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- EMDB-61569: human GM-CSF with Fabs from autoantibodies, F1 and C. -

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Basic information

Entry
Database: EMDB / ID: EMD-61569
Titlehuman GM-CSF with Fabs from autoantibodies, F1 and C.
Map data
Sample
  • Complex: the complex of human GM-CSF with Fabs from its autoantibodies, F1 and C.
    • Complex: human GM-CSF
      • Protein or peptide: Granulocyte-macrophage colony-stimulating factor
    • Complex: F1 autoantibody for human GM-CSF
      • Protein or peptide: Fab region of F1 antibody heavy chain
      • Protein or peptide: Fab region of F1 antibody light chain
    • Complex: C autoantibody for human GM-CSF
      • Protein or peptide: Fab region of C antibody heavy chain
      • Protein or peptide: Fab region of C antibody light chain
KeywordsAutoimmune pulmonary alveolar proteinosis / autoantibody / IMMUNE SYSTEM
Function / homology
Function and homology information


granulocyte macrophage colony-stimulating factor receptor binding / histamine secretion / response to silicon dioxide / epithelial fluid transport / positive regulation of interleukin-23 production / myeloid dendritic cell differentiation / positive regulation of podosome assembly / dendritic cell differentiation / regulation of circadian sleep/wake cycle, sleep / myeloid cell differentiation ...granulocyte macrophage colony-stimulating factor receptor binding / histamine secretion / response to silicon dioxide / epithelial fluid transport / positive regulation of interleukin-23 production / myeloid dendritic cell differentiation / positive regulation of podosome assembly / dendritic cell differentiation / regulation of circadian sleep/wake cycle, sleep / myeloid cell differentiation / granulocyte macrophage colony-stimulating factor receptor complex / granulocyte-macrophage colony-stimulating factor signaling pathway / cellular response to granulocyte macrophage colony-stimulating factor stimulus / response to fluid shear stress / positive regulation of leukocyte proliferation / positive regulation of macrophage derived foam cell differentiation / cell surface receptor signaling pathway via STAT / RUNX1 regulates transcription of genes involved in differentiation of myeloid cells / Interleukin-10 signaling / macrophage differentiation / Interleukin-3, Interleukin-5 and GM-CSF signaling / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / Interleukin receptor SHC signaling / cell surface receptor signaling pathway via JAK-STAT / cytokine activity / growth factor activity / cellular response to lipopolysaccharide / RAF/MAP kinase cascade / positive regulation of cell migration / immune response / negative regulation of DNA-templated transcription / positive regulation of gene expression / positive regulation of cell population proliferation / extracellular region / plasma membrane
Similarity search - Function
Granulocyte-macrophage colony-stimulating factor / Granulocyte-macrophage colony-stimulating factor / Granulocyte-macrophage colony-stimulating factor signature. / Granulocyte-macrophage colony-simulating factor (GM-CSF) / Four-helical cytokine-like, core
Similarity search - Domain/homology
Granulocyte-macrophage colony-stimulating factor
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsKishikawa J / Kato T / Kurosaki T / Inoue T
Funding support Japan, 2 items
OrganizationGrant numberCountry
Japan Society for the Promotion of Science (JSPS)23K07625 Japan
Other private26-2-40 Japan
CitationJournal: Nat Commun / Year: 2026
Title: Affinity- and epitope-dependent pathogenicity of GM-CSF autoantibodies in patients with autoimmune pulmonary alveolar proteinosis.
Authors: Shinji Futami / Chie Kawai / Jun-Ichi Kishikawa / Masaki Hirose / Hiroshi Kida / Po-Hung Wang / Kazuo Yamashita / Fumihiko Ishikawa / Takayuki Kato / Yoshikazu Inoue / Atsushi Kumanogoh / ...Authors: Shinji Futami / Chie Kawai / Jun-Ichi Kishikawa / Masaki Hirose / Hiroshi Kida / Po-Hung Wang / Kazuo Yamashita / Fumihiko Ishikawa / Takayuki Kato / Yoshikazu Inoue / Atsushi Kumanogoh / Tomohiro Kurosaki / Takeshi Inoue /
Abstract: Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare lung disease caused by autoantibodies targeting granulocyte-macrophage colony-stimulating factor (GM-CSF). Although serum GM-CSF ...Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare lung disease caused by autoantibodies targeting granulocyte-macrophage colony-stimulating factor (GM-CSF). Although serum GM-CSF autoantibody levels are markedly increased in aPAP patients, total antibody titer does not correlate with disease severity. Here, we characterize 186 monoclonal anti-GM-CSF autoantibodies derived from GM-CSF-specific B cells in 28 aPAP patients with varying disease severity, including three longitudinal cohorts, to determine whether epitope specificity and affinity of the autoantibodies contribute to disease pathophysiology. We classify these antibodies into two groups based on their epitopes: class 1 (targeting A, BD, or D epitopes) and class 2 (targeting B or C epitopes). In class 1 antibodies, affinity strongly correlates with neutralization activity, whereas this relationship is weak or absent in class 2 antibodies. High-affinity class 1 antibodies are present at higher levels in patients with more severe disease and are sufficient to induce PAP symptoms in a humanized mouse model. Thus, these findings identify epitope specificity and affinity as key determinants of pathogenicity and provide a mechanistic framework for understanding why total serum autoantibody levels fail to reflect disease severity in aPAP.
History
DepositionSep 17, 2024-
Header (metadata) releaseMar 25, 2026-
Map releaseMar 25, 2026-
UpdateOct 7, 2026-
Current statusOct 7, 2026Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_61569.png

