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Unliganded <jats:italic>apo<\/jats:italic>\u2010PlzA is important for vertebrate infection, while liganded <jats:italic>holo<\/jats:italic>\u2010PlzA is important for survival in the tick; however, the biological function of PlzA has remained enigmatic. Here, we report that PlzA has RNA chaperone activity that is inhibited by c\u2010di\u2010GMP binding. <jats:italic>Holo<\/jats:italic>\u2010 and <jats:italic>apo<\/jats:italic>\u2010PlzA bind RNA and accelerate RNA annealing, while only <jats:italic>apo<\/jats:italic>\u2010PlzA can strand displace and unwind double\u2010stranded RNA. Guided by the crystal structure of PlzA, we identified several key aromatic amino acids protruding from the <jats:italic>N<\/jats:italic>\u2010 and <jats:italic>C<\/jats:italic>\u2010terminal domains that are required for RNA\u2010binding and unwinding activity. Our findings illuminate c\u2010di\u2010GMP as a switch controlling the RNA chaperone activity of PlzA, and we propose that complex RNA\u2010mediated modulatory mechanisms allow PlzA to regulate gene expression during both the vector and host phases of the <jats:italic>B. burgdorferi<\/jats:italic> life cycle.<\/jats:p>","DOI":"10.1111\/mmi.15066","type":"journal-article","created":{"date-parts":[[2023,4,22]],"date-time":"2023-04-22T06:46:41Z","timestamp":1682146001000},"page":"711-727","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["<scp>c\u2010di\u2010GMP<\/scp> regulates activity of the <scp>PlzA RNA<\/scp> chaperone from the Lyme disease spirochete"],"prefix":"10.1111","volume":"119","author":[{"given":"Taylor","family":"Van\u00a0Gundy","sequence":"first","affiliation":[{"name":"Bacterial Diseases Branch, Division of Vector\u2010Borne Diseases, National Center for Emerging and Zoonotic Infectious Diseases Center for Disease Control and Prevention  Fort Collins Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dhara","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology Virginia Commonwealth University Medical Center  Richmond Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce E.","family":"Bowler","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry University of Montana  Missoula Montana USA"},{"name":"Center for Biomolecular Structure and Dynamics University of Montana  Missoula Montana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael T.","family":"Rothfuss","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry University of Montana  Missoula Montana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allie J.","family":"Hall","sequence":"additional","affiliation":[{"name":"Bacterial Diseases Branch, Division of Vector\u2010Borne Diseases, National Center for Emerging and Zoonotic Infectious Diseases Center for Disease Control and Prevention  Fort Collins Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Davies","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology University of South Alabama  Mobile Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura S.","family":"Hall","sequence":"additional","affiliation":[{"name":"Division of Biological Sciences University of Montana  Missoula Montana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Drecktrah","sequence":"additional","affiliation":[{"name":"Division of Biological Sciences University of Montana  Missoula Montana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard T.","family":"Marconi","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology Virginia Commonwealth University Medical Center  Richmond Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8352-7593","authenticated-orcid":false,"given":"D. 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