Plasmodium falciparum causes the severe form of malaria and is responsible for significant mortality in humans. Blood stage merozoites invade erythrocytes, an essential process requiring multiple parasite ligand-host receptor interactions. Two families of merozoite invasion ligands of the erythrocyte binding-like (EBL) proteins and reticulocyte binding homologues (Rh) play pivotal roles in merozoite invasion. Most of these invasion ligands are redundant due to the ability of the parasite to use alternative ligands to mediate invasion. The exception is Rh5, a member of the Rh family being the only ligand indispensable for invasion, indicating this protein carries out distinct functions and is therefore a promising candidate for blood stage malaria vaccine development. Rh5 assembles with Ripr and CyRPA to form a multi-subunit Rh5-CyRPA-Ripr protein complex of ~ 200 kDa on the merozoite surface. The Rh5-CyRPA-Ripr complex binds to the receptor basigin on the surface of erythrocytes and this led to transfer of biomolecules across the erythrocyte membrane essential for invasion.
We used single particle cryo-electron microscopy (cryo-EM) to characterise the structure of the P. falciparum Rh5-CyRPA-Ripr invasion complex. Along with new biochemical data, this study advances our understanding on the molecular mechanism of merozoite invasion into human erythrocytes.