title: Structural and functional properties of region II-plus of the malaria circumsporozoite protein.
abstract: During feeding, infected mosquitos inject malaria sporozoites into the host circulation. Within minutes, the parasites are found in the liver where they initiate the first stage of malaria infection. All species of malaria sporozoites are uniformly covered by the circumsporozoite protein (CS), which contains a conserved COOH-terminal sequence called region II-plus. We have previously shown that region II-plus is the parasite's hepatocyte-binding ligand and that this ligand binds to heparan sulfate proteoglycans (HSPGs) on the hepatocyte membrane. Using a series of substituted region II-plus peptides, we show here that the downstream basic amino acids as well as the interdispersed hydrophobic residues are required for binding of CS to hepatocyte HSPGs. We also show that this positively charged stretch of amino acids must be aggregated in order to bind to the receptor. On the basis of this information, we have synthesized a multiple antigen peptide that mimics the hepatocyte-binding ligand. This construct inhibits both CS binding to HepG2 cells in vitro as well as CS clearance in mice.
authors.affiliation: Michael Heidelberger Division of Immunology, Department of Pathology, New York University Medical Center, New York 10016.
authors.forename: P
authors.initials: P
authors.lastname: Sinnis
authors.forename: P
authors.initials: P
authors.lastname: Clavijo
authors.forename: D
authors.initials: D
authors.lastname: Fenyö
authors.forename: B T
authors.initials: BT
authors.lastname: Chait
authors.forename: C
authors.initials: C
authors.lastname: Cerami
authors.forename: V
authors.initials: V
authors.lastname: Nussenzweig
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016782:Apicomplexa / Q000472:pathogenicity; D005260:Female; D019812:Heparan Sulfate Proteoglycans; D006497:Heparan Sulfate / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D008970:Molecular Weight; D011509:Proteoglycans / Q000378:metabolism; D015800:Protozoan Proteins / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D019812:Heparan Sulfate Proteoglycans; D006497:Heparan Sulfate; D011509:Proteoglycans; D015800:Protozoan Proteins; C041595:circumsporozoite protein, Protozoan