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- EMDB-61321: Cryo-EM structure of human SOD1 (WT) amyloid filament -

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Basic information

Entry
Database: EMDB / ID: EMD-61321
TitleCryo-EM structure of human SOD1 (WT) amyloid filament
Map data
Sample
  • Complex: Amyloid filament of human wild-type SOD1 protein
    • Protein or peptide: Superoxide dismutase [Cu-Zn]
Keywordsamyloid / filament / superoxide dismutase 1 / amyotrophic lateral sclerosis / PROTEIN FIBRIL
Function / homology
Function and homology information


action potential initiation / neurofilament cytoskeleton organization / protein phosphatase 2B binding / regulation of organ growth / relaxation of vascular associated smooth muscle / anterograde axonal transport / positive regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / response to superoxide / regulation of T cell differentiation in thymus / peripheral nervous system myelin maintenance ...action potential initiation / neurofilament cytoskeleton organization / protein phosphatase 2B binding / regulation of organ growth / relaxation of vascular associated smooth muscle / anterograde axonal transport / positive regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / response to superoxide / regulation of T cell differentiation in thymus / peripheral nervous system myelin maintenance / retina homeostasis / auditory receptor cell stereocilium organization / hydrogen peroxide biosynthetic process / retrograde axonal transport / superoxide anion generation / regulation of GTPase activity / myeloid cell homeostasis / muscle cell cellular homeostasis / superoxide metabolic process / heart contraction / superoxide dismutase / Detoxification of Reactive Oxygen Species / transmission of nerve impulse / negative regulation of reproductive process / negative regulation of developmental process / superoxide dismutase activity / regulation of multicellular organism growth / response to axon injury / ectopic germ cell programmed cell death / neuronal action potential / ovarian follicle development / positive regulation of phagocytosis / axon cytoplasm / dendrite cytoplasm / glutathione metabolic process / embryo implantation / Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation / removal of superoxide radicals / reactive oxygen species metabolic process / thymus development / regulation of mitochondrial membrane potential / positive regulation of superoxide anion generation / positive regulation of cytokine production / determination of adult lifespan / locomotory behavior / placenta development / sensory perception of sound / response to hydrogen peroxide / small GTPase binding / mitochondrial intermembrane space / regulation of blood pressure / negative regulation of inflammatory response / peroxisome / Platelet degranulation / protein-folding chaperone binding / response to heat / cytoplasmic vesicle / gene expression / spermatogenesis / negative regulation of neuron apoptotic process / response to ethanol / intracellular iron ion homeostasis / positive regulation of MAPK cascade / mitochondrial matrix / positive regulation of apoptotic process / copper ion binding / response to xenobiotic stimulus / neuronal cell body / apoptotic process / protein homodimerization activity / protein-containing complex / mitochondrion / extracellular space / extracellular exosome / zinc ion binding / extracellular region / nucleoplasm / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Copper/Zinc superoxide dismutase signature 1. / Superoxide dismutase (Cu/Zn) / superoxide dismutase copper chaperone / Superoxide dismutase, copper/zinc, binding site / Copper/Zinc superoxide dismutase signature 2. / Superoxide dismutase, copper/zinc binding domain / Copper/zinc superoxide dismutase (SODC) / Superoxide dismutase-like, copper/zinc binding domain superfamily
Similarity search - Domain/homology
Superoxide dismutase [Cu-Zn]
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 3.39 Å
AuthorsBaek Y / Kim H / Lee D / Kim D / Jo E / Roh S-H / Ha N-C
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Proc Natl Acad Sci U S A / Year: 2025
Title: Structural insights into the role of reduced cysteine residues in SOD1 amyloid filament formation.
Authors: Yeongjin Baek / Hyunmin Kim / Dukwon Lee / Doyeon Kim / Eunbyul Jo / Soung-Hun Roh / Nam-Chul Ha /
Abstract: The formation of superoxide dismutase 1 (SOD1) filaments has been implicated in amyotrophic lateral sclerosis (ALS). Although the disulfide bond formed between Cys57 and Cys146 in the active state ...The formation of superoxide dismutase 1 (SOD1) filaments has been implicated in amyotrophic lateral sclerosis (ALS). Although the disulfide bond formed between Cys57 and Cys146 in the active state has been well studied, the role of the reduced cysteine residues, Cys6 and Cys111, in SOD1 filament formation remains unclear. In this study, we investigated the role of reduced cysteine residues by determining and comparing cryoelectron microscopy (cryo-EM) structures of wild-type (WT) and C6A/C111A SOD1 filaments under thiol-based reducing and metal-depriving conditions, starting with protein samples possessing enzymatic activity. The C6A/C111A mutant SOD1 formed filaments more rapidly than the WT protein. The mutant structure had a unique paired-protofilament arrangement, with a smaller filament core than that of the single-protofilament structure observed in WT SOD1. Although the single-protofilament form developed more slowly, cross-seeding experiments demonstrated the predominance of single-protofilament morphology over paired protofilaments, regardless of the presence of the Cys6 and Cys111 mutations. These findings highlight the importance of the number of amino acid residues within the filament core in determining the energy requirements for assembly. Our study provides insights into ALS pathogenesis by elucidating the initiation and propagation of filament formation, which potentially leads to deleterious amyloid filaments.
History
DepositionAug 27, 2024-
Header (metadata) releaseJan 15, 2025-
Map releaseJan 15, 2025-
UpdateFeb 5, 2025-
Current statusFeb 5, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_61321.png

