Functional diversification between two related Plasmodium falciparum merozoite invasion ligands is determined by changes in the cytoplasmic domain.
The pathogenesis of Plasmodium falciparum depends on efficient invasion into host erythrocytes. Parasite ligands encoded by multi-gene families interact with erythrocyte receptors. P. falciparum reticulocyte binding protein homologues (PfRhs) are expressed at the apical surface of invasive merozoites and have divergent ectodomains that are postulated to bind different erythrocyte receptors. Variant expression of these paralogues results in the use of alternative invasion pathways. Two PfRh proteins, PfRh2a and PfRh2b, are identical for 2700 N-terminal amino acids and differ only in a C-terminal 500 amino acid region, which includes a unique ectodomain, transmembrane domain and cytoplasmic domain. Despite their similarity, PfRh2b is required for a well-defined invasion pathway while PfRh2a is not required or sufficient for this pathway. Mapping the genomic region encoding these proteins revealed a recombinogenic locus with PfRh2a and PfRh2b in a head-to-head orientation. We have generated viable PfRh2a/2b chimeric parasites to identify the regions required for alternative invasion pathway utilization. We find that the differential ability to use these pathways is conferred by the cytoplasmic domains of PfRh2a and PfRh2b, not the ectodomain or transmembrane regions. Our results highlight the importance of the cytoplasmic domain for functional diversification of a major adhesive ligand family in malaria parasites.
Dvorin
Jeffrey D
JD
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
Bei
Amy K
AK
Coleman
Bradley I
BI
Duraisingh
Manoj T
MT
D000818:Animals; D004912:Erythrocytes / Q000469:parasitology; D008024:Ligands; D008288:Malaria / Q000469:parasitology; D052940:Merozoites / Q000378:metabolism; D010963:Plasmodium falciparum / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D011995:Recombination, Genetic
D008024:Ligands; D015800:Protozoan Proteins; D011993:Recombinant Fusion Proteins; C551090:Rh2a protein, Plasmodium falciparum; C545352:Rh2b protein, Plasmodium falciparum