Binding and invasion of liver cells by Plasmodium falciparum sporozoites. Essential involvement of the amino terminus of circumsporozoite protein.
Plasmodium sporozoites display circumsporozoite (CS) protein on their surface, which is involved in the attachment of sporozoites to liver cells. CS protein is a member of the thrombospondin type I repeat (TSR) domain family and possess a single copy of TSR domain toward its carboxyl terminus. We show by a direct measurement the correlation between the binding activity of various segments of the CS protein and their ability to inhibit the invasion of liver cells by the sporozoites. We made eight truncated versions of Plasmodium falciparum CS protein to elucidate the role of various regions in the binding and invasion process. Deletion of the TSR domain actually enhanced binding activity by 2-3-fold without the loss of receptor specificity, indicating that TSR may not be the only domain in defining the specificity of binding. These same deletions blocked invasion of live sporozoites more efficiently than proteins that include the TSR domain. Deletion of as little as six amino acids from amino terminus of the protein, however, renders it incapable of binding to liver cells and as an inhibitor of sporozoite invasion. Hence, the binding of CS protein to liver cells and its ability to inhibit the invasion process are affected in a parallel manner, both positively and negatively, by sequence changes in the encoded CS gene. This indicates that both assays are measuring interrelated phenomenon and points to the essential involvement for the amino-terminal portion of the CS protein in these processes.
Rathore
Dharmendar
D
Growth and Development Section, Laboratory of Malaria and Vector Research, NIAID/National Institutes of Health, 4 Center Drive MSC 0425, Bethesda, MD 20892-0425, USA.
Sacci
John B
JB
de la Vega
Patricia
P
McCutchan
Thomas F
TF
D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D019765:Chondroitin ABC Lyase / Q000378:metabolism; D016264:Dextran Sulfate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000378:metabolism; D017353:Gene Deletion; D006493:Heparin / Q000737:chemistry / Q000494:pharmacology; D019763:Heparin Lyase / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008099:Liver / Q000469:parasitology*; D009154:Mutation; D010455:Peptides / Q000737:chemistry; D010957:Plasmids / Q000378:metabolism; D010963:Plasmodium falciparum / Q000472:pathogenicity*; D011134:Polysaccharides / Q000494:pharmacology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000737:chemistry* / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism
D000596:Amino Acids; D010455:Peptides; D011134:Polysaccharides; D015800:Protozoan Proteins; D011994:Recombinant Proteins; C041595:circumsporozoite protein, Protozoan; D006493:Heparin; D016264:Dextran Sulfate; C007789:fucoidan; D019765:Chondroitin ABC Lyase; D019763:Heparin Lyase