Downloads & links

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Map

FileDownload / File: emd_61321.map.gz / Format: CCP4 / Size: 137.1 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.)
0.76 Å/pix.
x 330 pix.
= 250.8 Å		0.76 Å/pix.
x 330 pix.
= 250.8 Å		0.76 Å/pix.
x 330 pix.
= 250.8 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.76 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0258
Minimum - Maximum-0.07461932 - 0.108422056
Average (Standard dev.)0.0007399696 (±0.0050122445)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions330330330
Spacing330330330
CellA=B=C: 250.8 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_61321_half_map_1.map
Projections & Slices
AxesZYX

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Half map: #1

Fileemd_61321_half_map_2.map
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Sample components

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Entire : Amyloid filament of human wild-type SOD1 protein

EntireName: Amyloid filament of human wild-type SOD1 protein
Components
  • Complex: Amyloid filament of human wild-type SOD1 protein
    • Protein or peptide: Superoxide dismutase [Cu-Zn]

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Supramolecule #1: Amyloid filament of human wild-type SOD1 protein

SupramoleculeName: Amyloid filament of human wild-type SOD1 protein / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 34.6 kDa/nm

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Macromolecule #1: Superoxide dismutase [Cu-Zn]

MacromoleculeName: Superoxide dismutase [Cu-Zn] / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO / EC number: superoxide dismutase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 16.70657 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
GAMDPEFMAT KAVCVLKGDG PVQGIINFEQ KESNGPVKVW GSIKGLTEGL HGFHVHEFGD NTAGCTSAGP HFNPLSRKHG GPKDEERHV GDLGNVTADK DGVADVSIED SVISLSGDHC IIGRTLVVHE KADDLGKGGN EESTKTGNAG SRLACGVIGI A Q

UniProtKB: Superoxide dismutase [Cu-Zn]

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statehelical array

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Sample preparation

Concentration4.4 mg/mL
BufferpH: 7
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: TFS Selectris X / Energy filter - Slit width: 10 eV
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Number grids imaged: 1 / Number real images: 3102 / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.4000000000000001 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 165000
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

Final reconstructionApplied symmetry - Helical parameters - Δz: 4.82 Å
Applied symmetry - Helical parameters - Δ&Phi: -1.91 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.39 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 4.0) / Number images used: 92864
Segment selectionNumber selected: 99812 / Software - Name: RELION (ver. 4.0) / Software - details: start-end manual picking
Startup modelType of model: NONE / Details: used relion_helix_inimodel2d program
Final angle assignmentType: NOT APPLICABLE / Software - Name: RELION (ver. 4.0)
FSC plot (resolution estimation)

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Atomic model buiding 1

SoftwareName: Coot
RefinementSpace: REAL / Protocol: AB INITIO MODEL
Output model

PDB-9jbo:
Cryo-EM structure of human SOD1 (WT) amyloid filament

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