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Structural basis for DARC binding in reticulocyte invasion by Plasmodium vivax

Author

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  • Re’em Moskovitz

    (University of Oxford)

  • Tossapol Pholcharee

    (University of Oxford)

  • Sophia M. DonVito

    (London School of Hygiene and Tropical Medicine)

  • Bora Guloglu

    (University of Oxford)

  • Edward Lowe

    (University of Oxford)

  • Franziska Mohring

    (London School of Hygiene and Tropical Medicine)

  • Robert W. Moon

    (London School of Hygiene and Tropical Medicine)

  • Matthew K. Higgins

    (University of Oxford)

Abstract

The symptoms of malaria occur during the blood stage of infection, when the parasite replicates within human red blood cells. The human malaria parasite, Plasmodium vivax, selectively invades reticulocytes in a process which requires an interaction between the ectodomain of the human DARC receptor and the Plasmodium vivax Duffy-binding protein, PvDBP. Previous studies have revealed that a small helical peptide from DARC binds to region II of PvDBP (PvDBP-RII). However, it is also known that sulphation of tyrosine residues on DARC affects its binding to PvDBP and these residues were not observed in previous structures. We therefore present the structure of PvDBP-RII bound to sulphated DARC peptide, showing that a sulphate on tyrosine 41 binds to a charged pocket on PvDBP-RII. We use molecular dynamics simulations, affinity measurements and growth-inhibition experiments in parasites to confirm the importance of this interaction. We also reveal the epitope for vaccine-elicited growth-inhibitory antibody DB1. This provides a complete understanding of the binding of PvDBP-RII to DARC and will guide the design of vaccines and therapeutics to target this essential interaction.

Suggested Citation

  • Re’em Moskovitz & Tossapol Pholcharee & Sophia M. DonVito & Bora Guloglu & Edward Lowe & Franziska Mohring & Robert W. Moon & Matthew K. Higgins, 2023. "Structural basis for DARC binding in reticulocyte invasion by Plasmodium vivax," Nature Communications, Nature, vol. 14(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39357-w
    DOI: 10.1038/s41467-023-39357-w
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    References listed on IDEAS

    as
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    3. Saurabh Kumar Singh & Rachna Hora & Hassan Belrhali & Chetan E. Chitnis & Amit Sharma, 2006. "Structural basis for Duffy recognition by the malaria parasite Duffy-binding-like domain," Nature, Nature, vol. 439(7077), pages 741-744, February.
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