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- EMDB-0560: Structure of the human frataxin-bound iron-sulfur cluster assembl... -

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Entry
Database: EMDB / ID: EMD-0560
TitleStructure of the human frataxin-bound iron-sulfur cluster assembly complex
Map dataHuman frataxin-bound iron-sulfur cluster assembly complex
Sample
  • Complex: The human frataxin-bound iron-sulfur cluster assembly complex
    • Protein or peptide: Cysteine desulfurase, mitochondrial
    • Protein or peptide: LYR motif-containing protein 4
    • Protein or peptide: Acyl carrier protein
    • Protein or peptide: Iron-sulfur cluster assembly enzyme ISCU, mitochondrial
    • Protein or peptide: Frataxin, mitochondrial
  • Ligand: PYRIDOXAL-5'-PHOSPHATE
  • Ligand: S-[2-({N-[(2R)-2-hydroxy-3,3-dimethyl-4-(phosphonooxy)butanoyl]-beta-alanyl}amino)ethyl] dodecanethioate
  • Ligand: ZINC ION
Keywordshuman frataxin-bound iron-sulfur cluster assembly complex / TRANSFERASE / OXIDOREDUCTASE
Function / homology
Function and homology information


: / negative regulation of iron ion import across plasma membrane / molybdopterin cofactor metabolic process / proprioception / Molybdenum cofactor biosynthesis / positive regulation of lyase activity / positive regulation of succinate dehydrogenase activity / : / L-cysteine desulfurase complex / iron incorporation into metallo-sulfur cluster ...: / negative regulation of iron ion import across plasma membrane / molybdopterin cofactor metabolic process / proprioception / Molybdenum cofactor biosynthesis / positive regulation of lyase activity / positive regulation of succinate dehydrogenase activity / : / L-cysteine desulfurase complex / iron incorporation into metallo-sulfur cluster / [4Fe-4S] cluster assembly / Mitochondrial iron-sulfur cluster biogenesis / Complex III assembly / iron chaperone activity / positive regulation of mitochondrial electron transport, NADH to ubiquinone / Maturation of TCA enzymes and regulation of TCA cycle / cysteine desulfurase / cysteine desulfurase activity / negative regulation of organ growth / positive regulation of catalytic activity / mitochondrial respiratory chain complex III assembly / Mo-molybdopterin cofactor biosynthetic process / Mitochondrial protein import / mitochondrial [2Fe-2S] assembly complex / iron-sulfur cluster assembly complex / oxidative phosphorylation / response to iron ion / embryo development ending in birth or egg hatching / [2Fe-2S] cluster assembly / adult walking behavior / heme biosynthetic process / negative regulation of multicellular organism growth / organ growth / muscle cell cellular homeostasis / iron-sulfur cluster assembly / ferroxidase / negative regulation of release of cytochrome c from mitochondria / acyl carrier activity / ferroxidase activity / protein autoprocessing / iron-sulfur cluster binding / ferric iron binding / ferrous iron binding / 2 iron, 2 sulfur cluster binding / cellular response to hydrogen peroxide / pyridoxal phosphate binding / iron ion transport / Maturation of replicase proteins / positive regulation of cell growth / molecular adaptor activity / intracellular iron ion homeostasis / nuclear body / mitochondrial matrix / iron ion binding / positive regulation of cell population proliferation / centrosome / negative regulation of apoptotic process / protein homodimerization activity / mitochondrion / zinc ion binding / nucleoplasm / metal ion binding / nucleus / cytosol / cytoplasm
Similarity search - Function
