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

• Verfasst von: Berger, Fiona [VerfasserIn]
• Verfasst von: Gómez, Guillermo [VerfasserIn]
• Verfasst von: Sanchez, Cecilia P. [VerfasserIn]
• Verfasst von: Posch, Britta [VerfasserIn]
• Verfasst von: Planelles, Gabrielle [VerfasserIn]
• Verfasst von: Sohraby, Farzin [VerfasserIn]
• Verfasst von: Nunes-Alves, Ariane [VerfasserIn]
• Verfasst von: Lanzer, Michael [VerfasserIn]
• Titel: pH-dependence of the Plasmodium falciparum chloroquine resistance transporter is linked to the transport cycle
• Verf.angabe: Fiona Berger, Guillermo M. Gomez, Cecilia P. Sanchez, Britta Posch, Gabrielle Planelles, Farzin Sohraby, Ariane Nunes-Alves & Michael Lanzer
• Jahr: 2023
• Umfang: 16 S.
• Illustrationen: Illustrationen
• Fussnoten: Veröffentlicht: 15. Juli 2023 ; Gesehen am 28.08.2023
• Titel Quelle: Enthalten in: Nature Communications
• Ort Quelle: [London] : Nature Publishing Group UK, 2010
• Jahr Quelle: 2023
• Band/Heft Quelle: 14(2023), Artikel-ID 4234, Seite 1-16
• ISSN Quelle: 2041-1723
• DOI: doi:10.1038/s41467-023-39969-2
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Infection
• Sach-SW: Molecular modelling
• Sach-SW: Parasite biology
• K10plus-PPN: 1858047285
• K10plus-PPN:
  Universitätsbibliothek
• Lokale URL UB: Zum Volltext

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.