Structure of malaria invasion protein RH5 with erythrocyte basigin and blocking antibodies

• Published in: Nature (London) 2014-11, Vol.515 (7527), p.427-430
• Main Authors: Wright, Katherine E., Hjerrild, Kathryn A., Bartlett, Jonathan, Douglas, Alexander D., Jin, Jing, Brown, Rebecca E., Illingworth, Joseph J., Ashfield, Rebecca, Clemmensen, Stine B., de Jongh, Willem A., Draper, Simon J., Higgins, Matthew K.
• Format: Article
• Language: English
• Subjects: 631/326/417; 631/535/1266; Analysis; Antibodies; Antibodies, Blocking - chemistry; Antibodies, Blocking - immunology; Antigens, Protozoan - chemistry; Antigens, Protozoan - immunology; Basigin - chemistry; Basigin - immunology; Binding Sites; Crystal structure; Crystallography, X-Ray; Epitopes - chemistry; Epitopes - immunology; Erythrocytes; Erythrocytes - chemistry; Health aspects; Host-Parasite Interactions - immunology; Humanities and Social Sciences; Humans; Hydrogen bonds; Invasive species; letter; Ligands; Malaria; Malaria - parasitology; Models, Molecular; Monoclonal antibodies; multidisciplinary; Parasites; Plasmodium falciparum - chemistry; Plasmodium falciparum - immunology; Protein binding; Proteins; Protozoan Proteins - chemistry; Protozoan Proteins - immunology; Science; Vaccines; Vector-borne diseases; Viral antibodies
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature13715

Reticulocyte-binding protein homologue 5 (PfRH5) of Plasmodium falciparum , the malaria parasite, is known to be necessary for red blood cell invasion, making PfRH5 a promising vaccine candidate; here the X-ray crystallographic structure of PfRH5 in complex with basigin and with inhibitory antibodies is determined. Malaria invasion protein structure Each species of the malaria parasite Plasmodium contains at least one reticulocyte-binding protein homologue (RH) protein, which together with erythrocyte binding-like proteins plays a part in erythrocyte invasion, a key step in the parasites' life cycle. The reticulocyte-binding protein homologue 5 (PfRH5) of P. falciparum interacts with the erythrocyte surface protein basigin and has been identified as a promising vaccine candidate. Here Matthew Higgins and colleagues describe the X-ray crystallographic structure of PfRH5 in complex with basigin and also with inhibitory antibodies. The structure reveals a fold with a kite-like architecture with binding sites for basigin and the antibodies at one tip. Invasion of host erythrocytes is essential to the life cycle of Plasmodium parasites and development of the pathology of malaria. The stages of erythrocyte invasion, including initial contact, apical reorientation, junction formation, and active invagination, are directed by coordinated release of specialized apical organelles and their parasite protein contents 1 . Among these proteins, and central to invasion by all species, are two parasite protein families, the reticulocyte-binding protein homologue (RH) and erythrocyte-binding like proteins, which mediate host–parasite interactions 2 . RH5 from Plasmodium falciparum (PfRH5) is the only member of either family demonstrated to be necessary for erythrocyte invasion in all tested strains, through its interaction with the erythrocyte surface protein basigin (also known as CD147 and EMMPRIN) 3 , 4 . Antibodies targeting PfRH5 or basigin efficiently block parasite invasion in vitro 4 , 5 , 6 , 7 , 8 , 9 , making PfRH5 an excellent vaccine candidate. Here we present crystal structures of PfRH5 in complex with basigin and two distinct inhibitory antibodies. PfRH5 adopts a novel fold in which two three-helical bundles come together in a kite-like architecture, presenting binding sites for basigin and inhibitory antibodies at one tip. This provides the first structural insight into erythrocyte binding by the Plasmodium RH protein family and identifies novel inhibitory