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Malaria parasite erythrocytic stages comprise of repeated bursts of parasites via cyclical invasion of host erythrocytes using dedicated receptor-ligand interactions. A family of erythrocyte-binding proteins from  Plasmodium knowlesi  ( Pk ) and  Plasmodium vivax  ( Pv ) attach to human Duffy antigen receptor for chemokines (DARC) via their Duffy binding-like domains (DBLs) for invasion. Here we provide a novel, testable and overarching interaction model that rationalizes even contradictory pieces of evidence that have so far existed in the literature on  Pk / Pv -DBL/DARC binding determinants. We further address the conundrum of how parasite-encoded  Pk / Pv -DBLs recognize human DARC and collate evidence for two distinct DARC integration sites on  Pk / Pv -DBLs.

Engagement Rules That Underpin DBL-DARC Interactions for Ingress of Plasmodium knowlesi and Plasmodium vivax Into Human Erythrocytes