SufA

SufA (PF3D7_0522700) is the A-type carrier protein of the Plasmodium apicoplast SUF [Fe-S] cluster assembly pathway, functioning to accept assembled [Fe-S] clusters and transfer them to downstream apo-proteins (PMID:28695709). It exists as a homodimer that coordinates an [Fe4S4] cluster via conserved cysteine residues at the dimer interface, and it physically engages the SufB scaffold component (PMID:28695709, PMID:27033210). In P. falciparum, in vitro transfer assays show SufA can relay clusters from the SufB-C2-D scaffold, though the NifU-like protein PfNfu performs [4Fe-4S] transfer more efficiently (PMID:28695709); work on the P. vivax ortholog demonstrates SufA accepts sulfur mobilized by the SufSE complex and, with an iron source, assembles clusters that are transferred to the apo-target IspG (PMID:27033210, PMID:30721667). All apicoplast SUF proteins including SufA localize to the apicoplast (PMID:24586983, PMID:27033210). Genetically, SufA is individually dispensable for asexual blood-stage growth and across the complete life cycle in P. berghei (PMID:24586983), and in P. falciparum its individual loss is tolerated but its combined deletion with NfuApi is synthetically lethal, establishing that SufA and NfuApi act redundantly to deliver [Fe-S] clusters to ferredoxin and other essential apicoplast proteins (PMID:35164549).

1. 2014 High

   Establishing whether SufA is required for parasite viability was the first question; genetic ablation showed it is dispensable, redirecting attention to functional redundancy rather than essentiality.

   Evidence Targeted gene deletion and endogenous fluorescent tagging in P. berghei across the full life cycle

   PMID:24586983

   Open questions at the time

   • Does not test redundancy with other carrier proteins
   • Dispensability shown in P. berghei, not directly in P. falciparum blood stage
2. 2016 Medium

   The biochemical identity of SufA as an Fe-S carrier was addressed by showing the ortholog assembles a [Fe4S4] cluster and coordinates it at a homodimer interface, defining its structural mode of cluster binding.

   Evidence UV-visible and EPR spectroscopy plus interface modeling and apicoplast co-localization of the P. vivax ortholog

   PMID:27033210

   Open questions at the time

   • Interaction with SufB is partly computational
   • Shown for P. vivax ortholog, not directly PF3D7_0522700
   • No mutagenesis of the coordinating cysteines
3. 2017 Medium

   Whether SufA is the primary cluster carrier was tested by comparative transfer assays, which showed SufA transfers clusters from the SufB-C2-D scaffold but less efficiently than PfNfu, hinting at overlapping carrier roles.

   Evidence In vitro Fe-S assembly/transfer assays, interaction experiments, and in vivo cross-linking in P. falciparum

   PMID:28695709

   Open questions at the time

   • No mutagenesis or structural validation of SufA specifically
   • Efficiency comparison uses a model target protein, not physiological substrates
4. 2019 Medium

   The downstream endpoint of SufA-mediated transfer was defined by reconstituting cluster delivery to a specific apo-target, IspG, from sulfur mobilized by SufSE.

   Evidence In vitro assembly and transfer assays using proteins from P. vivax clinical isolates

   PMID:30721667

   Open questions at the time

   • In vitro reconstitution only, not in cellulo
   • P. vivax proteins, physiological relevance in P. falciparum not directly tested
5. 2022 High

   The paradox of SufA dispensability was resolved by demonstrating synthetic lethality with NfuApi, establishing that SufA and NfuApi redundantly deliver clusters to ferredoxin and other essential apicoplast proteins.

   Evidence Single and double conditional deletions in the P. falciparum PfMev apicoplast metabolic bypass line

   PMID:35164549

   Open questions at the time

   • Does not resolve substrate-level division of labor between SufA and NfuApi
   • Mechanism of redundant recruitment to targets unknown

• It remains unknown which endogenous P. falciparum apo-targets SufA services versus NfuApi, and what structural or regulatory features partition their overlapping carrier functions.
• No structure of P. falciparum SufA
• Physiological substrate specificity in P. falciparum undefined
• No mutagenesis of cluster-coordinating residues in PF3D7_0522700