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PlzA has been implicated in the regulation of many borrelial processes, but the effector mechanism of PlzA was not previously known. Here, we report that PlzA can bind DNA and RNA and that nucleic acid binding requires c\u2010di\u2010GMP, with the affinity of PlzA for nucleic acids increasing as concentrations of c\u2010di\u2010GMP were increased. A mutant PlzA that is incapable of binding c\u2010di\u2010GMP did not bind to any tested nucleic acids. We also determined that PlzA interacts predominantly with the major groove of DNA and that sequence length and G\u2013C content play a role in DNA binding affinity. PlzA is a dual\u2010domain protein with a PilZ\u2010like N\u2010terminal domain linked to a canonical C\u2010terminal PilZ domain. Dissection of the domains demonstrated that the separated N\u2010terminal domain bound nucleic acids independently of c\u2010di\u2010GMP. The C\u2010terminal domain, which includes the c\u2010di\u2010GMP binding motifs, did not bind nucleic acids under any tested conditions. Our data are supported by computational docking, which predicts that c\u2010di\u2010GMP binding at the C\u2010terminal domain stabilizes the overall protein structure and facilitates PlzA\u2010DNA interactions via residues in the N\u2010terminal domain. Based on our data, we propose that levels of c\u2010di\u2010GMP during the various stages of the enzootic life cycle direct PlzA binding to regulatory targets.<\/jats:p>","DOI":"10.1111\/mmi.15254","type":"journal-article","created":{"date-parts":[[2024,3,25]],"date-time":"2024-03-25T21:45:59Z","timestamp":1711403159000},"page":"1039-1062","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["<i>Borrelia burgdorferi<\/i>\n                    <scp>PlzA<\/scp>\n                    is a\n                    <scp>cyclic\u2010di\u2010GMP<\/scp>\n                    dependent\n                    <scp>DNA<\/scp>\n                    and\n                    <scp>RNA<\/scp>\n                    binding protein"],"prefix":"10.1111","volume":"121","author":[{"given":"Nerina","family":"Jusufovic","sequence":"first","affiliation":[{"name":"Microbiology, Immunology and Molecular Genetics University of Kentucky College of Medicine, University of Kentucky  Lexington Kentucky USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew C.","family":"Krusenstjerna","sequence":"additional","affiliation":[{"name":"Microbiology, Immunology and Molecular Genetics University of Kentucky College of Medicine, University of Kentucky  Lexington Kentucky USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christina R.","family":"Savage","sequence":"additional","affiliation":[{"name":"Microbiology, Immunology and Molecular Genetics University of Kentucky College of Medicine, University of Kentucky  Lexington Kentucky USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy C.","family":"Saylor","sequence":"additional","affiliation":[{"name":"Microbiology, Immunology and Molecular Genetics University of Kentucky College of Medicine, University of Kentucky  Lexington Kentucky USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catherine 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