ISD11

ISD11 (PF3D7_1311000) is a mitochondrion-localized component of the ISC iron-sulfur cluster biogenesis pathway in P. falciparum, restricted exclusively to the mitochondrion so that the Isc pathway cannot contribute to apicoplast Fe-S cluster synthesis (PMID:24086138). It partners with the cysteine desulfurase PfIscS to form a PfIscS-PfIsd11 complex that, together with the scaffold protein PfIscU, assembles into an unusual symmetric hetero-hexamer [2×(2PfIscS-2PfIsd11-2PfIscU)] built around a PfIscS tetramer rather than the canonical dimer seen in other organisms (PMID:34032321). The ISD11-Nfs1 (PfIscS) complex is bound and stabilized by mitochondrial ACP (mACP), an association that occurs despite the absence of the 4-phosphopantetheine group that mediates this interaction in other eukaryotes; loss of mACP destabilizes Nfs1 and the downstream Rieske Fe-S protein of ETC complex III (PMID:34612205). Beyond these findings, no further mechanistic detail specific to ISD11 has been characterized in the available corpus.

1. 2013 Medium

   It was unknown which compartment the Plasmodium Isc pathway serves; localizing ISD11 with IscS to the mitochondrion established that this Fe-S biogenesis machinery is mitochondrial and cannot supply the apicoplast.

   Evidence Subcellular fractionation/localization of IscS and its effector ISD11 in P. falciparum

   PMID:24086138

   Open questions at the time

   • Does not resolve ISD11's own molecular role within the complex versus IscS
   • No quantitative import or topology data for ISD11 specifically
2. 2021 High

   The quaternary organization of the desulfurase machinery was undefined; structural and biochemical reconstitution showed ISD11 partners with PfIscS and PfIscU in a hetero-hexamer built on a PfIscS tetramer, revealing a non-canonical assembly.

   Evidence SAXS, spectral studies and biochemical reconstitution of the PfIscS-PfIsd11-PfIscU complex

   PMID:34032321

   Open questions at the time

   • The specific contribution of ISD11 to the tetrameric arrangement is not isolated
   • No high-resolution structure of ISD11 within the complex
3. 2021 High

   How the ISD11-containing desulfurase complex is stabilized was unknown; mACP was shown to bind and stabilize the ISD11-Nfs1 complex in a Ppant-independent manner, linking Fe-S biogenesis to downstream ETC complex III integrity.

   Evidence Binding/pulldown assays and ligand-dependent mACP knockdown with loss of Nfs1 and Rieske Fe-S protein readouts

   PMID:34612205

   Open questions at the time

   • The direct ISD11-mACP interaction interface is not mapped
   • Whether mACP loss destabilizes ISD11 itself is not directly reported

• The precise molecular function ISD11 contributes to cysteine desulfurase activity, its essentiality, and how its non-canonical assembly and mACP dependence affect parasite Fe-S output remain unresolved.
• No conditional knockdown or knockout of ISD11 itself in the corpus
• No high-resolution structure of ISD11
• Functional consequence of the tetramer-based assembly for cluster synthesis untested