CDPK1 (Plasmodium falciparum 3D7, P62344, PF3D7_0217500) - curation notes

Note: automated deep research was unavailable in this environment (Falcon auth
failure, invalid OpenAI key). These notes are a manual literature review based on the
UniProt record, the cached publications in publications/, and a targeted web search
(which identified and cached PMID:29311293).

Identity and domain architecture

• Calcium-dependent protein kinase 1 (PfCDPK1; old names PfCPK, PFB0815w). CDPKs are
  a plant/alveolate kinase family that fuse a Ser/Thr kinase domain to a junction (J)
  domain and a calmodulin-like domain (CLD) with four EF hands; they do not need
  separate calmodulin.
• PMID:8142371
• PMID:8142371
• EF-hand sites I and II are critical for activation:
  PMID:8142371
• The CLD binds the J-domain P3 region in a Ca2+-dependent manner:
  PMID:23204525
• Autophosphorylation and the N-terminal extension contribute to activation:
  PMID:22539638
• Truncation removing the J domain/CLD gives Ca2+-independent activity
  PMID:19307175.

Localization

• N-myristoylation (Gly2), palmitoylation (Cys3) and a basic cluster anchor it to membranes:
  PMID:15491359
• PV and tubovesicular network in trophozoites:
  PMID:15491359
• Parasite plasma membrane of merozoites (most consistent result across labs):
  PMID:18768477;
  PMID:23548171;
  PMID:32003970.
• Host erythrocyte membrane: reported by IFA in one study
  PMID:23204525
  but not seen with endogenous GFP tagging (PMID:23548171, above). Treat as unresolved / minor.
• Peripheral localization also in gametocytes and gametes:
  PMID:29311293.

Activity and substrates

• Motor complex substrates MTIP and GAP45:
  PMID:18768477;
  PMID:22479457
• RKIP (PfPE-PB1) as in vitro substrate/modulator:
  PMID:17123645.
• Phosphoproteomic substrate set incl. IMC proteins and PKA-R:
  PMID:28680058;
  PMID:28680058.
• SERA5 (contested protease) phosphorylation:
  PMID:29716996.
• RhopH3 S804:
  PMID:33024030
• Upstream: phosphorylated by PKG at S64
  PMID:26149123.
• 14-3-3I binds phospho-S64 motif; scaffolds a CDPK1/PKAr/14-3-3I complex:
  PMID:32484216;
  PMID:32817103.

Biological role

• Microneme secretion / invasion:
  PMID:23204525;
  PMID:28680058
• Conflicting view: DD knockdown had no phenotype, J-domain expression arrests early schizogony
  PMID:23548171.
• KO possible only in T145M background; slow asexual growth and loss of gametogenesis:
  PMID:29311293
• Drug target; inhibitor series do not cleanly correlate with growth inhibition
  PMID:25070106

Curation calls (summary)

• Core MF: GO:0009931 calcium-dependent protein serine/threonine kinase activity.
  Generic kinase rows (GO:0004672, GO:0004674) and the IBA GO:0004683
  (Ca2+/calmodulin-dependent) are modified to GO:0009931: CDPKs carry their own CLD and
  are activated by Ca2+ alone (PMID:8142371).
• GO:0005516 calmodulin binding (IBA) removed: no evidence; the PAINT node spans
  CaMK/CRK-like kinases that do bind CaM, but CDPKs are CaM-independent.
• GO:0009410 response to xenobiotic stimulus removed: inhibitor-sensitivity screening
  (PMID:25070106) is not a biological process of the gene product.
• Nucleus (IBA) flagged as over-annotation: myristoylated/palmitoylated membrane kinase,
  no nuclear localization reported.
• Location: plasma membrane accepted as core; PV/PVM/host PM/cytoplasm/motile cilium
  kept as non-core; generic "membrane" modified to plasma membrane + PVM.
• No microneme-secretion-specific GO term exists; GO:1903307 positive regulation of
  regulated secretory pathway accepted as best available.