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- EMDB-19359: Structure of the core ISC complex under turnover conditions (frat... -

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Entry
Database: EMDB / ID: EMD-19359
TitleStructure of the core ISC complex under turnover conditions (frataxin-bound)
Map datasharpened map
Sample
  • Complex: Human core ISC complex (NFS1-ISD11-ACP1-ISCU2-FXN/FDX2) under turnover conditions
    • 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: Frataxin mature form
    • Protein or peptide: Acyl carrier protein
  • Ligand: FE (II) ION
  • 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


positive regulation of lyase activity / iron-sulfur cluster chaperone activity / negative regulation of iron ion import across plasma membrane / molybdopterin cofactor metabolic process / proprioception / Molybdenum cofactor biosynthesis / L-cysteine desulfurase complex / [4Fe-4S] cluster assembly / Mitochondrial iron-sulfur cluster biogenesis / sulfur carrier activity ...positive regulation of lyase activity / iron-sulfur cluster chaperone activity / negative regulation of iron ion import across plasma membrane / molybdopterin cofactor metabolic process / proprioception / Molybdenum cofactor biosynthesis / L-cysteine desulfurase complex / [4Fe-4S] cluster assembly / Mitochondrial iron-sulfur cluster biogenesis / sulfur carrier activity / 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 / Mo-molybdopterin cofactor biosynthetic process / mitochondrial respiratory chain complex III assembly / embryo development ending in birth or egg hatching / Mitochondrial protein import / iron-sulfur cluster assembly complex / mitochondrial [2Fe-2S] assembly complex / oxidative phosphorylation / response to iron ion / [2Fe-2S] cluster assembly / heme biosynthetic process / adult walking behavior / negative regulation of multicellular organism growth / organ growth / lipid A biosynthetic process / iron-sulfur cluster assembly / muscle cell cellular homeostasis / lipid biosynthetic process / ferroxidase / negative regulation of release of cytochrome c from mitochondria / acyl binding / acyl carrier activity / protein autoprocessing / ferroxidase activity / iron-sulfur cluster binding / phosphopantetheine binding / ferric iron binding / protein maturation / enzyme activator activity / iron ion transport / ferrous iron binding / 2 iron, 2 sulfur cluster binding / cellular response to hydrogen peroxide / fatty acid biosynthetic process / pyridoxal phosphate binding / Maturation of replicase proteins / molecular adaptor activity / intracellular iron ion homeostasis / nuclear body / mitochondrial matrix / iron ion binding / response to xenobiotic stimulus / lipid binding / centrosome / negative regulation of apoptotic process / structural molecule activity / protein homodimerization activity / mitochondrion / zinc ion binding / nucleoplasm / metal ion binding / nucleus / membrane / cytoplasm / cytosol
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 / Pyridoxal phosphate-dependent transferase, small domain / Carrier protein (CP) domain profile. / Phosphopantetheine binding ACP 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 BL21(DE3) (bacteria)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.49 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 18, 2024-
Current statusDec 18, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_19359.png

Downloads & links

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Map

FileDownload / File: emd_19359.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationsharpened map
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 288 pix.
= 238.464 Å		0.83 Å/pix.
x 288 pix.
= 238.464 Å		0.83 Å/pix.
x 288 pix.
= 238.464 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.828 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.17
Minimum - Maximum-0.8963005 - 1.403305
Average (Standard dev.)0.0010661781 (±0.038304746)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 238.464 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_19359_msk_1.map
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Additional map: unsharpened map

Fileemd_19359_additional_1.map
Annotationunsharpened map
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Half map: half map 1

Fileemd_19359_half_map_1.map
Annotationhalf map 1
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Half map: half map 2

Fileemd_19359_half_map_2.map
Annotationhalf map 2
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Sample components

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Entire : Human core ISC complex (NFS1-ISD11-ACP1-ISCU2-FXN/FDX2) under tur...

EntireName: Human core ISC complex (NFS1-ISD11-ACP1-ISCU2-FXN/FDX2) under turnover conditions
Components
  • Complex: Human core ISC complex (NFS1-ISD11-ACP1-ISCU2-FXN/FDX2) under turnover conditions
    • 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: Frataxin mature form
    • Protein or peptide: Acyl carrier protein
  • Ligand: FE (II) ION
  • 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 core ISC complex (NFS1-ISD11-ACP1-ISCU2-FXN/FDX2) under tur...

SupramoleculeName: Human core ISC complex (NFS1-ISD11-ACP1-ISCU2-FXN/FDX2) under turnover conditions
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: Frataxin mature form

MacromoleculeName: Frataxin mature form / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 14.554985 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString:
SNASGTLGHP GSLDETTYER LAEETLDSLA EFFEDLADKP YTFEDYDVSF GSGVLTVKLG GDLGTYVINK QTPNKQIWLS SPSSGPKRY DWTGKNWVYS HDGVSLHELL AAELTKALKT KLDLSSLAYS GKDA

UniProtKB: Frataxin, 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: 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: water

MacromoleculeName: water / type: ligand / ID: 8 / Number of copies: 157 / 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: 2.49 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.1.2) / Number images used: 276036
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

6nzu


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

PDB-8rme:
Structure of the core ISC complex under turnover conditions (frataxin-bound)

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