SufC

SufC (PF3D7_1413500) is a nuclear-encoded ATPase that is imported into the P. falciparum apicoplast, where it functions in the SUF pathway of [Fe-S] cluster biogenesis (PMID:21722645, PMID:24586983). Recombinant SufC hydrolyzes ATP in vitro and interacts with the apicoplast-genome-encoded SufB through an internal region of SufB (PMID:21722645). Together with apicoplast-targeted SufD, SufC assembles into a SufB–SufC2–SufD scaffold complex that reconstitutes [4Fe-4S] clusters in vitro, and SufD stimulates the ATPase activity of SufC (PMID:28695709). SufC is essential for parasite survival in both P. berghei, where its gene is refractory to deletion in asexual blood stages (PMID:24586983), and P. falciparum, where conditional deletion is lethal unless rescued by IPP supplementation (PMID:37166116). Unlike loss of SufS, SufC deletion does not cause loss of the apicoplast organelle or its genome, establishing that SufC's essential role lies specifically in the FeS cluster assembly steps rather than in organelle maintenance (PMID:37166116).

1. 2003 Low

   Establishing whether the plastid-encoded SufB and the nucleus-encoded SufC physically associate was needed to define whether a SufBC assembly complex exists in the parasite apicoplast.

   Evidence Physical interaction assay between plastid-encoded SufB and imported SufC

   PMID:12594924

   Open questions at the time

   • Interaction method not fully described in the source
   • No mutagenesis or orthogonal confirmation reported
   • Functional consequence of the interaction not addressed
2. 2011 Medium

   Determining that SufC is an active ATPase localized to the apicoplast and binds a defined region of SufB provided the first biochemical characterization of SufC's enzymatic activity and its partner interface.

   Evidence Recombinant ATPase assay, apicoplast localization, and affinity co-elution of SufB from parasite lysate with recombinant SufC in P. falciparum

   PMID:21722645

   Open questions at the time

   • ATPase activity shown only with recombinant protein, not in cellular context
   • Stoichiometry of the SufB–SufC complex not defined
   • Functional coupling of ATP hydrolysis to cluster assembly not tested
3. 2013 Medium

   Perturbing the Suf pathway with a dominant negative mutant tested whether the pathway is essential beyond isoprenoid precursor supply and whether it maintains the apicoplast itself.

   Evidence Dominant negative mutant, IPP chemical bypass, apicoplast fluorescence microscopy, and organellar genome PCR in P. falciparum

   PMID:24086138

   Open questions at the time

   • The dominant negative targets the broader Suf pathway rather than SufC specifically
   • Does not isolate SufC's individual contribution to the phenotype
4. 2014 Medium

   Testing whether SufC can be genetically deleted established that it is required for blood-stage parasite survival in a rodent malaria model and confirmed apicoplast localization in vivo.

   Evidence Targeted gene deletion refractoriness and endogenous fluorescent tagging with live imaging in P. berghei

   PMID:24586983

   Open questions at the time

   • Refractoriness to deletion infers essentiality indirectly
   • Mechanism of essentiality not addressed
   • Restricted to asexual blood stages
5. 2017 High

   Reconstituting the SufB–SufC2–SufD complex and showing it assembles [4Fe-4S] clusters in vitro defined the molecular scaffold in which SufC operates and revealed that SufD stimulates its ATPase activity.

   Evidence In vitro interaction assays, in vivo cross-linking, in vitro [4Fe-4S] cluster assembly, and ATPase assay with SufD in P. falciparum

   PMID:28695709

   Open questions at the time

   • Structural basis of ATPase stimulation by SufD not resolved
   • Downstream recipients of assembled clusters not identified
   • How ATP hydrolysis is coupled to cluster transfer unknown
6. 2023 High

   Conditional deletion of SufC with chemical bypass distinguished its essential role in FeS cluster assembly from organelle maintenance, showing that unlike SufS, SufC loss does not destroy the apicoplast or its genome.

   Evidence Conditional gene deletion with IPP chemical bypass, apicoplast fluorescence microscopy, and organellar genome PCR in P. falciparum

   PMID:37166116

   Open questions at the time

   • The essential FeS-dependent downstream client(s) causing lethality not identified
   • Mechanistic reason for the divergent phenotype from SufS not resolved

• The essential downstream [Fe-S] cluster recipient proteins whose maturation depends on SufC, and the structural coupling between SufC ATP hydrolysis and cluster assembly/transfer, remain unresolved.
• No client apoprotein of the SufBC2D scaffold identified in the corpus
• No structure of the P. falciparum SufBC2D complex
• Mechanism linking ATPase cycle to cluster transfer unknown