Babesia divergens and Neospora caninum apical membrane antigen 1 structures reveal selectivity and plasticity in apicomplexan parasite host cell invasion. (13th December 2012)

• Record Type: Journal Article
• Authors: Tonkin, Michelle L.; Crawford, Joanna; Lebrun, Maryse L.; Boulanger, Martin J.
• Is Part Of: Protein science. Volume 22:Number 1(2013:Jan.)
• Page Start: 114
• Page End: 127
• Publication Date: 2012-12-13
• Subjects: Proteins -- Periodicals; 572.6
• DOI: 10.1002/pro.2193
• Languages: English
• ISSNs: 0961-8368

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>Host cell invasion by the obligate intracellular apicomplexan parasites, including <italic>Plasmodium</italic> (malaria) and <italic>Toxoplasma</italic> (toxoplasmosis), requires a step‐wise mechanism unique among known host–pathogen interactions. A key step is the formation of the moving junction (MJ) complex, a circumferential constriction between the apical tip of the parasite and the host cell membrane that traverses in a posterior direction to enclose the parasite in a protective vacuole essential for intracellular survival. The leading model of MJ assembly proposes that Rhoptry Neck Protein 2 (RON2) is secreted into the host cell and integrated into the membrane where it serves as the receptor for apical membrane antigen 1 (AMA1) on the parasite surface. We have previously demonstrated that the AMA1‐RON2 interaction is an effective target for inhibiting apicomplexan invasion. To better understand the AMA1‐dependant molecular recognition events that promote invasion, including the significant AMA1‐RON2 interaction, we present the structural characterization of AMA1 from the apicomplexan parasites <italic>Babesia divergens</italic> (<italic>Bd</italic>AMA1) and <italic>Neospora caninum</italic> (<italic>Nc</italic>AMA1) by X‐ray crystallography. These studies offer intriguing structural insight into the RON2‐binding surface groove in the AMA1 apical domain, which shows clear evidence for receptor–ligand co‐evolution, and the hyper variability of the membrane proximal domain, which in <italic>Plasmodium</italic> is responsible for direct binding to erythrocytes. By incorporating the structural analysis of <italic>Bd</italic>AMA1 and <italic>Nc</italic>AMA1 with existing AMA1 structures and complexes we were able to define conserved pockets in the AMA1 apical groove that could be targeted for the design of broadly reactive therapeutics.</p> </abstract>