Protein Kinase Signaling in Malaria Parasites

Protein kinases orchestrate critical regulatory pathways in Plasmodium species by transferring phosphate groups to target proteins, thereby modulating their activity, localisation and interactions. In malaria parasites, protein kinase signalling underpins essential processes including host erythrocyte invasion, intracellular development, motility and transmission through the mosquito vector. Central to these pathways are cyclic nucleotide-dependent kinases, notably cGMP-dependent protein kinase (PKG) and cAMP-dependent protein kinase (PKA), which respond to second messengers and integrate environmental cues into precise phosphorylation events. Calcium-dependent protein kinases (CDPKs) translate fluctuations in intracellular Ca2+ into phosphorylation of motor-complex components and regulatory factors. Global profiling of phosphorylation sites has revealed that PKG acts as a signalling hub, connecting cyclic nucleotide turnover, phosphoinositide metabolism and calcium release to coordinate egress, gliding motility and invasion. Downstream of these kinases lie parasite-specific substrates such as glideosome proteins and microneme secretion factors, making these pathways attractive targets for novel antimalarial interventions. Emerging chemical inhibitors and genetic tools continue to illuminate the interconnected networks of cyclic nucleotide and calcium signalling that drive the complex lifecycle of malaria parasites.

Research from Nature Portfolio

Recent studies have advanced our understanding of cyclic nucleotide-dependent kinases as drug targets. A medicinal chemistry programme identified a series of imidazopyridine compounds that inhibit PfPKG with subnanomolar potency, abolish blood-stage proliferation in vitro and clear infection in murine models while blocking transmission to mosquitoes. Structural analyses of PKG–inhibitor complexes elucidated the molecular basis for high selectivity and potency, guiding optimisation of lead compounds. In parallel, conditional knockdown of the calcium-dependent protein kinase PfCDPK1, combined with comparative phosphoproteomics, delineated its essential role in erythrocyte invasion. This work uncovered PfCDPK1 substrates within the inner membrane complex and actomyosin motor apparatus, and revealed cross-talk whereby PfCDPK1 phosphorylates the regulatory subunit of PfPKA, thus integrating calcium and cAMP signalling during merozoite entry into host cells.

Protein Kinase Signaling in Malaria Parasites publication trend

The graph below shows the total number of articles in protein kinase signaling in malaria parasites across all publications each year (not limited to Nature Index journals).

Technical terms

Protein kinase: Enzyme that catalyses transfer of a phosphate group from ATP to specific amino acids on target proteins, regulating their function.

Phosphorylation: Reversible attachment of a phosphate group to a protein, altering its activity, stability or localisation.

cGMP (cyclic guanosine monophosphate): Intracellular second messenger synthesised by guanylate cyclases, activating PKG and downstream pathways.

PKG (cGMP-dependent protein kinase): Serine/threonine kinase activated by cGMP, central to egress, motility and invasion signalling.

CDPK (calcium-dependent protein kinase): Kinase family that senses intracellular Ca2+ fluctuations via EF-hand motifs and phosphorylates key substrates.

Phosphoproteomics: Global analytical approach to identify and quantify phosphorylated proteins and their modification sites.

References

1. Protein kinase PfPK2 mediated signalling is critical for host erythrocyte invasion by malaria parasite. PLOS Pathogens (2023).
2. Apicomplexan phosphodiesterases in cyclic nucleotide turnover: conservation, function, and therapeutic potential. mBio (2023).
3. Characterizing the Specific Recognition of Xanthurenic Acid by GEP1 and GEP1-GCα Interactions in cGMP Signaling Pathway in Gametogenesis of Malaria Parasites. International Journal of Molecular Sciences (2023).
4. A potent series targeting the malarial cGMP-dependent protein kinase clears infection and blocks transmission. Nature Communications (2017).
5. PfCDPK1 mediated signaling in erythrocytic stages of Plasmodium falciparum. Nature Communications (2017).
6. Phosphoproteomics reveals malaria parasite Protein Kinase G as a signalling hub regulating egress and invasion. Nature Communications (2015).
7. Phosphoinositide Metabolism Links cGMP-Dependent Protein Kinase G to Essential Ca2+ Signals at Key Decision Points in the Life Cycle of Malaria Parasites. PLOS Biology (2014).
8. The Motor Complex of Plasmodium falciparum PHOSPHORYLATION BY A CALCIUM-DEPENDENT PROTEIN KINASE*. Journal of Biological Chemistry (2008).
9. Cyclic nucleotide signalling in malaria parasites. Open Biology (2017).