pH-dependence of the Plasmodium falciparum chloroquine resistance transporter is linked to the transport cycle

Fiona Berger, Guillermo M. Gomez, Cecilia P. Sanchez, Britta Posch, Gabrielle Planelles, Farzin Sohraby, Ariane Nunes-Alves () and Michael Lanzer ()
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Fiona Berger: Parasitology, Universitätsklinikum Heidelberg
Guillermo M. Gomez: Parasitology, Universitätsklinikum Heidelberg
Cecilia P. Sanchez: Parasitology, Universitätsklinikum Heidelberg
Britta Posch: Parasitology, Universitätsklinikum Heidelberg
Gabrielle Planelles: INSERM, Centre de Recherche des Cordeliers, Unité 1138, CNRS ERL8228, Université Pierre et Marie Curie and Université Paris-Descartes
Farzin Sohraby: Technische Universität Berlin
Ariane Nunes-Alves: Technische Universität Berlin
Michael Lanzer: Parasitology, Universitätsklinikum Heidelberg

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract The chloroquine resistance transporter, PfCRT, of the human malaria parasite Plasmodium falciparum is sensitive to acidic pH. Consequently, PfCRT operates at 60% of its maximal drug transport activity at the pH of 5.2 of the digestive vacuole, a proteolytic organelle from which PfCRT expels drugs interfering with heme detoxification. Here we show by alanine-scanning mutagenesis that E207 is critical for pH sensing. The E207A mutation abrogates pH-sensitivity, while preserving drug substrate specificity. Substituting E207 with Asp or His, but not other amino acids, restores pH-sensitivity. Molecular dynamics simulations and kinetics analyses suggest an allosteric binding model in which PfCRT can accept both protons and chloroquine in a partial noncompetitive manner, with increased proton concentrations decreasing drug transport. Further simulations reveal that E207 relocates from a peripheral to an engaged location during the transport cycle, forming a salt bridge with residue K80. We propose that the ionized carboxyl group of E207 acts as a hydrogen acceptor, facilitating transport cycle progression, with pH sensing as a by-product.

Date: 2023
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DOI: 10.1038/s41467-023-39969-2

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