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Prepublished online as a Blood First Edition Paper on April 30, 2002; DOI 10.1182/blood-2002-01-0101.
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Blood, 1 August 2002, Vol. 100, No. 3, pp. 1048-1054
RED CELLS
Plasmodium falciparum cysteine protease falcipain-2
cleaves erythrocyte membrane skeletal proteins at late stages of
parasite development
Manjit Hanspal,
Meenakshi Dua,
Yuichi Takakuwa,
Athar H. Chishti, and
Akiko Mizuno
From the Department of Biomedical Research, St
Elizabeth's Medical Center, Tufts University School of Medicine,
Boston, MA; and the Department of Biochemistry, School of Medicine,
Tokyo Women's Medical University, Japan.
Plasmodium falciparum-derived cysteine protease
falcipain-2 cleaves host erythrocyte hemoglobin at acidic pH and
specific components of the membrane skeleton at neutral pH. Analysis of stage-specific expression of these 2 proteolytic activities of falcipain-2 shows that hemoglobin-hydrolyzing activity is maximum in
early trophozoites and declines rapidly at late stages, whereas the
membrane skeletal protein hydrolyzing activity is markedly increased at the late trophozoite and schizont stages.
Among the erythrocyte membrane skeletal proteins, ankyrin and protein
4.1 are cleaved by native and recombinant falcipain-2 near their
C-termini. To identify the precise peptide sequence at the hydrolysis
site of protein 4.1, we used a recombinant construct of protein 4.1 as
substrate followed by MALDI-MS analysis of the cleaved product. We show
that falcipain-2-mediated cleavage of protein 4.1 occurs immediately
after lysine 437, which lies within a region of the spectrin-actin-binding domain critical for erythrocyte membrane stability. A 16-mer peptide containing the cleavage site
completely inhibited the enzyme activity and blocked
falcipain-2-induced fragmentation of erythrocyte ghosts.
Based on these results, we propose that falcipain-2 cleaves hemoglobin
in the acidic food vacuole at the early trophozoite stage, whereas it
cleaves specific components of the red cell skeleton at the late
trophozoite and schizont stages. It is the proteolysis of skeletal
proteins that causes membrane instability, which, in turn, facilitates
parasite release in vivo.
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