LYRM4, LYR domain / : / Frataxin / ISC system FeS cluster assembly, IscU scaffold / Frataxin/CyaY / Frataxin conserved site / Frataxin-like domain / Frataxin family signature. / Frataxin family profile. / Frataxin-like domain ...LYRM4, LYR domain / : / Frataxin / ISC system FeS cluster assembly, IscU scaffold / Frataxin/CyaY / Frataxin conserved site / Frataxin-like domain / Frataxin family signature. / Frataxin family profile. / Frataxin-like domain / Cysteine desulfurase IscS / NIF system FeS cluster assembly, NifU, N-terminal / NifU-like N terminal domain / Frataxin/CyaY superfamily / Cysteine desulfurase / Aminotransferase class-V, pyridoxal-phosphate binding site / Aminotransferases class-V pyridoxal-phosphate attachment site. / Aminotransferase class V domain / Aminotransferase class-V / Complex 1 LYR protein domain / Complex 1 protein (LYR family) / Acyl carrier protein (ACP) / Phosphopantetheine attachment site / Phosphopantetheine attachment site. / Phosphopantetheine attachment site / ACP-like superfamily / Carrier protein (CP) domain profile. / Phosphopantetheine binding ACP domain / Pyridoxal phosphate-dependent transferase, small domain / Pyridoxal phosphate-dependent transferase, major domain / Pyridoxal phosphate-dependent transferase
Similarity search - Domain/homology
Acyl carrier protein / Frataxin, mitochondrial / Iron-sulfur cluster assembly enzyme ISCU / LYR motif-containing protein 4 / Cysteine desulfurase
Similarity search - Component
Biological speciesHomo sapiens (human) / Escherichia coli (E. coli)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsFox NG / Yu X
CitationJournal: Nat Commun / Year: 2019
Title: Structure of the human frataxin-bound iron-sulfur cluster assembly complex provides insight into its activation mechanism.
Authors: Nicholas G Fox / Xiaodi Yu / Xidong Feng / Henry J Bailey / Alain Martelli / Joseph F Nabhan / Claire Strain-Damerell / Christine Bulawa / Wyatt W Yue / Seungil Han /
Abstract: The core machinery for de novo biosynthesis of iron-sulfur clusters (ISC), located in the mitochondria matrix, is a five-protein complex containing the cysteine desulfurase NFS1 that is activated by ...The core machinery for de novo biosynthesis of iron-sulfur clusters (ISC), located in the mitochondria matrix, is a five-protein complex containing the cysteine desulfurase NFS1 that is activated by frataxin (FXN), scaffold protein ISCU, accessory protein ISD11, and acyl-carrier protein ACP. Deficiency in FXN leads to the loss-of-function neurodegenerative disorder Friedreich's ataxia (FRDA). Here the 3.2 Å resolution cryo-electron microscopy structure of the FXN-bound active human complex, containing two copies of the NFS1-ISD11-ACP-ISCU-FXN hetero-pentamer, delineates the interactions of FXN with other component proteins of the complex. FXN binds at the interface of two NFS1 and one ISCU subunits, modifying the local environment of a bound zinc ion that would otherwise inhibit NFS1 activity in complexes without FXN. Our structure reveals how FXN facilitates ISC production through stabilizing key loop conformations of NFS1 and ISCU at the protein-protein interfaces, and suggests how FRDA clinical mutations affect complex formation and FXN activation.
History
DepositionFeb 14, 2019-
Header (metadata) releaseMar 13, 2019-
Map releaseMay 22, 2019-
UpdateApr 2, 2025-
Current statusApr 2, 2025Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.0425
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.0425
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  • Surface view with fitted model
  • Atomic models: PDB-6nzu
  • Surface level: 0.0425
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_0560.png

Downloads & links

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Map

FileDownload / File: emd_0560.map.gz / Format: CCP4 / Size: 30.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationHuman frataxin-bound iron-sulfur cluster assembly complex
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.09 Å/pix.
x 200 pix.
= 217.2 Å		1.09 Å/pix.
x 200 pix.
= 217.2 Å		1.09 Å/pix.
x 200 pix.
= 217.2 Å

Surface

Projections

Slices (1/3)