Downloads & links

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Map

FileDownload / File: emd_61569.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.01 Å/pix.
x 300 pix.
= 303.75 Å		1.01 Å/pix.
x 300 pix.
= 303.75 Å		1.01 Å/pix.
x 300 pix.
= 303.75 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.0125 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.18
Minimum - Maximum-0.7103071 - 0.80907893
Average (Standard dev.)-0.000009117716 (±0.02063241)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 303.75 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_61569_msk_1.map
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Additional map: #1

Fileemd_61569_additional_1.map
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Half map: #2

Fileemd_61569_half_map_1.map
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Half map: #1

Fileemd_61569_half_map_2.map
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Sample components

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Entire : the complex of human GM-CSF with Fabs from its autoantibodies, F1...

EntireName: the complex of human GM-CSF with Fabs from its autoantibodies, F1 and C.
Components
  • Complex: the complex of human GM-CSF with Fabs from its autoantibodies, F1 and C.
    • Complex: human GM-CSF
      • Protein or peptide: Granulocyte-macrophage colony-stimulating factor
    • Complex: F1 autoantibody for human GM-CSF
      • Protein or peptide: Fab region of F1 antibody heavy chain
      • Protein or peptide: Fab region of F1 antibody light chain
    • Complex: C autoantibody for human GM-CSF
      • Protein or peptide: Fab region of C antibody heavy chain
      • Protein or peptide: Fab region of C antibody light chain

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Supramolecule #1: the complex of human GM-CSF with Fabs from its autoantibodies, F1...

SupramoleculeName: the complex of human GM-CSF with Fabs from its autoantibodies, F1 and C.
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 50 kDa/nm

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Supramolecule #2: human GM-CSF

SupramoleculeName: human GM-CSF / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #5
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: F1 autoantibody for human GM-CSF

SupramoleculeName: F1 autoantibody for human GM-CSF / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #4: C autoantibody for human GM-CSF

SupramoleculeName: C autoantibody for human GM-CSF / type: complex / ID: 4 / Parent: 1 / Macromolecule list: #3-#4
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Fab region of F1 antibody heavy chain

MacromoleculeName: Fab region of F1 antibody heavy chain / type: protein_or_peptide / ID: 1 / Details: C-terminal is His x6 tag for purification / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.706588 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAQLQESGPG VVKPSETLSL TCSVSDSAIR KYYWSWIRQP PGQGLEYIGY IYASGSSFYN PSFKSRVSMS VDATNNQFYL KLTSVTAAD TAVYYCAAIT GTTDLWGRGT LVTVSSASTK GPSVFPLAPS SKSTSGGTAA LGCLVKDYFP EPVTVSWNSG A LTSGVHTF ...String:
MAQLQESGPG VVKPSETLSL TCSVSDSAIR KYYWSWIRQP PGQGLEYIGY IYASGSSFYN PSFKSRVSMS VDATNNQFYL KLTSVTAAD TAVYYCAAIT GTTDLWGRGT LVTVSSASTK GPSVFPLAPS SKSTSGGTAA LGCLVKDYFP EPVTVSWNSG A LTSGVHTF PAVLQSSGLY SLSSVVTVPS SSLGTQTYIC NVNHKPSNTK VDKRVEPKSC DKTHTNGHHH HHH

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Macromolecule #2: Fab region of F1 antibody light chain

