Structural basis for DARC binding in reticulocyte invasion by Plasmodium vivax

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.

Structural Space of the Duffy Antigen/Receptor for Chemokines’ Intrinsically Disordered Ectodomain 1 Explored by Temperature Replica-Exchange Molecular Dynamics Simulations

“…Importantly, this observation is in perfect agreement with the experimental data, where the only part of the ECD1 that could be successfully crystallized was the α-helix at the position Phe22-Tyr30 [35], thus validating our approach and results. This work complements the recently proposed molecular dynamics simulations and experiments performed on the sulfated DARC peptide, showing that a sulfate on tyrosine 41 binds to a charged pocket on PvDBP-RII [91], which is important in regards to the difficulty in designing a P. vivax vaccine [92][93][94].…”

Genetic associations with ratios between protein levels detect new pQTLs and reveal protein-protein interactions

“…A structural basis for DARC binding to P. vivax ’s Duffy-binding protein involving the region around the p.Gly42Asp variant has been proposed. 39 …”

Structure‐based design of a Plasmodium vivax Duffy‐binding protein immunogen focuses the antibody response to functional epitopes

“…DBP‐II engages DARC by forming a 2:2 complex in which an N‐terminal helix in each DARC monomer is bound at the interface between DBL domains (Batchelor et al, 2011 , 2014 ). The DBP/DARC‐binding interface was recently expanded to include a sulfated tyrosine binding site adjacent to the primary DARC binding site (Moskovitz et al, 2023 ). Each DBL domain contains three subdomains – S1, S2, and S3 – and the S1 and S2 subdomains contain the receptor‐binding and dimerization interfaces.…”