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Crystal structure of Plasmodium knowlesi apical membrane antigen 1 and its complex with an invasion-inhibitory monoclonal antibody.

Vulliez-Le Normand B, Faber BW, Saul FA, van der Eijk M, Thomas AW, Singh B, Kocken CH, Bentley GA - PLoS ONE (2015)

Bottom Line: R31C2 inhibits binding of the Rhoptry Neck Protein 2 (RON2) receptor by steric blocking of the hydrophobic groove and by preventing the displacement of the D2 loop which is essential for exposing the complete binding site on AMA1.PkAMA1 is much less polymorphic than the P. falciparum and P. vivax orthologues.Unlike these two latter species, there are no polymorphic sites close to the RON2-binding site of PkAMA1, suggesting that P. knowlesi has not developed a mechanism of immune escape from the host's humoral response to AMA1.

View Article: PubMed Central - PubMed

Affiliation: Institut Pasteur, Unité d'Immunologie Structurale, Département de Biologie Structurale et Chimie, Paris, France; CNRS URA 2185, Paris, France.

ABSTRACT
The malaria parasite Plasmodium knowlesi, previously associated only with infection of macaques, is now known to infect humans as well and has become a significant public health problem in Southeast Asia. This species should therefore be targeted in vaccine and therapeutic strategies against human malaria. Apical Membrane Antigen 1 (AMA1), which plays a role in Plasmodium merozoite invasion of the erythrocyte, is currently being pursued in human vaccine trials against P. falciparum. Recent vaccine trials in macaques using the P. knowlesi orthologue PkAMA1 have shown that it protects against infection by this parasite species and thus should be developed for human vaccination as well. Here, we present the crystal structure of Domains 1 and 2 of the PkAMA1 ectodomain, and of its complex with the invasion-inhibitory monoclonal antibody R31C2. The Domain 2 (D2) loop, which is displaced upon binding the Rhoptry Neck Protein 2 (RON2) receptor, makes significant contacts with the antibody. R31C2 inhibits binding of the Rhoptry Neck Protein 2 (RON2) receptor by steric blocking of the hydrophobic groove and by preventing the displacement of the D2 loop which is essential for exposing the complete binding site on AMA1. R31C2 recognizes a non-polymorphic epitope and should thus be cross-strain reactive. PkAMA1 is much less polymorphic than the P. falciparum and P. vivax orthologues. Unlike these two latter species, there are no polymorphic sites close to the RON2-binding site of PkAMA1, suggesting that P. knowlesi has not developed a mechanism of immune escape from the host's humoral response to AMA1.

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Comparison of the D2 loop of PkAMA1 and PfAMA1.(A) PkAMA1. (B) PfAMA1 (PDB entry 2Z8V). The two structures are viewed from equivalent orientations and are shown in surface representation with Domain 1 in green, Domain 2 in light brown, and the D2 loop in red. The D2 loop conformation of both orthologues is shown in ribbon representation and the N- and C-terminal residues are labelled.
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pone.0123567.g007: Comparison of the D2 loop of PkAMA1 and PfAMA1.(A) PkAMA1. (B) PfAMA1 (PDB entry 2Z8V). The two structures are viewed from equivalent orientations and are shown in surface representation with Domain 1 in green, Domain 2 in light brown, and the D2 loop in red. The D2 loop conformation of both orthologues is shown in ribbon representation and the N- and C-terminal residues are labelled.

Mentions: The D2 loop is functionally important as it must be displaced to fully expose the binding site for the RON receptor. Nonetheless, this region is more variable among the different Plasmodium homologues than is the sequence variability over the complete ectodomain [50]. Interestingly, the D2 loop adopts a different conformation in PkAMA1 to that which has been observed in PfAMA1 (Fig 7). This could be due to sequence differences between the two homologues or could arise from inherent flexibility in this region of AMA1.


Crystal structure of Plasmodium knowlesi apical membrane antigen 1 and its complex with an invasion-inhibitory monoclonal antibody.

Vulliez-Le Normand B, Faber BW, Saul FA, van der Eijk M, Thomas AW, Singh B, Kocken CH, Bentley GA - PLoS ONE (2015)

Comparison of the D2 loop of PkAMA1 and PfAMA1.(A) PkAMA1. (B) PfAMA1 (PDB entry 2Z8V). The two structures are viewed from equivalent orientations and are shown in surface representation with Domain 1 in green, Domain 2 in light brown, and the D2 loop in red. The D2 loop conformation of both orthologues is shown in ribbon representation and the N- and C-terminal residues are labelled.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4401722&req=5

pone.0123567.g007: Comparison of the D2 loop of PkAMA1 and PfAMA1.(A) PkAMA1. (B) PfAMA1 (PDB entry 2Z8V). The two structures are viewed from equivalent orientations and are shown in surface representation with Domain 1 in green, Domain 2 in light brown, and the D2 loop in red. The D2 loop conformation of both orthologues is shown in ribbon representation and the N- and C-terminal residues are labelled.
Mentions: The D2 loop is functionally important as it must be displaced to fully expose the binding site for the RON receptor. Nonetheless, this region is more variable among the different Plasmodium homologues than is the sequence variability over the complete ectodomain [50]. Interestingly, the D2 loop adopts a different conformation in PkAMA1 to that which has been observed in PfAMA1 (Fig 7). This could be due to sequence differences between the two homologues or could arise from inherent flexibility in this region of AMA1.

Bottom Line: R31C2 inhibits binding of the Rhoptry Neck Protein 2 (RON2) receptor by steric blocking of the hydrophobic groove and by preventing the displacement of the D2 loop which is essential for exposing the complete binding site on AMA1.PkAMA1 is much less polymorphic than the P. falciparum and P. vivax orthologues.Unlike these two latter species, there are no polymorphic sites close to the RON2-binding site of PkAMA1, suggesting that P. knowlesi has not developed a mechanism of immune escape from the host's humoral response to AMA1.

View Article: PubMed Central - PubMed

Affiliation: Institut Pasteur, Unité d'Immunologie Structurale, Département de Biologie Structurale et Chimie, Paris, France; CNRS URA 2185, Paris, France.

ABSTRACT
The malaria parasite Plasmodium knowlesi, previously associated only with infection of macaques, is now known to infect humans as well and has become a significant public health problem in Southeast Asia. This species should therefore be targeted in vaccine and therapeutic strategies against human malaria. Apical Membrane Antigen 1 (AMA1), which plays a role in Plasmodium merozoite invasion of the erythrocyte, is currently being pursued in human vaccine trials against P. falciparum. Recent vaccine trials in macaques using the P. knowlesi orthologue PkAMA1 have shown that it protects against infection by this parasite species and thus should be developed for human vaccination as well. Here, we present the crystal structure of Domains 1 and 2 of the PkAMA1 ectodomain, and of its complex with the invasion-inhibitory monoclonal antibody R31C2. The Domain 2 (D2) loop, which is displaced upon binding the Rhoptry Neck Protein 2 (RON2) receptor, makes significant contacts with the antibody. R31C2 inhibits binding of the Rhoptry Neck Protein 2 (RON2) receptor by steric blocking of the hydrophobic groove and by preventing the displacement of the D2 loop which is essential for exposing the complete binding site on AMA1. R31C2 recognizes a non-polymorphic epitope and should thus be cross-strain reactive. PkAMA1 is much less polymorphic than the P. falciparum and P. vivax orthologues. Unlike these two latter species, there are no polymorphic sites close to the RON2-binding site of PkAMA1, suggesting that P. knowlesi has not developed a mechanism of immune escape from the host's humoral response to AMA1.

Show MeSH
Related in: MedlinePlus