuronidase activity / fibroblast growth factor receptor binding / vitamin D binding / Downstream signaling of activated FGFR1 / Phospholipase C-mediated cascade: FGFR1 / energy reserve metabolic process / response to vitamin D / negative regulation of systemic arterial blood pressure / response to angiotensin / beta-glucosidase activity / PI-3K cascade:FGFR1 / fibroblast growth factor binding / PI3K Cascade / fibroblast growth factor receptor signaling pathway / positive regulation of bone mineralization / SHC-mediated cascade:FGFR1 / calcium ion homeostasis / FRS-mediated FGFR1 signaling / response to activity / determination of adult lifespan / Negative regulation of FGFR1 signaling / hormone activity / Constitutive Signaling by Aberrant PI3K in Cancer / PIP3 activates AKT signaling / RAF/MAP kinase cascade / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / carbohydrate metabolic process / apical plasma membrane / extracellular space / extracellular exosome / extracellular region / membrane / plasma membrane
Similarity search - Function
Glycosyl hydrolases family 1, N-terminal conserved site / Glycosyl hydrolases family 1 N-terminal signature. / Glycosyl hydrolase family 1 / Glycoside hydrolase family 1 / Glycoside hydrolase superfamily
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.29 Å
AuthorsSchnicker NJ / Xu Z / Mohammad A / Gakhar L / Huang CL
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)RO1 DK100605 United States
CitationJournal: Sci Rep / Year: 2025
Title: Conformational landscape of soluble α-klotho revealed by cryogenic electron microscopy.
Authors: Nicholas J Schnicker / Zhen Xu / Mohammad Amir / Lokesh Gakhar / Chou-Long Huang /
Abstract: α-Klotho (KLA) is a type-1 membranous protein that can associate with fibroblast growth factor receptor (FGFR) to form co-receptor for FGF23. The ectodomain of unassociated KLA is shed as soluble ...α-Klotho (KLA) is a type-1 membranous protein that can associate with fibroblast growth factor receptor (FGFR) to form co-receptor for FGF23. The ectodomain of unassociated KLA is shed as soluble KLA (sKLA) to exert FGFR/FGF23-independent pleiotropic functions. The previously determined X-ray crystal structure of the extracellular region of sKLA in complex with FGF23 and FGFR1c suggests that sKLA functions solely as an on-demand coreceptor for FGF23. To understand the FGFR/FGF23-independent pleiotropic functions of sKLA, we investigated biophysical properties and structure of apo-sKLA. Single particle cryogenic electron microscopy (cryo-EM) revealed a 3.3 Å resolution structure of apo-sKLA that overlays well with its counterpart in the ternary complex with several distinct features. Compared to the ternary complex, the KL2 domain of apo-sKLA is more flexible. Three-dimensional variability analysis revealed that apo-sKLA adopts conformations with different KL1-KL2 interdomain bending and rotational angles. Mass photometry revealed that sKLA can form a stable structure with FGFR and/or FGF23 as well as sKLA dimer in solution. Cryo-EM supported the dimeric structure of sKLA. Recent studies revealed that FGF23 contains two KLA-binding sites. Our computational studies revealed that each site binds separate KLA in the dimer. The potential multiple forms and shapes of sKLA support its role as FGFR-independent hormone with pleiotropic functions. The ability of FGF23 to engage two KLA's simultaneously raises a potential new mechanism of action for FGF23-mediated signaling by the membranous klotho.
History
DepositionAug 3, 2023-
Header (metadata) releaseAug 14, 2024-
Map releaseAug 14, 2024-
UpdateFeb 26, 2025-
Current statusFeb 26, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_41452.png

Downloads & links

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Map

FileDownload / File: emd_41452.map.gz / Format: CCP4 / Size: 149.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationfull map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.65 Å/pix.
x 340 pix.
= 221.238 Å		0.65 Å/pix.
x 340 pix.
= 221.238 Å		0.65 Å/pix.
x 340 pix.
= 221.238 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.6507 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.03
Minimum - Maximum-0.0016833987 - 2.5598834
Average (Standard dev.)0.0017162851 (±0.031842988)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions340340340
Spacing340340340
CellA=B=C: 221.23799 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: half map B

Fileemd_41452_half_map_1.map
Annotationhalf map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map A

Fileemd_41452_half_map_2.map
Annotationhalf map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Human aKlotho

EntireName: Human aKlotho
Components
  • Complex: Human aKlotho
    • Protein or peptide: Klotho

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Supramolecule #1: Human aKlotho

SupramoleculeName: Human aKlotho / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 130 KDa

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Macromolecule #1: Klotho

MacromoleculeName: Klotho / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 109.993688 KDa
Recombinant expressionOrganism: Mus musculus (house mouse)
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 CSFFHTRKSH HHHHH

UniProtKB: Klotho

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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

Concentration0.5 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormula
25.0 mMHEPES
300.0 mMNaCl
1.0 mMTCEP

Details: 25mM HEPES pH7.5, 300mM NaCl, 1mM TCEP
GridModel: Quantifoil R2/1 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 279 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Number real images: 8676 / Average exposure time: 1.099 sec. / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 100.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 130000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 7891498
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

5w21

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.29 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 115398
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 3.3.1)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 3.3.1)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

5w21


Chain - Chain ID: A / Chain - Source name: PDB / Chain - Initial model type: experimental model
Output model

PDB-8toh:
Cryo-EM structure of monomeric alpha-Klotho

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