CDPK6

CDPK6 (PF3D7_1122800) is a calcium-dependent protein kinase implicated in the transition of Plasmodium sporozoites from a migratory to an invasive state. In P. berghei, gene disruption increases sporozoite cell traversal activity while reducing hepatocyte invasion and impairing CSP cleavage, placing CDPK6 in a signaling pathway that couples sporozoite contact with highly sulfated heparan sulfate proteoglycans to secretion of the CSP-cleaving protease and the switch to productive invasion (PMID:20951971, PMID:33191548, PMID:32866196). In P. falciparum, CDPK6 transcript is upregulated when CDPK1 activity is genetically compromised, consistent with a compensatory role, though this is a transcript-level observation rather than a direct functional test (PMID:27923926, PMID:29311293). CDPK6 has an atypical domain organization relative to CDPK1–5, with an unusually long sequence and variant EF-hand arrangement (PMID:34589185), and yeast two-hybrid screening links it to several candidate partners (PMID:24267797). Beyond the P. berghei loss-of-function phenotype (PMID:20951971, PMID:33191548, PMID:32866196), no direct enzymatic characterization, in vivo substrate, or reciprocally validated interaction of CDPK6 has been established in the available corpus.

1. 2006 Low

   Establishing that CDPK6 is structurally distinct from the other Plasmodium CDPKs framed it as a non-canonical member of the family whose function could not be assumed from CDPK1–5.

   Evidence Sequence/domain analysis of PfCDPK6 as summarized in review literature

   PMID:34589185

   Open questions at the time

   • based on computational/sequence analysis, not experimental structural validation
   • functional consequence of the atypical EF-hand arrangement unknown
   • no direct demonstration of calcium binding or kinase activity
2. 2007 Medium

   Loss-of-function genetics answered what CDPK6 does at the cellular level, showing it drives the sporozoite switch from cell traversal to hepatocyte invasion via a pathway required for CSP cleavage.

   Evidence cdpk6 gene disruption in P. berghei with readouts of cell traversal, hepatocyte invasion, and CSP cleavage

   PMID:20951971 PMID:32866196 PMID:33191548

   Open questions at the time

   • the direct substrate of CDPK6 and the identity of the CSP-cleaving protease it regulates are not defined
   • molecular link between HSPG contact and CDPK6 activation not established
   • phenotype shown in P. berghei; not tested in P. falciparum
3. 2016 Low

   Y2H screening began to map candidate CDPK6 partners, offering hypotheses for its interaction network beyond the invasion phenotype.

   Evidence Yeast two-hybrid assays identifying 11 partner proteins for PfCDPK6

   PMID:24267797

   Open questions at the time

   • Y2H interactions not confirmed by reciprocal Co-IP or in vivo validation
   • functional significance of each partner unknown
   • diverse partner set (kinetochore, chromatin, SNARE, rhoptry) not reconciled into a coherent pathway
4. 2018 Low

   Transcriptomic profiling in CDPK1-perturbed P. falciparum raised the possibility that CDPK6 acts as a compensatory kinase downstream of or parallel to PKG when CDPK1 is impaired.

   Evidence Transcript quantification (qPCR/RNA-seq) in P. falciparum CDPK1 T145M gatekeeper mutant and CDPK1 knockout parasites

   PMID:27923926 PMID:29311293

   Open questions at the time

   • compensation inferred from transcript upregulation, not directly tested functionally
   • no evidence CDPK6 protein activity increases or substitutes for CDPK1
   • position relative to PKG remains speculative
5. 2020 Medium

   A genetic epistasis screen tested whether CDPK6 functionally overlaps with CDPK4 in blood-stage growth and found no synthetic interaction, constraining models of CDPK6 redundancy.

   Evidence cdpk6 deletion in a PKGT619Q/CDPK4-KO P. berghei background with asexual growth readout

   PMID:30315162

   Open questions at the time

   • negative result does not define what CDPK6 does in blood stages
   • tested only for CDPK4 complementation, not other kinases
   • no biochemical activity assessed

• The core enzymatic behavior of CDPK6 — its in vivo substrates, calcium dependence, and the mechanism linking HSPG sensing to CSP cleavage — remains uncharacterized.
• no direct kinase assay or substrate identification for CDPK6
• the CSP-cleaving protease regulated downstream is not identified
• Y2H partners lack orthogonal validation and pathway placement