Abstract
Plasmodium parasites use specialized ligands which bind to red blood cell (RBC) receptors during invasion. Defining the mechanism of receptor recognition is essential for the design of interventions against malaria. Here, we present the structural basis for Duffy antigen (DARC) engagement by P. vivax Duffy binding protein (DBP). We used NMR to map the core region of the DARC ectodomain contacted by the receptor binding domain of DBP (DBP-RII) and solved two distinct crystal structures of DBP-RII bound to this core region of DARC. Isothermal titration calorimetry studies show these structures are part of a multi-step binding pathway, and individual point mutations of residues contacting DARC result in a complete loss of RBC binding by DBP-RII. Two DBP-RII molecules sandwich either one or two DARC ectodomains, creating distinct heterotrimeric and heterotetrameric architectures. The DARC N-terminus forms an amphipathic helix upon DBP-RII binding. The studies reveal a receptor binding pocket in DBP and critical contacts in DARC, reveal novel targets for intervention, and suggest that targeting the critical DARC binding sites will lead to potent disruption of RBC engagement as complex assembly is dependent on DARC binding. These results allow for models to examine inter-species infection barriers, Plasmodium immune evasion mechanisms, P. knowlesi receptor-ligand specificity, and mechanisms of naturally acquired P. vivax immunity. The step-wise binding model identifies a possible mechanism by which signaling pathways could be activated during invasion. It is anticipated that the structural basis of DBP host-cell engagement will enable development of rational therapeutics targeting this interaction.
Highlights
Plasmodium vivax is a widely distributed human parasite, with 40% of the world’s population at risk of infection and an estimated 70–130 million cases of P. vivax malaria each year [1,2]
To identify critical binding contacts during parasite red blood cell invasion and determine the molecular basis of Duffy Binding Protein (DBP) receptor recognition, we identified the minimal region of Duffy antigen/receptor for chemokines (DARC) contacted by DBP and performed structural studies on the minimal binding domain of DBP in complex with the minimal region from DARC
The structural and functional studies of DBP and DARC presented here may aid in the rational design of vaccines and invasion inhibitory therapeutics
Summary
Plasmodium vivax is a widely distributed human parasite, with 40% of the world’s population at risk of infection and an estimated 70–130 million cases of P. vivax malaria each year [1,2]. P. vivax is prevalent in India, Southeast Asia, and South America [1], but is rare in most of Sub-Saharan Africa [3] This rarity is the result of a silencing mutation in the Duffy blood group, found at frequencies near fixation in Sub-Saharan Africa [4], that confers resistance to P. vivax [5]. This phenotype has arisen independently at least three times, and P. vivax in malaria endemic regions has driven selection for the Duffy negative phenotype. DARC is an atypical GPCR, thought to serve as a ‘reservoir’ for excess inflammatory chemokines [8]
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