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

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 in...

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Main Authors: Berger, Fiona (Author) , Gómez, Guillermo (Author) , Sanchez, Cecilia P. (Author) , Posch, Britta (Author) , Planelles, Gabrielle (Author) , Sohraby, Farzin (Author) , Nunes-Alves, Ariane (Author) , Lanzer, Michael (Author)
Format: Article (Journal)
Language:English
Published: 2023
In: Nature Communications
Year: 2023, Volume: 14, Pages: 1-16
ISSN:2041-1723
DOI:10.1038/s41467-023-39969-2
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41467-023-39969-2
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41467-023-39969-2
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Author Notes:Fiona Berger, Guillermo M. Gomez, Cecilia P. Sanchez, Britta Posch, Gabrielle Planelles, Farzin Sohraby, Ariane Nunes-Alves & Michael Lanzer
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Summary: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.
Item Description:Veröffentlicht: 15. Juli 2023
Gesehen am 28.08.2023
Physical Description:Online Resource
ISSN:2041-1723
DOI:10.1038/s41467-023-39969-2

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