Abstract
Identifying functionally critical regions of the malaria antigen AMA1 (apical membrane antigen 1) is necessary to understand the significance of the polymorphisms within this antigen for vaccine development. The crystal structure of AMA1 in complex with the Fab fragment of inhibitory monoclonal antibody 1F9 reveals that 1F9 binds to the AMA1 solvent-exposed hydrophobic trough, confirming its importance. 1F9 uses the heavy and light chain complementarity-determining regions (CDRs) to wrap around the polymorphic loops adjacent to the trough, but uses a ridge of framework residues to bind to the hydrophobic trough. The resulting 1F9-AMA1–combined buried surface of 2,470 Å2 is considerably larger than previously reported Fab–antigen interfaces. Mutations of polymorphic AMA1 residues within the 1F9 epitope disrupt 1F9 binding and dramatically reduce the binding of affinity-purified human antibodies. Moreover, 1F9 binding to AMA1 is competed by naturally acquired human antibodies, confirming that the 1F9 epitope is a frequent target of immunological attack.
Highlights
Malaria is a global health problem that results in up to 3 million deaths annually [1,2]
Malaria caused by Plasmodium falciparum causes more than 1 million deaths annually, and the development of a vaccine against this parasite is a major public health priority
We show that mutagenesis of key residues on the loops surrounding the hydrophobic trough is sufficient to interfere with monoclonal antibody (mAb) 1F9 binding, and that the binding of both 1F9 and 4G2 to apical membrane antigen 1 (AMA1) is competed by naturally acquired human antibodies
Summary
Malaria is a global health problem that results in up to 3 million deaths annually [1,2]. Identifying the antigens recognized by protective immune responses induced by malaria has been difficult, but many proteins associated with the merozoite surface or apical organelles are targets of antibodies that block merozoite invasion. One such antigen that shows promise as a vaccine candidate is apical membrane antigen 1 (AMA1). Recombinant AMA1 ectodomain is highly effective at inducing protection in animal models of human malaria [8,9]. Protection induced by AMA1 is mediated by antibodies that recognize conformational epitopes on the surface of the protein. Rabbit and human anti-AMA1 antibodies have been shown to efficiently inhibit parasite invasion of erythrocytes in vitro [12]
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