Structural basis for DARC binding in reticulocyte invasion by Plasmodium vivax

Area of Science:

• * Molecular parasitology
• * Structural biology
• * Immunology

Background:

• * Malaria symptoms arise during the blood stage, when Plasmodium parasites replicate in red blood cells.
• * Plasmodium vivax selectively invades reticulocytes, requiring interaction between the Duffy Antigen Receptor (DARC) and the Plasmodium vivax Duffy-binding protein (PvDBP).
• * Previous structures lacked insight into how tyrosine sulfation on DARC affects PvDBP binding.

Purpose of the Study:

• * To elucidate the structure of PvDBP region II (PvDBP-RII) bound to a sulfated DARC peptide.
• * To investigate the role of tyrosine sulfation in the DARC-PvDBP interaction.
• * To identify the epitope of a growth-inhibitory antibody (DB1).

Main Methods:

• * X-ray crystallography to determine the structure of PvDBP-RII bound to sulfated DARC peptide.
• * Molecular dynamics simulations to analyze binding interactions.
• * Affinity measurements and in vitro parasite growth-inhibition assays.

Main Results:

• * The structure reveals a sulfate group on tyrosine 41 of the DARC peptide binding to a charged pocket on PvDBP-RII.
• * Molecular dynamics, affinity, and growth-inhibition experiments confirm the critical role of this sulfated tyrosine interaction.
• * The epitope for the vaccine-elicited growth-inhibitory antibody DB1 was identified.

Conclusions:

• * This study provides a comprehensive understanding of how PvDBP-RII binds to DARC, including the crucial role of tyrosine sulfation.
• * The findings offer insights into the mechanism of red blood cell invasion by Plasmodium vivax.
• * The results will guide the rational design of novel vaccines and therapeutics targeting this essential parasitic interaction.