The most polymorphic residue on Plasmodium falciparum apical membrane antigen 1 determines binding of an invasion-inhibitory antibody.
Apical membrane antigen 1 (AMA1) is currently one of the leading malarial vaccine candidates. Anti-AMA1 antibodies can inhibit the invasion of erythrocytes by Plasmodium merozoites and prevent the multiplication of blood-stage parasites. Here we describe an anti-AMA1 monoclonal antibody (MAb 1F9) that inhibits the invasion of Plasmodium falciparum parasites in vitro. We show that both reactivity of MAb 1F9 with AMA1 and MAb 1F9-mediated invasion inhibition were strain specific. Site-directed mutagenesis of a fragment of AMA1 displayed on M13 bacteriophage identified a single polymorphic residue in domain I of AMA1 that is critical for MAb 1F9 binding. The identities of all other polymorphic residues investigated in this domain had little effect on the binding of the antibody. Examination of the P. falciparum AMA1 crystal structure localized this residue to a surface-exposed alpha-helix at the apex of the polypeptide. This description of a polymorphic inhibitory epitope on AMA1 adds supporting evidence to the hypothesis that immune pressure is responsible for the polymorphisms seen in this molecule.
Coley
A M
AM
Biochemistry Dept., La Trobe University, Victoria 3086, Australia.
Parisi
K
K
Masciantonio
R
R
Hoeck
J
J
Casey
J L
JL
Murphy
V J
VJ
Harris
K S
KS
Batchelor
A H
AH
Anders
R F
RF
Foley
M
M
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000913:Antibodies, Protozoan / Q000276:immunology*; D000953:Antigens, Protozoan / Q000737:chemistry / Q000276:immunology*; D018604:Epitope Mapping; D004912:Erythrocytes / Q000469:parasitology; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000276:immunology*; D008969:Molecular Sequence Data; D010963:Plasmodium falciparum / Q000276:immunology*; D011487:Protein Conformation; D015800:Protozoan Proteins / Q000737:chemistry / Q000276:immunology*; D013045:Species Specificity
D000911:Antibodies, Monoclonal; D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D008565:Membrane Proteins; D015800:Protozoan Proteins; C090077:apical membrane antigen I, Plasmodium