pH-dependence of the Plasmodium falciparum chloroquine resistance transporter is linked to the transport cycle - Sorbonne Université Access content directly
Journal Articles Nature Communications Year : 2023

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

Fiona Berger
  • Function : Author
Guillermo M Gomez
Cecilia P Sanchez
  • Function : Author
Britta Posch
  • Function : Author
Farzin Sohraby
  • Function : Author
Ariane Nunes-Alves
Michael Lanzer

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 abro- gates 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.
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hal-04255540 , version 1 (24-10-2023)

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Fiona Berger, Guillermo M Gomez, Cecilia P Sanchez, Britta Posch, Gabrielle Planelles, et al.. pH-dependence of the Plasmodium falciparum chloroquine resistance transporter is linked to the transport cycle. Nature Communications, 2023, 14, ⟨10.1038/s41467-023-39969-2⟩. ⟨hal-04255540⟩
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