Interaction between Plasmodium falciparum Apical Membrane Antigen 1 and the Rhoptry Neck Protein Complex Defines a Key Step in the Erythrocyte Invasion Process of Malaria Parasites

Abstract

Invasion of host cells by apicomplexan parasites, including Plasmodium falciparum and Toxoplasma gondii, is a multistep process. Central to invasion is the formation of a tight junction, an aperture in the host cell through which the parasite pulls itself before settling into a newly formed parasitophorous vacuole. Two protein groups, derived from different secretory organelles, the micronemal protein AMA1 and the rhoptry proteins RON2, RON4, and RON5, have been shown to form part of this structure, with antibodies targeting P. falciparum AMA1 known to inhibit invasion, probably via disruption of its association with the PfRON proteins. Inhibitory AMA1-binding peptides have also been described that block P. falciparum merozoite invasion of the erythrocyte. One of these, R1, blocks invasion some time after initial attachment to the erythrocyte and reorientation of the merozoite to its apical pole. Here we show that the R1 peptide binds the PfAMA1 hydrophobic trough and demonstrate that binding to this region prevents its interaction with the PfRON complex. We show that this defined association between PfAMA1 and the PfRON complex occurs after reorientation and engagement of the actomyosin motor and argue that it precedes rhoptry release. We propose that the formation of the AMA1-RON complex is essential for secretion of the rhoptry contents, which then allows the establishment of parasite infection within the parasitophorous vacuole.

Insights into Duffy Binding-like Domains through the Crystal Structure and Function of the Merozoite Surface Protein MSPDBL2 from Plasmodium falciparum

“…They were also colocalized on the surface of free merozoites, although PfMSPDBL2 appeared to be more concentrated at the apical end of the cell as indicated by its close apposition to RON4, a protein located in the neck of the rhoptries (Fig. 2C, bottom row) (37). This confirmed previous work showing that PfMSPDBL1 was located on the merozoite surface and also demonstrated that PfMSPDBL2 had a similar localization consistent with them having similar functions (14).…”

Toxoplasmaaldolase is required for metabolism but dispensable for host-cell invasion

“…(9)(10)(11). AMA1 has similar topology with TRAP/MIC2 with its bulky ectodomain binding to rhoptry neck proteins (RONs) that are secreted from the rhoptries and inserted into host plasma membrane to mediate formation of a moving junction between the host and parasite membranes (12)(13)(14)(15). The cytoplasmic tail of AMA1 (AMA1t) also binds rabbit ALD in vitro, and a TgAMA1 mutant with a pair of aromatic residues changed to alanines (i.e., F547A, W548A) disrupts aldolase binding in vitro and blocks host-cell invasion (16).…”

Sialic acids: Key determinants for invasion by the Apicomplexa

“…The roles of MICs (TgMIC8, PfEBA175 and PfAMA1) in the process leading to the secretion by the rhoptry organelles (Kessler et al, 2008;Richard et al, 2010;Singh et al, 2010) is an exiting new aspect of receptor-ligand interactions in apicomplexans and of the mechanism of host cell invasion. Molecular genetic studies in Plasmodium and Toxoplasma suggest that signal transduction is likely mediated by the cytoplasmic domains of these MICs (Gilberger et al, 2003;Treeck et al, 2009).…”

“…Microneme proteins (MICs) are key mediators of cytoadherence, but also play other essential and non-overlapping roles in the invasion process (Carruthers and Tomley, 2008;Soldati-Favre, 2008). Notably, recent studies have highlighted the roles of MICs (TgMIC8 in Toxoplasma gondii; PfEBA175 and PfAMA1 in Plasmodium falciparum) in the process leading to secretion by the rhoptries (Kessler et al, 2008;Richard et al, 2010;Singh et al, 2010).…”