Structural basis for DARC binding in reticulocyte invasion by Plasmodium vivax

Moskovitz, R.; Pholcharee, T.; DonVito, S.; Guloglu, B.; Lowe, E.; Mohring, F.; Moon, R. W.; Higgins, M. K.

doi:10.1101/2023.02.28.530453

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bioRxiv · 10.1101/2023.02.28.530453

Structural basis for DARC binding in reticulocyte invasion by Plasmodium vivax

Moskovitz, R.·Pholcharee, T.·DonVito, S.·Guloglu, B.·Lowe, E.·Mohring, F.·Moon, R. W.·Higgins, M. K.

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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 have therefore determined 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.

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Moskovitz, R., Pholcharee, T., DonVito, S., Guloglu, B., Lowe, E., Mohring, F., Moon, R. W., Higgins, M. K.. 2023-02-28. Structural basis for DARC binding in reticulocyte invasion by Plasmodium vivax. https://doi.org/10.1101/2023.02.28.530453

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