PKB

PKB (PF3D7_1246900) is a Plasmodium falciparum protein kinase B homologue that functions as a calcium-responsive serine/threonine kinase expressed predominantly in schizonts and merozoites (PMID:15024016). Unlike mammalian PKB, it lacks a pleckstrin homology domain; instead, its unusual N-terminal region serves a negative regulatory role, and its catalytic activation requires autophosphorylation of Ser-271 in the activation loop (PMID:15024016). Rather than relying on lipid-based recruitment, PKB is activated by calmodulin binding to a domain mapped within this same N-terminal region in a calcium-dependent manner, with calmodulin associating with PKB in intact parasites (PMID:16809343). Phospholipase C acts upstream by triggering calcium release from intracellular stores, placing PKB within a PLC–Ca2+–calmodulin–PKB signaling cascade (PMID:16809343). Beyond this activation logic, no physiological substrates or downstream effectors of PKB have been characterized in the available corpus.

1. 2004 Medium

   Establishing whether P. falciparum encodes a functional PKB and how it achieves catalytic activation mattered because the parasite enzyme diverges structurally from its mammalian counterpart; the work showed a stage-specific kinase activated by activation-loop autophosphorylation rather than by canonical lipid signaling.

   Evidence In vitro biochemical and autophosphorylation assays with N-terminal domain dissection and inhibitor studies in P. falciparum

   PMID:15024016

   Open questions at the time

   • No physiological substrate identified
   • Functional consequence of Ser-271 autophosphorylation in vivo not tested
   • Mechanism by which the N-terminal region represses catalysis not structurally defined
2. 2006 Medium

   Because PKB lacks the PH domain used by mammalian orthologs for activation, the upstream input was unknown; identifying calmodulin as a calcium-dependent activator binding the N-terminal region defined a PLC–Ca2+–CaM–PKB cascade as the route to enzyme activation.

   Evidence CaM-binding domain mapping, co-immunoprecipitation of CaM with PKB in parasite lysates, calcium-dependent binding/activation assays, and PLC inhibitor experiments in P. falciparum

   PMID:16809343

   Open questions at the time

   • Downstream substrates and biological output of activated PKB not identified
   • Findings from a single lab without independent replication
   • Physiological trigger for PLC activation in schizonts/merozoites not defined

• The downstream branch of the pathway remains open: no physiological substrate, effector, or cellular process controlled by PKB has been established.
• No substrate identified
• No genetic knockout or conditional depletion phenotype reported
• Role in merozoite/schizont biology or invasion not tested