Plasmodium falciparum, the causative agent of the most severe form of malaria in 
humans invades erythrocytes using multiple ligand-receptor interactions. The P. 
falciparum reticulocyte binding-like homologue proteins (PfRh or PfRBL) are 
important for entry of the invasive merozoite form of the parasite into red 
blood cells. We have analysed two members of this protein family, PfRh2a and 
PfRh2b, and show they undergo a complex series of proteolytic cleavage events 
before and during merozoite invasion. We show that PfRh2a undergoes a cleavage 
event in the transmembrane region during invasion consistent with activity of 
the membrane associated PfROM4 protease that would result in release of the 
ectodomain into the supernatant. We also show that PfRh2a and PfRh2b bind to red 
blood cells and have defined the erythrocyte-binding domain to a 15 kDa region 
at the N-terminus of each protein. Antibodies to this receptor-binding region 
block merozoite invasion demonstrating the important function of this domain. 
This region of PfRh2a and PfRh2b has potential in a combination vaccine with 
other erythrocyte binding ligands for induction of antibodies that would block a 
broad range of invasion pathways for P. falciparum into human erythrocytes.