The Plasmodium circumsporozoite protein is proteolytically processed during cell invasion.
The circumsporozoite protein (CSP) is the major surface protein of Plasmodium sporozoites, the infective stage of malaria. Although CSP has been extensively studied as a malaria vaccine candidate, little is known about its structure. Here, we show that CSP is proteolytically cleaved by a papain family cysteine protease of parasite origin. Our data suggest that the highly conserved region I, found just before the repeat region, contains the cleavage site. Cleavage occurs on the sporozoite surface when parasites contact target cells. Inhibitors of CSP processing inhibit cell invasion in vitro, and treatment of mice with E-64, a highly specific cysteine protease inhibitor, completely inhibits sporozoite infectivity in vivo.
Coppi
Alida
A
Department of Medical and Molecular Parasitology, New York University School of Medicine, New York, NY 10010, USA.
Pinzon-Ortiz
Consuelo
C
Hutter
Christina
C
Sinnis
Photini
P
D000595:Amino Acid Sequence; D000818:Animals; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D015151:Immunoblotting; D047468:Immunoprecipitation; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008288:Malaria / Q000517:prevention & control*; D008969:Molecular Sequence Data; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D010961:Plasmodium / Q000378:metabolism* / Q000472:pathogenicity; D015800:Protozoan Proteins / Q000378:metabolism*; D034101:Sporozoites / Q000378:metabolism / Q000472:pathogenicity; D014774:Virulence / Q000187:drug effects
D015853:Cysteine Proteinase Inhibitors; D010455:Peptides; D015800:Protozoan Proteins; C041595:circumsporozoite protein, Protozoan; D003546:Cysteine Endopeptidases; D007930:Leucine; C024974:E 64