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A lipocalin mediates unidirectional heme biomineralization in malaria parasites
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
ID
4612418
Author(s)
Matz, Joachim M.; Drepper, Benjamin; Blum, Thorsten B.; van Genderen, Eric; Burrell, Alana; Martin, Peer; Stach, Thomas; Collinson, Lucy M.; Abrahams, Jan Pieter; Matuschewski, Kai; Blackman, Michael J.
During blood-stage development, malaria parasites are challenged with the detoxification of enormous amounts of heme released during the proteolytic catabolism of erythrocytic hemoglobin. They tackle this problem by sequestering heme into bioinert crystals known as hemozoin. The mechanisms underlying this biomineralization process remain enigmatic. Here, we demonstrate that both rodent and human malaria parasite species secrete and internalize a lipocalin-like protein, PV5, to control heme crystallization. Transcriptional deregulation of; PV5; in the rodent parasite; Plasmodium berghei; results in inordinate elongation of hemozoin crystals, while conditional; PV5; inactivation in the human malaria agent; Plasmodium falciparum; causes excessive multidirectional crystal branching. Although hemoglobin processing remains unaffected, PV5-deficient parasites generate less hemozoin. Electron diffraction analysis indicates that despite the distinct changes in crystal morphology, neither the crystalline order nor unit cell of hemozoin are affected by impaired PV5 function. Deregulation of; PV5; expression renders; P. berghei; hypersensitive to the antimalarial drugs artesunate, chloroquine, and atovaquone, resulting in accelerated parasite clearance following drug treatment in vivo. Together, our findings demonstrate the; Plasmodium; -tailored role of a lipocalin family member in hemozoin formation and underscore the heme biomineralization pathway as an attractive target for therapeutic exploitation.
