C-terminal aromatic residue of Plasmodium ferredoxin important for the interaction with ferredoxin: NADP(H) oxidoreductase: possible involvement for artemisinin resistance of human malaria parasites

Author:

Kimata-Ariga Yoko1,Sakamoto Asako1,Kamatani Miho1,Saitoh Takashi2,Hase Toshiharu3

Affiliation:

1. Department of Biological Chemistry, College of Agriculture, Graduate School of Sciences and Technology for Innovation, Yamaguchi University, Yoshida, Yamaguchi 753-8515, Japan

2. Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Hokkaido University of Science, Maeda, Teine, Sapporo, Hokkaido 006-8585, Japan

3. Laboratory of Regulation of Biological Reactions, Division of Protein Chemistry, Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan

Abstract

Abstract The malaria parasite (Plasmodium sp.) contains a plastid-derived organelle called the apicoplast, which is essential for the growth of the parasite. In this organelle, a redox system comprising plant-type ferredoxin (Fd) and Fd: NADP(H) oxidoreductase (FNR) supplies reducing power for the crucial metabolic pathways. Electron transfer between Plasmodium falciparum Fd (PfFd) and FNR (PfFNR) is performed with higher affinity and specificity than those of plant Fd and FNR. We investigated the structural basis for such superior protein–protein interaction by focussing on the Plasumodium-specific regions of PfFd. Significant contribution of the C-terminal region of PfFd for the electron transfer with PfFNR was revealed by exchanging the C-terminal three residues between plant Fd and PfFd. Further site-directed mutagenesis of the PfFd C-terminal residues indicated that the presence of aromatic residue at Positions 96 and 97 contributes to the lower Km for PfFNR. Physical binding analyses using fluorescence and calorimetric measurements supported the results. A mutation from Asp to Tyr at position 97 of PfFd was recently reported to be strongly associated with P. falciparum resistance to artemisinin, the front line anti-malarial drug. Thus, the enhanced interaction of PfFd D97Y protein with PfFNR could be involved in artemisinin resistance of human malaria parasites.

Funder

Scientific Research

Japan Society for the Promotion of Science

Publisher

Oxford University Press (OUP)

Subject

Molecular Biology,Biochemistry,General Medicine

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