IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-39969-2.html
   My bibliography  Save this article

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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Fiona Berger & Guillermo M. Gomez & Cecilia P. Sanchez & Britta Posch & Gabrielle Planelles & Farzin Sohraby & Ariane Nunes-Alves & Michael Lanzer, 2023. "pH-dependence of the Plasmodium falciparum chloroquine resistance transporter is linked to the transport cycle," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39969-2
    DOI: 10.1038/s41467-023-39969-2
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-39969-2
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-023-39969-2?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Hiromi Gunshin & Bryan Mackenzie & Urs V. Berger & Yoshimi Gunshin & Michael F. Romero & Walter F. Boron & Stephan Nussberger & John L. Gollan & Matthias A. Hediger, 1997. "Cloning and characterization of a mammalian proton-coupled metal-ion transporter," Nature, Nature, vol. 388(6641), pages 482-488, July.
    2. Jonathan Kim & Yong Zi Tan & Kathryn J. Wicht & Satchal K. Erramilli & Satish K. Dhingra & John Okombo & Jeremie Vendome & Laura M. Hagenah & Sabrina I. Giacometti & Audrey L. Warren & Kamil Nosol & P, 2019. "Structure and drug resistance of the Plasmodium falciparum transporter PfCRT," Nature, Nature, vol. 576(7786), pages 315-320, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Layimar Cegarra & Andrea Colins & Ziomara P Gerdtzen & Marco T Nuñez & J Cristian Salgado, 2019. "Mathematical modeling of the relocation of the divalent metal transporter DMT1 in the intestinal iron absorption process," PLOS ONE, Public Library of Science, vol. 14(6), pages 1-26, June.
    2. Bing Guo & Victor Borda & Roland Laboulaye & Michele D. Spring & Mariusz Wojnarski & Brian A. Vesely & Joana C. Silva & Norman C. Waters & Timothy D. O’Connor & Shannon Takala-Harrison, 2024. "Strong positive selection biases identity-by-descent-based inferences of recent demography and population structure in Plasmodium falciparum," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    3. Jianying Zhu & Qi Zhang & Hui Zhang & Zuoqiang Shi & Mingxu Hu & Chenglong Bao, 2023. "A minority of final stacks yields superior amplitude in single-particle cryo-EM," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    4. Gunnar F. Kwakye & Monica M.B. Paoliello & Somshuvra Mukhopadhyay & Aaron B. Bowman & Michael Aschner, 2015. "Manganese-Induced Parkinsonism and Parkinson’s Disease: Shared and Distinguishable Features," IJERPH, MDPI, vol. 12(7), pages 1-22, July.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39969-2. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.