CDPK7

PfCDPK7 (PF3D7_1123100) is an atypical calcium-dependent protein kinase that couples phosphoinositide signaling to phospholipid biosynthesis and is essential for progression through the erythrocytic asexual cycle of P. falciparum (PMID:24895132, PMID:34866326). It has a non-canonical domain organization in which a pleckstrin homology (PH) domain lies adjacent to the kinase domain, with two N-terminal calcium-binding EF-hands; the PH domain binds PI(4,5)P2, providing a lipid-recognition module that guides its subcellular targeting (PMID:24895132). Functionally, PfCDPK7 is placed downstream of the lipid kinase PfPI4K: it binds 4'-phosphorylated phosphoinositides generated by PfPI4K, and pharmacological inhibition of PfPI4K disrupts the vesicular localization of PfCDPK7 (PMID:34866326). Once localized, PfCDPK7 promotes phosphatidylcholine synthesis by phosphorylating and stabilizing two enzymes of the PC biosynthetic pathway, phosphoethanolamine-N-methyltransferase (PMT) and ethanolamine kinase (EK); loss of PfCDPK7 leaves both enzymes hypophosphorylated and leads to PMT degradation (PMID:34866326). Genetic disruption stalls the ring-to-trophozoite transition and attenuates proliferation, establishing PfCDPK7 as essential for blood-stage growth (PMID:24895132).

1. 2014 Medium

   Establishing that PfCDPK7 is a structurally atypical kinase with a lipid-binding module addressed how a calcium-dependent kinase might be spatially targeted rather than acting diffusely in the cytosol.

   Evidence Domain analysis plus a biochemical PI(4,5)P2-binding assay on the PH domain

   PMID:24895132

   Open questions at the time

   • Localization consequence of PI(4,5)P2 binding was inferred, not directly shown
   • Kinase substrates and calcium dependence of activity not defined at this stage
2. 2014 Medium

   Genetic disruption tested whether PfCDPK7 is required in asexual blood stages, revealing an essential role with a defined block at the ring-to-trophozoite transition.

   Evidence Reverse genetics disruption of PfCDPK7 with blood-stage growth and stage-progression readouts

   PMID:24895132

   Open questions at the time

   • Molecular basis linking loss of kinase activity to the maturation block not resolved in this study
   • Single lab, single genetic strategy
3. 2018 Low

   Identifying a physical interaction with the RCC1-motif protein PfRCC-PIP raised the possibility of a scaffolding/anchoring platform for PfCDPK7 regulation.

   Evidence Co-immunoprecipitation/pull-down between the RCC1-motif region and PfCDPK7

   PMID:30429842

   Open questions at the time

   • Single interaction assay with no functional follow-up for the CDPK7 interaction
   • No reciprocal validation or in vivo relevance to kinase activity established
4. 2021 High

   Phosphoproteomics and lipidomics defined the downstream output of PfCDPK7, showing it drives phosphatidylcholine synthesis by phosphorylating and stabilizing PMT and EK.

   Evidence Quantitative phosphoproteomics and phospholipid analysis in PfCDPK7 knockdown/disruption parasites

   PMID:34866326

   Open questions at the time

   • Direct kinase-substrate relationship versus indirect regulation not fully separated for each enzyme
   • Mechanism linking PMT hypophosphorylation to its degradation unresolved
5. 2021 High

   Pharmacological epistasis placed PfCDPK7 downstream of PfPI4K, showing that PfPI4K-generated 4'-phosphorylated phosphoinositides recruit PfCDPK7 to vesicular membranes.

   Evidence PIP-binding assay, PfPI4K inhibitor (MMV390048) treatment with localization imaging, and phospholipid analysis

   PMID:34866326

   Open questions at the time

   • Precise vesicular compartment identity not defined
   • Whether calcium/EF-hand engagement modulates lipid-dependent recruitment not addressed

• The role of the N-terminal EF-hands and calcium signaling in controlling PfCDPK7 activation, and the full complement of its direct substrates, remain uncharacterized in the available corpus.
• No demonstration that calcium binding regulates PfCDPK7 kinase activity in vivo
• Direct substrate repertoire beyond PMT/EK not mapped
• No structural model of the multidomain enzyme