title: Structure-function-immunogenicity studies of PfEMP1 domain DBL2βPF11_0521, a malaria parasite ligand for ICAM-1.
abstract: Plasmodium falciparum virulence has been ascribed to its ability to sequester in deep vascular beds, mediated by the variant surface antigen family PfEMP1 binding endothelial receptors like ICAM-1. We previously observed that naturally-acquired antibodies that block a PfEMP1 domain, DBL2β of PF11_0521 allele, from binding to the human ICAM1 receptor, reduce the risk of malaria hospitalization in children. Here, we find that DBL2βPF11_0521 binds ICAM-1 in the low nM range and relate the structure of this domain with its function and immunogenicity. We demonstrate that the interaction with ICAM-1 is not impaired by point mutations in the N-terminal subdomain or in the flexible Loop 4 of DBL2βPF11_0521, although both substructures were previously implicated in binding ICAM-1. These data will help to refine the existing model of DBLβ::ICAM-1 interactions. Antibodies raised against full-length DBL2βPF11_0521, but not truncated forms lacking the N terminal fragment, block its interaction with ICAM-1. Our data suggest that full length domain is optimal for displaying functional epitopes and has a broad surface of interaction with ICAM-1 that is not disrupted by individual amino acid substitutions at putative key residues. This information might be important for the future design of anti-malarial vaccines based on PfEMP1 antigens.
authors.affiliation: Seattle Biomedical Research Institute, Seattle, Washington, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Gullingsrud
authors.forename: Tracy
authors.initials: T
authors.lastname: Saveria
authors.forename: Emily
authors.initials: E
authors.lastname: Amos
authors.forename: Patrick E
authors.initials: PE
authors.lastname: Duffy
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Oleinikov
mesh_terms: D000818:Animals; D000913:Antibodies, Protozoan / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D004926:Escherichia coli / Q000378:metabolism; D006801:Humans; D055767:Immobilized Proteins / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D008024:Ligands; D016778:Malaria, Falciparum / Q000469:parasitology*; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism; D010271:Parasites / Q000502:physiology*; D010963:Plasmodium falciparum / Q000276:immunology / Q000502:physiology*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000913:Antibodies, Protozoan; D055767:Immobilized Proteins; D008024:Ligands; D050505:Mutant Proteins; D015800:Protozoan Proteins; D018799:Intercellular Adhesion Molecule-1