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.086 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0425 / Movie #1: 0.0425
Minimum - Maximum-0.20349748 - 0.33728746
Average (Standard dev.)-0.00007063915 (±0.011196485)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions200200200
Spacing200200200
CellA=B=C: 217.2 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0861.0861.086
M x/y/z200200200
origin x/y/z0.0000.0000.000
length x/y/z217.200217.200217.200
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS200200200
D min/max/mean-0.2030.337-0.000

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Supplemental data

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Mask #1

Fileemd_0560_msk_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Half map: Human frataxin-bound iron-sulfur cluster assembly complex, half map 1

Fileemd_0560_half_map_1.map
AnnotationHuman frataxin-bound iron-sulfur cluster assembly complex, half map 1
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Human frataxin-bound iron-sulfur cluster assembly complex, half map 2

Fileemd_0560_half_map_2.map
AnnotationHuman frataxin-bound iron-sulfur cluster assembly complex, half map 2
Projections & Slices
AxesZYX

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Histogram (log scale)

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Sample components

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Entire : The human frataxin-bound iron-sulfur cluster assembly complex

EntireName: The human frataxin-bound iron-sulfur cluster assembly complex
Components
  • Complex: The human frataxin-bound iron-sulfur cluster assembly complex
    • Protein or peptide: Cysteine desulfurase, mitochondrial
    • Protein or peptide: LYR motif-containing protein 4
    • Protein or peptide: Acyl carrier protein
    • Protein or peptide: Iron-sulfur cluster assembly enzyme ISCU, mitochondrial
    • Protein or peptide: Frataxin, mitochondrial
  • Ligand: PYRIDOXAL-5'-PHOSPHATE
  • Ligand: S-[2-({N-[(2R)-2-hydroxy-3,3-dimethyl-4-(phosphonooxy)butanoyl]-beta-alanyl}amino)ethyl] dodecanethioate
  • Ligand: ZINC ION

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Supramolecule #1: The human frataxin-bound iron-sulfur cluster assembly complex

SupramoleculeName: The human frataxin-bound iron-sulfur cluster assembly complex
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 186 KDa

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Macromolecule #1: Cysteine desulfurase, mitochondrial

MacromoleculeName: Cysteine desulfurase, mitochondrial / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: cysteine desulfurase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 44.850371 KDa
Recombinant expressionOrganism: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
SequenceString: MLRPLYMDVQ ATTPLDPRVL DAMLPYLINY YGNPHSRTHA YGWESEAAME RARQQVASLI GADPREIIFT SGATESNNIA IKGVARFYR SRKKHLITTQ TEHKCVLDSC RSLEAEGFQV TYLPVQKSGI IDLKELEAAI QPDTSLVSVM TVNNEIGVKQ P IAEIGRIC ...String:
MLRPLYMDVQ ATTPLDPRVL DAMLPYLINY YGNPHSRTHA YGWESEAAME RARQQVASLI GADPREIIFT SGATESNNIA IKGVARFYR SRKKHLITTQ TEHKCVLDSC RSLEAEGFQV TYLPVQKSGI IDLKELEAAI QPDTSLVSVM TVNNEIGVKQ P IAEIGRIC SSRKVYFHTD AAQAVGKIPL DVNDMKIDLM SISGHKIYGP KGVGAIYIRR RPRVRVEALQ SGGGQERGMR SG TVPTPLV VGLGAACEVA QQEMEYDHKR ISKLSERLIQ NIMKSLPDVV MNGDPKHHYP GCINLSFAYV EGESLLMALK DVA LSSGSA CTSASLEPSY VLRAIGTDED LAHSSIRFGI GRFTTEEEVD YTVEKCIQHV KRLREMSPLW EMVQDGIDLK SIKW TQH

UniProtKB: Cysteine desulfurase

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Macromolecule #2: LYR motif-containing protein 4

MacromoleculeName: LYR motif-containing protein 4 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 10.850562 KDa
Recombinant expressionOrganism: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
SequenceString:
SMAASSRAQV LALYRAMLRE SKRFSAYNYR TYAVRRIRDA FRENKNVKDP VEIQTLVNKA KRDLGVIRRQ VHIGQLYSTD KLIIENRDM PRT

