Molecular mechanisms of erythrocyte invasion in malaria

The symptoms of malaria occur as Plasmodium parasites divide within our blood cells. This requires parasites to invade cells through an active, dynamic, parasite-driven process. Here, we combine structural biology with precision genetic modification of parasites to show how three essential pieces of invasion machinery function in the deadliest malaria parasite, Plasmodium falciparum. The three protein complexes under study are: (i) The PfPCRCR complex, which is essential for Plasmodium falciparum to commit to invading an erythrocyte. (ii) The CLAMP-CLIP-SPATR complex, which is essential to trigger discharge of the Plasmodium rhoptry organelles containing molecular machinery required for parasite invasion. (iii) The RON complex, which is essential for formation of the moving junction, which is the dynamic anchor point between parasite and erythrocyte. We will: • Reveal the structure and conformational dynamics of each complex. • Identify novel parasite and erythrocyte binding partners and show how parasite complexes bind and modulate their function. • Make targeted, structure-guided, precision changes in parasites and use live cell imaging to assess effects on invasion. • Combine multiscale cryogenic electron and expansion microscopy imaging to study parasites trapped at specific stages in invasion. This study will provide mechanistic molecular snapshots of the invasion process and guide future rational therapeutic design.