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Alliance"],"published-print":{"date-parts":[[2019,6]]},"abstract":"<jats:p>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, <jats:italic>Toxoplasma gondii<\/jats:italic>. This bulky protein (477-kD), termed <jats:italic>Tg<\/jats:italic>ATPase<jats:sub>P<\/jats:sub>-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 (<jats:italic>Tg<\/jats:italic>PKG) is distributed in the cytomembranes. <jats:italic>Tg<\/jats:italic>ATPase<jats:sub>P<\/jats:sub>-GC is refractory to genetic deletion, and its CRISPR\/Cas9\u2013assisted disruption aborts the lytic cycle of <jats:italic>T. gondii<\/jats:italic>. Besides, Cre\/loxP\u2013mediated knockdown of <jats:italic>Tg<\/jats:italic>ATPase<jats:sub>P<\/jats:sub>-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 <jats:italic>Tg<\/jats:italic>PKG by a similar strategy recapitulated phenotypes of the <jats:italic>Tg<\/jats:italic>ATPase<jats:sub>P<\/jats:sub>-GC\u2013depleted mutant. Notably, despite a temporally restricted function, <jats:italic>Tg<\/jats:italic>ATPase<jats:sub>P<\/jats:sub>-GC is expressed constitutively throughout the lytic cycle, entailing a post-translational regulation of cGMP signaling. Not least, the occurrence of <jats:italic>Tg<\/jats:italic>ATPase<jats:sub>P<\/jats:sub>-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.<\/jats:p>","DOI":"10.26508\/lsa.201900402","type":"journal-article","created":{"date-parts":[[2019,6,24]],"date-time":"2019-06-24T19:29:58Z","timestamp":1561404598000},"page":"e201900402","update-policy":"https:\/\/doi.org\/10.26508\/lsa.crossmarkpolicy","source":"Crossref","is-referenced-by-count":30,"title":["An unusual and vital protein with guanylate cyclase and P4-ATPase domains in a pathogenic protist"],"prefix":"10.26508","volume":"2","author":[{"given":"\u00d6zlem","family":"G\u00fcnay-Esiyok","sequence":"first","affiliation":[{"name":"Institute of Biology, Faculty of Life Sciences, Humboldt University, Berlin, 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