Apicomplexan parasites employ common mechanisms for protein secretion, translocation, and proteolytic processing of adhesins. Efficient invasion is mediated by coupling these events to promote apical attachment and cell entry. Toxoplasma gondii provides an excellent experimental system for delineating the molecular mechanisms of invasion by this important group of parasites. The proposed studies will focus on three key steps in parasite invasion using the Toxoplasma adhesin MIC2 as a model. MIC2 is a member of the TRAP family of proteins, which are important for invasion in Toxoplasma and malaria.
In AIM1 we will explore the role of the extracellular domains of MIC2 in multimerization and receptor binding. Following translocation to the posterior end of the cell, MIC2 and related adhesins are processed via an intramembranous cleavage event, before being shed into the supernatant. Disruption of MIC2 processing prevents efficient cell entry, highlighting the importance of this step.
In AIM2 we will characterize putative rhomboid-like proteases that process cell-surface adhesins such as MIC2 during invasion. MIC2 is a type I transmembrane protein that links adhesion to the cytoskeleton by interacting with aldolase. The specific interactions that mediate bridging between the C-terminal domain of MIC2, aldolase, and the cytoskeleton will be explored in detail in AIMS. Understanding these key steps will provide insights into the entry mechanisms utilized by T. gondii and related apicomplexans.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Pathogenic Eukaryotes Study Section (PTHE)
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Rogers, Martin J
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Washington University
Schools of Medicine
Saint Louis
United States
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Long, Shaojun; Brown, Kevin M; Sibley, L David (2018) CRISPR-mediated Tagging with BirA Allows Proximity Labeling in Toxoplasma gondii. Bio Protoc 8:
Brown, Kevin M; Sibley, L David (2018) Essential cGMP Signaling in Toxoplasma Is Initiated by a Hybrid P-Type ATPase-Guanylate Cyclase. Cell Host Microbe 24:804-816.e6
Brown, Kevin M; Long, Shaojun; Sibley, L David (2018) Conditional Knockdown of Proteins Using Auxin-inducible Degron (AID) Fusions in Toxoplasma gondii. Bio Protoc 8:
Shen, Bang; Brown, Kevin; Long, Shaojun et al. (2017) Development of CRISPR/Cas9 for Efficient Genome Editing in Toxoplasma gondii. Methods Mol Biol 1498:79-103
Jones, Nathaniel G; Wang, Qiuling; Sibley, L David (2017) Secreted protein kinases regulate cyst burden during chronic toxoplasmosis. Cell Microbiol 19:
Long, Shaojun; Anthony, Bryan; Drewry, Lisa L et al. (2017) A conserved ankyrin repeat-containing protein regulates conoid stability, motility and cell invasion in Toxoplasma gondii. Nat Commun 8:2236
Garcia, Celia R S; Alves, Eduardo; Pereira, Pedro H S et al. (2017) InsP3 Signaling in Apicomplexan Parasites. Curr Top Med Chem 17:2158-2165
Long, Shaojun; Brown, Kevin M; Drewry, Lisa L et al. (2017) Calmodulin-like proteins localized to the conoid regulate motility and cell invasion by Toxoplasma gondii. PLoS Pathog 13:e1006379
Rutaganira, Florentine U; Barks, Jennifer; Dhason, Mary Savari et al. (2017) Inhibition of Calcium Dependent Protein Kinase 1 (CDPK1) by Pyrazolopyrimidine Analogs Decreases Establishment and Reoccurrence of Central Nervous System Disease by Toxoplasma gondii. J Med Chem 60:9976-9989
Brown, Kevin M; Long, Shaojun; Sibley, L David (2017) Plasma Membrane Association by N-Acylation Governs PKG Function in Toxoplasma gondii. MBio 8:

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