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 with- out 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 nu- clear 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 inacces- sibility 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 con- comitant 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 na- tively folded denaturation resistant PfP2 tetramer cage, the Cys-Cys redox switch regulates the bind- ing and subsequent release of fatty acids on the IE surface. This mechanistic insight of fatty acids im- port inside IEs using synthetically induced denaturation resistant PfP2 tetramer provides an unique drug screening platform for novel small molecule screening against malaria.