A co-ligand complex anchors Plasmodium falciparum merozoites to the erythrocyte invasion receptor band 3.
In Plasmodium falciparum malaria, erythrocyte invasion by circulating merozoites may occur via two distinct pathways involving either a sialic acid-dependent or -independent mechanism. Earlier, we identified two nonglycosylated exofacial regions of erythrocyte band 3 termed 5ABC and 6A as an important host receptor in the sialic acid-independent invasion pathway. 5ABC, a major segment of this receptor, interacts with the 42-kDa processing product of merozoite surface protein 1 (MSP1(42)) through its 19-kDa C-terminal domain. Here, we show that two regions of merozoite surface protein 9 (MSP9), also known as acidic basic repeat antigen, interact directly with 5ABC during erythrocyte invasion by P. falciparum. Native MSP9 as well as recombinant polypeptides derived from two regions of MSP9 (MSP9/Delta1 and MSP9/Delta2) interacted with both 5ABC and intact erythrocytes. Soluble 5ABC added to the assay mixture drastically diminished the binding of MSP9 to erythrocytes. Recombinant MSP9/Delta1 and MSP9/Delta2 present in the culture medium blocked P. falciparum reinvasion into erythrocytes in vitro. Native MSP9 and MSP1(42), the two ligands binding to the 5ABC receptor, existed as a stable complex. Our results establish a novel concept wherein the merozoite exploits a specific complex of co-ligands on its surface to target a single erythrocyte receptor during invasion. This new paradigm poses a new challenge in the development of a vaccine for blood stage malaria.
Li
Xuerong
X
Division of Cell Biology, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02135, USA.
Chen
Huiqing
H
Oo
Thein H
TH
Daly
Thomas M
TM
Bergman
Lawrence W
LW
Liu
Shih-Chun
SC
Chishti
Athar H
AH
Oh
Steven S
SS
D000818:Animals; D001457:Anion Exchange Protein 1, Erythrocyte / Q000737:chemistry*; D015153:Blotting, Western; D002352:Carrier Proteins / Q000737:chemistry; D003470:Culture Media / Q000494:pharmacology; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000378:metabolism; D015723:Gene Library; D006801:Humans; D008024:Ligands; D008565:Membrane Proteins / Q000378:metabolism; D008954:Models, Biological; D010963:Plasmodium falciparum / Q000378:metabolism*; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000737:chemistry / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry; D020798:Two-Hybrid System Techniques
D001457:Anion Exchange Protein 1, Erythrocyte; D002352:Carrier Proteins; D003470:Culture Media; D018076:DNA, Complementary; D008024:Ligands; D008565:Membrane Proteins; D015800:Protozoan Proteins; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; C451423:erythrocyte binding protein-2, Plasmodium falciparum; C455300:merozoite surface protein 9, Plasmodium