Abstract
Toxosplasma gondii is the model parasite of the phylum Apicomplexa, which contains numerous obligate intracellular parasites of medical and veterinary importance, including Eimeria, Sarcocystis, Cryptosporidium, Cyclospora, and Plasmodium species. Members of this phylum actively enter host cells by a multistep process with the help of microneme protein (MIC) complexes that play important roles in motility, host cell attachment, moving junction formation, and invasion. T. gondii (Tg)MIC1-4-6 complex is the most extensively investigated microneme complex, which contributes to host cell recognition and attachment via the action of TgMIC1, a sialic acid-binding adhesin. Here, we report the structure of TgMIC4 and reveal its carbohydrate-binding specificity to a variety of galactose-containing carbohydrate ligands. The lectin is composed of six apple domains in which the fifth domain displays a potent galactose-binding activity, and which is cleaved from the complex during parasite invasion. We propose that galactose recognition by TgMIC4 may compromise host protection from galectin-mediated activation of the host immune system.
Highlights
TgMIC4 is an important microneme effector protein from Toxoplasma gondii
The Overall Structure of Apple Domain Pair from TgMIC4— Most previous structural studies of apple domains of various proteins have been focused on individual apple domains (30 – 32)
Sequence analysis reveals that TgMIC4 comprises six apple domains that occur in intimate pairs, with only 3 residues separating the first and second (A12), third and fourth (A34), and fifth and sixth (A56) domains [15]
Summary
TgMIC4 is an important microneme effector protein from Toxoplasma gondii. Results: The structure of TgMIC4 together with carbohydrate microarray analyses reveal a broad specificity for galactoseterminating sequences. Toxosplasma gondii is the model parasite of the phylum Apicomplexa, which contains numerous obligate intracellular parasites of medical and veterinary importance, including Eimeria, Sarcocystis, Cryptosporidium, Cyclospora, and Plasmodium species Members of this phylum actively enter host cells by a multistep process with the help of microneme protein (MIC) complexes that play important roles in motility, host cell attachment, moving junction formation, and invasion. T. gondii and other apicomplexan parasites, including Plasmodium species, rely on an active, phylum-specific host cell invasion process to establish infection. We combine atomic resolution studies with data from carbohydrate microarrays to reveal the basis of the interaction between TgMIC4 and a variety of galactose (Gal)-terminating oligosaccharides, and further define the interaction between TgMIC4 and TgMIC1 This reveals new features regarding both parasite-receptor interactions and the stoichiometry of the TgMIC1-4-6 complex
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