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- EMDB-19356: Structure of the FDX2-bound core ISC complex (proximal conformation) -

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Entry
Database: EMDB / ID: EMD-19356
TitleStructure of the FDX2-bound core ISC complex (proximal conformation)
Map datadensity-modified map (primary map)
Sample
  • Complex: Human FDX2-bound core ISC complex (NFS1-ISD11-ACP1-ISCU2-FDX2)
    • Protein or peptide: Isoform Mitochondrial of Cysteine desulfurase
    • Protein or peptide: LYR motif-containing protein 4
    • Protein or peptide: Isoform 1 of Iron-sulfur cluster assembly enzyme ISCU
    • Protein or peptide: Ferredoxin-2, mitochondrial
    • Protein or peptide: Acyl carrier protein
  • Ligand: FE (II) ION
  • Ligand: FE2/S2 (INORGANIC) CLUSTER
  • Ligand: S-[2-({N-[(2R)-2-hydroxy-3,3-dimethyl-4-(phosphonooxy)butanoyl]-beta-alanyl}amino)ethyl] dodecanethioate
  • Ligand: water
Keywordscysteine desulfurase / FeS biosynthesis / FeS biogenesis / mitochondria / Friedreich's ataxia / frataxin / ferredoxin / FDX2 / iron-sulfur cluster / TRANSFERASE
Function / homology
Function and homology information


Electron transport from NADPH to Ferredoxin / Defective CYP11A1 causes AICSR / negative regulation of iron ion import across plasma membrane / molybdopterin cofactor metabolic process / Molybdenum cofactor biosynthesis / L-cysteine desulfurase complex / iron incorporation into metallo-sulfur cluster / [4Fe-4S] cluster assembly / Mitochondrial iron-sulfur cluster biogenesis / Complex III assembly ...Electron transport from NADPH to Ferredoxin / Defective CYP11A1 causes AICSR / negative regulation of iron ion import across plasma membrane / molybdopterin cofactor metabolic process / Molybdenum cofactor biosynthesis / L-cysteine desulfurase complex / iron incorporation into metallo-sulfur cluster / [4Fe-4S] cluster assembly / Mitochondrial iron-sulfur cluster biogenesis / Complex III assembly / P450-containing electron transport chain / positive regulation of mitochondrial electron transport, NADH to ubiquinone / Maturation of TCA enzymes and regulation of TCA cycle / cysteine desulfurase / cysteine desulfurase activity / Mo-molybdopterin cofactor biosynthetic process / Pregnenolone biosynthesis / mitochondrial [2Fe-2S] assembly complex / iron-sulfur cluster assembly complex / [2Fe-2S] cluster assembly / lipid biosynthetic process / lipid A biosynthetic process / iron-sulfur cluster assembly / acyl binding / acyl carrier activity / iron-sulfur cluster binding / phosphopantetheine binding / Endogenous sterols / electron transport chain / ferrous iron binding / 2 iron, 2 sulfur cluster binding / fatty acid biosynthetic process / pyridoxal phosphate binding / Maturation of replicase proteins / molecular adaptor activity / intracellular iron ion homeostasis / electron transfer activity / nuclear body / mitochondrial matrix / iron ion binding / response to xenobiotic stimulus / lipid binding / centrosome / protein homodimerization activity / mitochondrion / zinc ion binding / nucleoplasm / metal ion binding / nucleus / membrane / cytosol / cytoplasm
Similarity search - Function
LYRM4, LYR domain / : / ISC system FeS cluster assembly, IscU scaffold / Adrenodoxin, iron-sulphur binding site / Adrenodoxin family, iron-sulfur binding region signature. / Cysteine desulfurase IscS / NIF system FeS cluster assembly, NifU, N-terminal / NifU-like N terminal domain / Adrenodoxin / Cysteine desulfurase ...LYRM4, LYR domain / : / ISC system FeS cluster assembly, IscU scaffold / Adrenodoxin, iron-sulphur binding site / Adrenodoxin family, iron-sulfur binding region signature. / Cysteine desulfurase IscS / NIF system FeS cluster assembly, NifU, N-terminal / NifU-like N terminal domain / Adrenodoxin / Cysteine desulfurase / Aminotransferase class-V, pyridoxal-phosphate binding site / Aminotransferases class-V pyridoxal-phosphate attachment site. / Aminotransferase class V domain / Aminotransferase class-V / 2Fe-2S iron-sulfur cluster binding domain / Complex 1 LYR protein domain / Complex 1 protein (LYR family) / Beta-grasp domain superfamily / Acyl carrier protein (ACP) / 2Fe-2S ferredoxin-type iron-sulfur binding domain profile. / 2Fe-2S ferredoxin-type iron-sulfur binding domain / 2Fe-2S ferredoxin-like superfamily / 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 / Ferredoxin-2, mitochondrial / Iron-sulfur cluster assembly enzyme ISCU / LYR motif-containing protein 4 / Cysteine desulfurase
Similarity search - Component
Biological speciesHomo sapiens (human) / Escherichia coli BL21(DE3) (bacteria)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.26 Å
AuthorsSteinhilper R / Murphy BJ
Funding support Germany, 1 items
OrganizationGrant numberCountry
Max Planck Society Germany
CitationJournal: Nat Commun / Year: 2024
Title: Two-stage binding of mitochondrial ferredoxin-2 to the core iron-sulfur cluster assembly complex.
Authors: Ralf Steinhilper / Linda Boß / Sven-A Freibert / Vinzent Schulz / Nils Krapoth / Susann Kaltwasser / Roland Lill / Bonnie J Murphy /
Abstract: Iron-sulfur (FeS) protein biogenesis in eukaryotes begins with the de novo assembly of [2Fe-2S] clusters by the mitochondrial core iron-sulfur cluster assembly (ISC) complex. This complex comprises ...Iron-sulfur (FeS) protein biogenesis in eukaryotes begins with the de novo assembly of [2Fe-2S] clusters by the mitochondrial core iron-sulfur cluster assembly (ISC) complex. This complex comprises the scaffold protein ISCU2, the cysteine desulfurase subcomplex NFS1-ISD11-ACP1, the allosteric activator frataxin (FXN) and the electron donor ferredoxin-2 (FDX2). The structural interaction of FDX2 with the complex remains unclear. Here, we present cryo-EM structures of the human FDX2-bound core ISC complex showing that FDX2 and FXN compete for overlapping binding sites. FDX2 binds in either a 'distal' conformation, where its helix F interacts electrostatically with an arginine patch of NFS1, or a 'proximal' conformation, where this interaction tightens and the FDX2-specific C terminus binds to NFS1, facilitating the movement of the [2Fe-2S] cluster of FDX2 closer to the ISCU2 FeS cluster assembly site for rapid electron transfer. Structure-based mutational studies verify the contact areas of FDX2 within the core ISC complex.
History
DepositionJan 5, 2024-
Header (metadata) releaseDec 18, 2024-
Map releaseDec 18, 2024-
UpdateDec 25, 2024-
Current statusDec 25, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_19356.png

