CDC50C

CDC50C (PF3D7_1029400) is a P4-ATPase chaperone/flippase cofactor that partners with different P4-ATPase subunits in a stage- and species-dependent manner to support Plasmodium development and mosquito transmission (PMID:35862778, PMID:34301597). In P. falciparum asexual blood stages, CDC50C is a direct binding partner of the putative phospholipid-transporting P4-ATPase ATP2, forming a CDC50C–ATP2 complex that is essential for intraerythrocytic development: conditional disruption of CDC50C arrests parasites at the trophozoite stage and impairs endocytosis of host hemoglobin and downstream hemozoin formation (PMID:35862778). In P. yoelii ookinetes, CDC50C instead co-localizes and physically interacts with the P4-ATPase ATP7 on the plasma membrane and acts as its flippase cofactor, with depletion phenocopying ATP7 deficiency and blocking mosquito midgut traversal and transmission (PMID:34301597). Beyond its role as a P4-ATPase partner in these two contexts, no additional catalytic or structural mechanism for CDC50C has been characterized in the available corpus.

1. 2020 Low

   Establishing a controllable way to deplete CDC50C was a prerequisite for probing its function, since the protein's essentiality could otherwise preclude genetic analysis.

   Evidence CRISPR/Cas9 AID tagging with auxin-induced degradation confirmed by Western blot/immunofluorescence across asexual, gametocyte, and ookinete stages in P. yoelii

   PMID:33307135

   Open questions at the time

   • Primarily a tool-development study with limited mechanistic follow-up reported here
   • Does not itself assign a molecular function to CDC50C
   • No partner or substrate identified in this work
2. 2021 Medium

   Whether CDC50C acts as a dedicated cofactor for a specific P4-ATPase in transmission stages was resolved by showing it partners with ATP7 on the ookinete plasma membrane.

   Evidence Co-localization imaging, co-immunoprecipitation, and AID-mediated conditional depletion with mosquito-infection phenotyping in P. yoelii

   PMID:34301597

   Open questions at the time

   • Direct biochemical demonstration of lipid-flipping activity by the CDC50C–ATP7 complex not shown
   • Whether CDC50C partners with additional P4-ATPases in ookinetes not resolved
   • Species conservation of the ATP7 partnership to P. falciparum not tested
3. 2022 Medium

   The blood-stage function of CDC50C was defined by identifying ATP2 as its partner and linking the complex to trophozoite maturation, hemoglobin endocytosis, and hemozoin formation.

   Evidence Gene tagging, co-immunoprecipitation, and conditional gene disruption with developmental, hemoglobin-uptake, and hemozoin readouts in P. falciparum

   PMID:35862778

   Open questions at the time

   • Direct enzymatic/flippase activity of the CDC50C–ATP2 complex not demonstrated biochemically
   • Mechanistic link between phospholipid transport and hemoglobin endocytosis not resolved
   • Single-lab characterization

• It remains unknown whether CDC50C directly confers or regulates phospholipid-flipping catalysis and how its partner choice (ATP2 vs ATP7) is determined across stages and species.
• No structural model of CDC50C or its P4-ATPase complexes
• No reconstituted biochemical assay of flippase activity
• Rules governing partner specificity across life-cycle stages unresolved