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Structure paper

TitleTwo-stage binding of mitochondrial ferredoxin-2 to the core iron-sulfur cluster assembly complex.
Journal, issue, pagesNat Commun, Vol. 15, Issue 1, Page 10559, Year 2024
Publish dateDec 4, 2024
AuthorsRalf Steinhilper / Linda Boß / Sven-A Freibert / Vinzent Schulz / Nils Krapoth / Susann Kaltwasser / Roland Lill / Bonnie J Murphy /
PubMed AbstractIron-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.
External linksNat Commun / PubMed:39632806 / PubMed Central
MethodsEM (single particle)
Resolution2.03 - 2.52 Å
Structure data

EMDB-19355: Structure of the FDX2-bound core ISC complex (consensus refinement)
Method: EM (single particle) / Resolution: 2.03 Å

19356

8rmc

EMDB-19356, PDB-8rmc:
Structure of the FDX2-bound core ISC complex (proximal conformation)
Method: EM (single particle) / Resolution: 2.26 Å

19357

8rmd

EMDB-19357, PDB-8rmd:
Structure of the FDX2-bound core ISC complex (distal conformation)
Method: EM (single particle) / Resolution: 2.52 Å

EMDB-19358: Structure of the core ISC complex under turnover conditions (consensus refinement)
Method: EM (single particle) / Resolution: 2.09 Å

19359

8rme

EMDB-19359, PDB-8rme:
Structure of the core ISC complex under turnover conditions (frataxin-bound)
Method: EM (single particle) / Resolution: 2.49 Å

19360

8rmf

EMDB-19360, PDB-8rmf:
Structure of the core ISC complex under turnover conditions (FDX2-bound in proximal conformation)
Method: EM (single particle) / Resolution: 2.33 Å

19361

8rmg

EMDB-19361, PDB-8rmg:
Structure of the core ISC complex under turnover conditions (FDX2-bound in distal conformation)
Method: EM (single particle) / Resolution: 2.46 Å

Chemicals

ChemComp-FE2:
Unknown entry

ChemComp-FES:
FE2/S2 (INORGANIC) CLUSTER

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

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
  • escherichia coli bl21(de3) (bacteria)
KeywordsTRANSFERASE / cysteine desulfurase / FeS biosynthesis / FeS biogenesis / mitochondria / Friedreich's ataxia / frataxin / ferredoxin / FDX2 / iron-sulfur cluster

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