Denaturation resistant P2 tetramer is required to import fatty acids into intraerythrocytic Plasmodium falciparum

Abstract

The initiation of asymmetric karyokinesis of intraerythrocytic Plasmodium falciparum (Pf) begins without dismantling the nuclear envelope showing the hallmark feature of closed mitosis (1-10). In Pf, karyokinesis precedes cytokinesis and cell body formation (6, 8-10). Regulation at the beginning of nuclear division either through checkpoints or by importing serum components was largely unknown. At the trophozoite stage, PfP2 tetramer trafficked to the infected erythrocyte (IE) surface and the inaccessibility of IE surface PfP2 to its bonafide ligand led to the arrest of nuclear division (11-13). Here we show that PfP2 tetramer localization on the IE surface and the beginning of nuclear division are concomitant in nature. Synthetically induced denaturation resistant PfP2 tetramer interacts with human serum fatty acids and phospholipids for its import into IEs at the beginning of karyokinesis. In the natively folded denaturation resistant PfP2 tetramer cage, the Cys-Cys redox switch regulates the binding and subsequent release of fatty acids on the IE surface. This mechanistic insight of fatty acids import inside IEs using synthetically induced denaturation resistant PfP2 tetramer provides an unique drug screening platform for novel small molecule screening against malaria.