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Media type:
E-Article
Title:
pH-dependence of the Plasmodium falciparum chloroquine resistance transporter is linked to the transport cycle
Contributor:
Berger, Fiona;
Gomez, Guillermo M.;
Sanchez, Cecilia P.;
Posch, Britta;
Planelles, Gabrielle;
Sohraby, Farzin;
Nunes-Alves, Ariane;
Lanzer, Michael
Published:
Springer Science and Business Media LLC, 2023
Published in:
Nature Communications, 14 (2023) 1
Language:
English
DOI:
10.1038/s41467-023-39969-2
ISSN:
2041-1723
Origination:
Footnote:
Description:
AbstractThe chloroquine resistance transporter, PfCRT, of the human malaria parasitePlasmodium falciparumis 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.