Downloads & links

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Map

FileDownload / File: emd_19356.map.gz / Format: CCP4 / Size: 9.3 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationdensity-modified map (primary map)
Projections & slices

Image control

Size
Brightness
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AxesX (Sec.)Y (Row.)Z (Col.)
0.83 Å/pix.
x 173 pix.
= 143.244 Å		0.83 Å/pix.
x 107 pix.
= 88.596 Å		0.83 Å/pix.
x 132 pix.
= 109.296 Å

Surface

Projections

Slices (1/3)

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Images are generated by Spider.

generated in cubic-lattice coordinate

Voxel sizeX=Y=Z: 0.828 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.35
Minimum - Maximum-3.9282312 - 7.1095743
Average (Standard dev.)0.000000000012682 (±0.47408393)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin918558
Dimensions107132173
Spacing173107132
CellA: 143.244 Å / B: 88.596 Å / C: 109.296 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_19356_msk_1.map
Projections & Slices
AxesZYX

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Additional map: unsharpened map

Fileemd_19356_additional_1.map
Annotationunsharpened map
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Additional map: auto-sharpened map

Fileemd_19356_additional_2.map
Annotationauto-sharpened map
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AxesZYX

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Half map: half map 2

Fileemd_19356_half_map_1.map
Annotationhalf map 2
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Half map: half map 1

Fileemd_19356_half_map_2.map
Annotationhalf map 1
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Sample components

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Entire : Human FDX2-bound core ISC complex (NFS1-ISD11-ACP1-ISCU2-FDX2)

EntireName: Human FDX2-bound core ISC complex (NFS1-ISD11-ACP1-ISCU2-FDX2)
Components
  • Complex: Human FDX2-bound core ISC complex (NFS1-ISD11-ACP1-ISCU2-FDX2)
    • Protein or peptide: Isoform Mitochondrial of Cysteine desulfurase
    • Protein or peptide: LYR motif-containing protein 4
    • Protein or peptide: Isoform 1 of Iron-sulfur cluster assembly enzyme ISCU
    • Protein or peptide: Ferredoxin-2, mitochondrial
    • Protein or peptide: Acyl carrier protein
  • Ligand: FE (II) ION
  • Ligand: FE2/S2 (INORGANIC) CLUSTER
  • Ligand: S-[2-({N-[(2R)-2-hydroxy-3,3-dimethyl-4-(phosphonooxy)butanoyl]-beta-alanyl}amino)ethyl] dodecanethioate
  • Ligand: water

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Supramolecule #1: Human FDX2-bound core ISC complex (NFS1-ISD11-ACP1-ISCU2-FDX2)

