Structural basis for inhibition of erythrocyte invasion by antibodies to Plasmodium falciparum protein CyRPA.

Lin Chen,Jennifer K Thompson,Alan F Cowman,Julie Healer,Michael C Lawrence,Wilson Wong,Ethan D Goddard-Borger,Yibin Xu

doi:10.7554/elife.21347

Lin Chen, Jennifer K Thompson + Show 6 more

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https://doi.org/10.7554/elife.21347

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Abstract

Plasmodium falciparum causes malaria in humans with over 450,000 deaths annually. The asexual blood stage involves invasion of erythrocytes by merozoites, in which they grow and divide to release daughter merozoites, which in turn invade new erythrocytes perpetuating the cycle responsible for malaria. A key step in merozoite invasion is the essential binding of PfRh5/CyRPA/PfRipr complex to basigin, a step linked to the formation of a pore between merozoites and erythrocytes. We show CyRPA interacts directly with PfRh5. An invasion inhibitory monoclonal antibody to CyRPA blocks binding of CyRPA to PfRh5 and complex formation thus illuminating the molecular mechanism for inhibition of parasite growth. We determined the crystal structures of CyRPA alone and in complex with an antibody Fab fragment. CyRPA has a six-bladed β-propeller fold, and we identify the region that interacts with PfRh5. This functionally conserved epitope is a potential target for vaccines against P. falciparum.

Highlights

The most severe form of malaria in humans is caused by P. falciparum with approximately 214 million cases and over 450,000 deaths each year occurring mostly in subtropical and tropical regions of the world (Who, 2015)
To determine if the recombinant cysteine-rich protective antigen (CyRPA) can bind to PfRh5 (Chen et al, 2014), we combined the two proteins and showed by size-exclusion chromatography (SEC) they are capable of forming a stable 1:1 complex
Together with the SEC result, this finding suggests an association between CyRPA and PfRh5 within the PfRh5/CyRPA/P. falciparum Rh5 interacting protein (PfRipr) complex during merozoite invasion

Summary

Introduction

The most severe form of malaria in humans is caused by P. falciparum with approximately 214 million cases and over 450,000 deaths each year occurring mostly in subtropical and tropical regions of the world (Who, 2015). Invasion of human erythrocytes by P. falciparum merozoites involves multiple interactions of ligands with host receptors in a complex multistep process that ends with the internalization of the parasite (reviewed in [Cowman and Crabb, 2006]). The initial interaction of the parasite with the erythrocyte membrane is driven by low affinity interactions involving surface proteins that facilitate apical reorientation. This is followed by high-affinity binding of specific host receptors to the erythrocyte binding-like (EBL) and reticulocyte binding-like homologues (PfRh or PfRBP) ligand families to specific host receptors (reviewed in (Cowman and Crabb, 2006).

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