UniProtKB: LYR motif-containing protein 4

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Macromolecule #3: Acyl carrier protein

MacromoleculeName: Acyl carrier protein / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Escherichia coli (E. coli)
Molecular weightTheoretical: 8.251055 KDa
Recombinant expressionOrganism: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
SequenceString:
MSTIEERVKK IIGEQLGVKQ EEVTNNASFV EDLGADSLDT VELVMALEEE FDTEIPDEEA EKITTVQAAI DYIN

UniProtKB: Acyl carrier protein

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Macromolecule #4: Iron-sulfur cluster assembly enzyme ISCU, mitochondrial

MacromoleculeName: Iron-sulfur cluster assembly enzyme ISCU, mitochondrial
type: protein_or_peptide / ID: 4 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 13.41258 KDa
Recombinant expressionOrganism: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
SequenceString:
MYHKKVVDHY ENPRNVGSLD KTSKNVGTGL VGAPACGDVM KLQIQVDEKG KIVDARFKTF GCGSAIASSS LATEWVKGKT VEEALTIKN TDIAKELCLP PVKLHCSMLA EDAIKAALAD YKLKQ

UniProtKB: Iron-sulfur cluster assembly enzyme ISCU

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Macromolecule #5: Frataxin, mitochondrial

MacromoleculeName: Frataxin, mitochondrial / type: protein_or_peptide / ID: 5 / Number of copies: 2 / Enantiomer: LEVO / EC number: ferroxidase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 14.501001 KDa
Recombinant expressionOrganism: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
SequenceString:
SMSGTLGHPG SLDETTYERL AEETLDSLAE FFEDLADKPY TFEDYDVSFG SGVLTVKLGG DLGTYVINKQ TPNKQIWLSS PSSGPKRYD WTGKNWVYSH DGVSLHELLA AELTKALKTK LDLSSLAYSG KDA

UniProtKB: Frataxin, mitochondrial

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Macromolecule #6: PYRIDOXAL-5'-PHOSPHATE

MacromoleculeName: PYRIDOXAL-5'-PHOSPHATE / type: ligand / ID: 6 / Number of copies: 2 / Formula: PLP
Molecular weightTheoretical: 247.142 Da
Chemical component information

ChemComp-PLP:
PYRIDOXAL-5'-PHOSPHATE

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Macromolecule #7: S-[2-({N-[(2R)-2-hydroxy-3,3-dimethyl-4-(phosphonooxy)butanoyl]-b...

MacromoleculeName: S-[2-({N-[(2R)-2-hydroxy-3,3-dimethyl-4-(phosphonooxy)butanoyl]-beta-alanyl}amino)ethyl] dodecanethioate
type: ligand / ID: 7 / Number of copies: 2 / Formula: 8Q1
Molecular weightTheoretical: 540.651 Da
Chemical component information

ChemComp-8Q1:
S-[2-({N-[(2R)-2-hydroxy-3,3-dimethyl-4-(phosphonooxy)butanoyl]-beta-alanyl}amino)ethyl] dodecanethioate

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Macromolecule #8: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 8 / Number of copies: 2 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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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

BufferpH: 7.5
GridDetails: unspecified
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 42.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 267153
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial model
PDB IDChain

5kz5

chain_id: A, source_name: PDB, initial_model_type: experimental model

5wkp

chain_id: A, source_name: PDB, initial_model_type: experimental model

5wkp

chain_id: B, source_name: PDB, initial_model_type: experimental model

5wkp

chain_id: C, source_name: PDB, initial_model_type: experimental model

5wkp

chain_id: D, source_name: PDB, initial_model_type: experimental model
SoftwareName: Coot
RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-6nzu:
Structure of the human frataxin-bound iron-sulfur cluster assembly complex

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