title: Determination of the molecular basis for a limited dimorphism, N417K, in the Plasmodium vivax Duffy-binding protein.
abstract: Invasion of human red blood cells by Plasmodium merozoites is vital for replication and survival of the parasite and, as such, is an attractive target for therapeutic intervention. Merozoite invasion is mediated by specific interactions between parasite ligands and host erythrocyte receptors. The P. vivax Duffy-binding protein (PvDBP) is heavily dependent on the interaction with the human Duffy blood group antigen/receptor for chemokines (DARC) for invasion. Region II of PvDBP contains many allelic polymorphisms likely to have arisen by host immune selection. Successful vaccine development necessitates a deeper understanding of the role of these polymorphisms in both parasite function and evasion of host immunity. A 3D structure of the homologous P. knowlesi DBP predicts that most variant residues are surface-exposed, including N417K, which is a dimorphic residue change that has previously been shown to be part of a linked haplotype that alters DBP sensitivity to inhibitory antibody. In natural isolates only two residues are found at this site, asparagine (N) and lysine (K). Site-directed mutagenesis of residue 417 was used to create a panel of 20 amino acid variants that were then examined for their binding phenotype and response to immune sera. Our results suggest that the observed dimorphism likely arose due to both structural requirements and immune selection pressure. To our knowledge, this is the first exhaustive examination of this kind of the role of a single amino acid residue in antigenic character and binding ability. Our results demonstrate that a single amino acid substitution can dramatically alter both the ability of the PvDBP to bind to human erythrocytes and its antigenic character.
authors.affiliation: Eck Institute for Global Health, University of Notre Dame, Notre Dame, Indiana, United States of America.
authors.forename: Amy M
authors.initials: AM
authors.lastname: McHenry
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Barnes
authors.forename: Francis B
authors.initials: FB
authors.lastname: Ntumngia
authors.forename: Christopher L
authors.initials: CL
authors.lastname: King
authors.forename: John H
authors.initials: JH
authors.lastname: Adams
mesh_terms: D000953:Antigens, Protozoan / Q000235:genetics*; D006801:Humans; D016297:Mutagenesis, Site-Directed; D010966:Plasmodium vivax / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D011485:Protein Binding; D015800:Protozoan Proteins / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000235:genetics*
chemical_list: D000953:Antigens, Protozoan; C066001:Duffy antigen binding protein, Plasmodium; D015800:Protozoan Proteins; D011956:Receptors, Cell Surface