MacromoleculeName: Fab region of F1 antibody light chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.494256 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MDIQMTQSPS SVSASVGDRV TITCRASQGI NRRLAWYQQK PGKAPKRLIY AVSTLQSGVP SRFNGSGSGT DFTLTVNNVQ PDDLAMYFC LQSNNYPLTF GGGTKVEIKR TVAAPSVFIF PPSDEQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD ...String:
MDIQMTQSPS SVSASVGDRV TITCRASQGI NRRLAWYQQK PGKAPKRLIY AVSTLQSGVP SRFNGSGSGT DFTLTVNNVQ PDDLAMYFC LQSNNYPLTF GGGTKVEIKR TVAAPSVFIF PPSDEQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD SKDSTYSLSS TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNRGEC

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Macromolecule #3: Fab region of C antibody heavy chain

MacromoleculeName: Fab region of C antibody heavy chain / type: protein_or_peptide / ID: 3 / Details: C terminal is His x6 tag for purification / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 25.442504 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MQVQLVQSGA EVKKPGSSMK VSCKTSGGTF DNYAFSWLRQ APGQGFEWMG SIMPILDFPQ YAEKFQGRLT ITADKSTNTA FIELSSLRP DDTAVYYCAR EGIAVGDVLA EYFQHWGHGT TVTVSSASTK GPSVFPLAPS SKSTSGGTAA LGCLVKDYFP E PVTVSWNS ...String:
MQVQLVQSGA EVKKPGSSMK VSCKTSGGTF DNYAFSWLRQ APGQGFEWMG SIMPILDFPQ YAEKFQGRLT ITADKSTNTA FIELSSLRP DDTAVYYCAR EGIAVGDVLA EYFQHWGHGT TVTVSSASTK GPSVFPLAPS SKSTSGGTAA LGCLVKDYFP E PVTVSWNS GALTSGVHTF PAVLQSSGLY SLSSVVTVPS SSLGTQTYIC NVNHKPSNTK VDKKVENLYF QGHHHHHH

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Macromolecule #4: Fab region of C antibody light chain

MacromoleculeName: Fab region of C antibody light chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.459273 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MDIVMTQSPD SLAVSLGGRA TINCKSSQSV FYGSRNKNFL AWYQQKPGQP PKLLFYWAST RESGVPDRFR SSGSGTEFTL TINSLQVED VAIYYCQQYY GHPLTFGGGT KVDIKRTVAA PSVFIFPPSD EQLKSGTASV VCLLNNFYPR EAKVQWKVDN A LQSGNSQE ...String:
MDIVMTQSPD SLAVSLGGRA TINCKSSQSV FYGSRNKNFL AWYQQKPGQP PKLLFYWAST RESGVPDRFR SSGSGTEFTL TINSLQVED VAIYYCQQYY GHPLTFGGGT KVDIKRTVAA PSVFIFPPSD EQLKSGTASV VCLLNNFYPR EAKVQWKVDN A LQSGNSQE SVTEQDSKDS TYSLSSTLTL SKADYEKHKV YACEVTHQGL SSPVTKSFNR GEC

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Macromolecule #5: Granulocyte-macrophage colony-stimulating factor

MacromoleculeName: Granulocyte-macrophage colony-stimulating factor / type: protein_or_peptide / ID: 5
Details: 1-17 residues are signal peptides cleaved in purified protein. 145-159 residues are avi-tag for purification 160 is a linker 161-166 residues are his-tag for purification
Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 17.191404 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
APARSPSPST QPWEHVNAIQ EARRLLNLSR DTAAEMNETV EVISEMFDLQ EPTCLQTRLE LYKQGLRGSL TKLKGPLTMM ASHYKQHCP PTPETSCATQ IITFESFKEN LKDFLLVIPF DCWEPVQEGL NDIFEAQKIE WHEGHHHHHH

UniProtKB: Granulocyte-macrophage colony-stimulating factor

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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

Concentration0.2 mg/mL
BufferpH: 7.5
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number real images: 3467 / Average electron dose: 65.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 0.054 mm / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 105000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 601878 / Details: topaz extraction
CTF correctionSoftware - Name: cryoSPARC (ver. 4.0.0) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL / In silico model: ab initio reconstruction job in cryosparc
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.0.0) / Number images used: 189815
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.0.0)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.0.0)
Final 3D classificationSoftware - Name: cryoSPARC (ver. 4.0.0)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

6bfq


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-9jkr:
human GM-CSF with Fabs from autoantibodies, F1 and C.

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