1. An unusual and vital protein with guanylate cyclase and P4-ATPase domains in a pathogenic protist.
- Author
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Günay-Esiyok Ö, Scheib U, Noll M, and Gupta N
- Subjects
- Adenosine Triphosphatases chemistry, Amino Acid Sequence, Protein Binding, Protein Multimerization, Protozoan Proteins chemistry, Protozoan Proteins metabolism, Structure-Activity Relationship, Toxoplasma classification, Toxoplasma enzymology, Toxoplasma genetics, Adenosine Triphosphatases metabolism, Guanylate Cyclase chemistry, Guanylate Cyclase metabolism, Protein Interaction Domains and Motifs
- Abstract
cGMP signaling is one of the master regulators of diverse functions in eukaryotes; however, its architecture and functioning in protozoans remain poorly understood. Herein, we report an exclusive guanylate cyclase coupled with N-terminal P4-ATPase in a common parasitic protist, Toxoplasma gondii This bulky protein (477-kD), termed Tg ATPase
P -GC to fairly reflect its envisaged multifunctionality, localizes in the plasma membrane at the apical pole of the parasite, whereas the corresponding cGMP-dependent protein kinase ( Tg PKG) is distributed in the cytomembranes. Tg ATPaseP -GC is refractory to genetic deletion, and its CRISPR/Cas9-assisted disruption aborts the lytic cycle of T. gondii Besides, Cre/loxP-mediated knockdown of Tg ATPaseP -GC reduced the synthesis of cGMP and inhibited the parasite growth due to impairments in the motility-dependent egress and invasion events. Equally, repression of Tg PKG by a similar strategy recapitulated phenotypes of the Tg ATPaseP -GC-depleted mutant. Notably, despite a temporally restricted function, Tg ATPaseP -GC is expressed constitutively throughout the lytic cycle, entailing a post-translational regulation of cGMP signaling. Not least, the occurrence of Tg ATPaseP -GC orthologs in several other alveolates implies a divergent functional repurposing of cGMP signaling in protozoans, and offers an excellent drug target against the parasitic protists., (© 2019 Günay-Esiyok et al.)- Published
- 2019
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