SupramoleculeName: Human FDX2-bound core ISC complex (NFS1-ISD11-ACP1-ISCU2-FDX2)
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Isoform Mitochondrial of Cysteine desulfurase

MacromoleculeName: Isoform Mitochondrial of Cysteine desulfurase / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: cysteine desulfurase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 45.165566 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: MSLRPLYMDV QATTPLDPRV LDAMLPYLIN YYGNPHSRTH AYGWESEAAM ERARQQVASL IGADPREIIF TSGATESNNI AIKGVARFY RSRKKHLITT QTEHKCVLDS CRSLEAEGFQ VTYLPVQKSG IIDLKELEAA IQPDTSLVSV MTVNNEIGVK Q PIAEIGRI ...String:
MSLRPLYMDV QATTPLDPRV LDAMLPYLIN YYGNPHSRTH AYGWESEAAM ERARQQVASL IGADPREIIF TSGATESNNI AIKGVARFY RSRKKHLITT QTEHKCVLDS CRSLEAEGFQ VTYLPVQKSG IIDLKELEAA IQPDTSLVSV MTVNNEIGVK Q PIAEIGRI CSSRKVYFHT DAAQAVGKIP LDVNDMKIDL MSISGH(LLP)IYG PKGVGAIYIR RRPRVRVEAL QSGGGQER G MRSGTVPTPL VVGLGAACEV AQQEMEYDHK RISKLSERLI QNIMKSLPDV VMNGDPKHHY PGCINLSFAY VEGESLLMA LKDVALSSGS ACTSASLEPS YVLRAIGTDE DLAHSSIRFG IGRFTTEEEV DYTVEKCIQH VKRLREMSPL WEMVQDGIDL KSIKWTQH

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: 13.502373 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString:
MGSSHHHHHH GSPTTENLYF QGHNMAASSR AQVLALYRAM LRESKRFSAY NYRTYAVRRI RDAFRENKNV KDPVEIQTLV NKAKRDLGV IRRQVHIGQL YSTDKLIIEN RDMPRT

UniProtKB: LYR motif-containing protein 4

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Macromolecule #3: Isoform 1 of Iron-sulfur cluster assembly enzyme ISCU

MacromoleculeName: Isoform 1 of Iron-sulfur cluster assembly enzyme ISCU / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 15.684119 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString:
MAYHKKVVDH YENPRNVGSL DKTSKNVGTG LVGAPACGDV MKLQIQVDEK GKIVDARFKT FGCGSAIASS SLATEWVKGK TVEEALTIK NTDIAKELCL PPVKLHCSML AEDAIKAALA DYKLKQEPKK GEAEKKLEHH HHHH

UniProtKB: Iron-sulfur cluster assembly enzyme ISCU

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Macromolecule #4: Ferredoxin-2, mitochondrial

MacromoleculeName: Ferredoxin-2, mitochondrial / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 13.344046 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString:
MASDVVNVVF VDRSGQRIPV SGRVGDNVLH LAQRHGVDLE GACEASLACS TCHVYVSEDH LDLLPPPEER EDDMLDMAPL LQENSRLGC QIVLTPELEG AEFTLPKITR NFYVDGHVPK PH

UniProtKB: Ferredoxin-2, mitochondrial

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Macromolecule #5: Acyl carrier protein

MacromoleculeName: Acyl carrier protein / type: protein_or_peptide / ID: 5 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Escherichia coli BL21(DE3) (bacteria)
Molecular weightTheoretical: 8.64546 KDa
SequenceString:
MSTIEERVKK IIGEQLGVKQ EEVTNNASFV EDLGADSLDT VELVMALEEE FDTEIPDEEA EKITTVQAAI DYINGHQA

UniProtKB: Acyl carrier protein

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Macromolecule #6: FE (II) ION

MacromoleculeName: FE (II) ION / type: ligand / ID: 6 / Number of copies: 2 / Formula: FE2
Molecular weightTheoretical: 55.845 Da

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Macromolecule #7: FE2/S2 (INORGANIC) CLUSTER

MacromoleculeName: FE2/S2 (INORGANIC) CLUSTER / type: ligand / ID: 7 / Number of copies: 1 / Formula: FES
Molecular weightTheoretical: 175.82 Da
Chemical component information

ChemComp-FES:
FE2/S2 (INORGANIC) CLUSTER

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Macromolecule #8: 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: 8 / 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 #9: water

MacromoleculeName: water / type: ligand / ID: 9 / Number of copies: 400 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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: 7.4
GridModel: Quantifoil R0.6/1 / Material: GOLD / Mesh: 300 / Support film - Material: GOLD / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 80.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.8 µm
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

Startup modelType of model: INSILICO MODEL
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 2.26 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.1.2) / Number images used: 449255
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

6nzu

source_name: PDB, initial_model_type: experimental model

2y5c

source_name: PDB, initial_model_type: experimental model
Output model

PDB-8rmc:
Structure of the FDX2-bound core ISC complex (proximal conformation)

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