Understanding an essential interaction required for red blood cell invasion in malaria caused by Plasmodium vivax

Plasmodium vivax is one of the two most prevalent human-infective malaria parasites and causes severe disease throughout much of the globe. However, it is largely absent across Africa, despite the prevalence of malaria caused by its cousin, Plasmodium falciparum. This is due to a change in the young red blood cells, known as reticulocytes, in many African people. This change, the DARC polymorphism, prevents Plasmodium vivax from invading the reticulocytes which normally make up its home.

The effectiveness of the DARC polymorphism highlights the importance of the interaction between the DARC receptor, found on red blood cells, and the PvDBP protein from Plasmodium vivax. This interaction is required for reticulocyte invasion, but it had not been visualised in full. For this reason, Re’em Moskovitz decided to crystallise the key regions of PvDBP and DARC which form the full interaction interface. As a bonus, the resulting structure also revealed the binding site of an antibody, DB1, which can block reticulocyte invasion by some strains of Plasmodium vivax.

Re'em structure revealed some interesting new insights. One of these was to show how a specific modification of DARC – the sulphation of tyrosine residue 41 – affected PvDBP binding. In a team effort, Poy Pholcharee assessed the importance of Y41 sulphation for DARC binding and multimerization and Bora Guloglu used molecular dynamics simulations to assess the effect of sulphation on the stability of these interactions. Meanwhile, Sophia DonVito and Rob Moon explored the effect of sulphation of residue 41 on the ability of peptides containing parts of DARC to prevent malaria parasites from invading red blood cells. These studies combined to show that residue 41 and its sulphation form an important part of the interaction interface between PvDBP and DARC.

By revealing new features of the DARC binding site of PvDBP, our work opens new avenues to block this interaction through therapeutics or vaccine design.

Moskovitz, R.*, Pholcharee, T.*, DonVito, S.M., Guloglu, B., Lowe, E., Mohring, F., Moon, R.W.  and Higgins, M.K. (2023) Structural basis for DARC binding in reticulocyte invasion by Plasmodium vivax. Nature Communications 14 3637