Landscape of the Plasmodium Interactome

Malaria represents a major global health issue, and the identification and prioritisation of new intervention targets remains an urgent priority. This search is significantly hampered by the fact that over a third of the genes of the malaria-causing Plasmodium parasites remain uncharacterized. We report the first large-scale interaction map of de novo protein assemblies in Plasmodium parasites, generated by combining blue native polyacrylamide electrophoresis with quantitative mass spectrometry and machine learning. Our integrative approach, which spans three different Plasmodium species, identified over twenty thousand putative protein interactions in Plasmodium schizonts, the majority of which are novel, and organized them into 600 complexes. We validate selected novel interactions, thus assigning putative functions in chromatin regulation to previously unannotated proteins and suggesting a role for an EELM2 domain-containing protein and a putative microrchidia protein as mechanistic links between complexes of AP2-domain transcription factors and epigenetic regulation. This represents the first high-confidence map of the native organisation of core conserved cellular processes in Plasmodium parasites. The network reveals putative functions of currently uncharacterized malaria proteins, provides mechanistic and structural insight, and reveals potential new therapeutic targets by grouping them into complexes with known targets.