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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,11,12]]},"abstract":"<jats:p>Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), the anion channel mutated in cystic fibrosis (CF) patients, is activated by the catalytic subunit of protein kinase A (PKA-C). PKA-C activates CFTR both noncatalytically, through binding, and catalytically, through phosphorylation of multiple serines in CFTR\u2019s regulatory (R) domain. Here, we identify key molecular determinants of the CFTR\/PKA-C interaction essential for these processes. By comparing CFTR current activation in the presence of ATP or an ATP analog unsuitable for phosphotransfer, as well as pseudosubstrate peptides of various lengths, we identify two distinct specific regions of the PKA-C surface which interact with CFTR to cause noncatalytic and catalytic CFTR stimulation, respectively. Whereas the \u201csubstrate site\u201d mediates CFTR phosphorylation, a distinct hydrophobic patch (the \u201cdocking site\u201d) is responsible for noncatalytic CFTR activation, achieved by stabilizing the R domain in a \u201creleased\u201d conformation permissive to channel gating. Furthermore, by comparing PKA-C variants with different posttranslational modification patterns, we find that direct membrane tethering of the kinase through its N-terminal myristoyl group is an unappreciated fundamental requirement for CFTR activation: PKA-C demyristoylation abolishes noncatalytic, and profoundly slows catalytic, CFTR stimulation. For the F508del CFTR mutant, present in ~90% of CF patients, maximal activation by demyristoylated PKA-C is reduced by ~10-fold compared to that by myristoylated PKA-C. Finally, in bacterial genera that contain common CF pathogens, we identify virulence factors that demyristoylate PKA-C in vitro, raising the possibility that during recurrent bacterial infections in CF patients, PKA-C demyristoylation may contribute to the exacerbation of lung disease.<\/jats:p>","DOI":"10.1073\/pnas.2407728121","type":"journal-article","created":{"date-parts":[[2024,11,4]],"date-time":"2024-11-04T15:05:22Z","timestamp":1730732722000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":6,"title":["Structural determinants of protein kinase A essential for CFTR channel activation"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7536-3066","authenticated-orcid":false,"given":"Csaba","family":"Mih\u00e1lyi","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Semmelweis University, Budapest H-1094, Hungary"},{"name":"Molecular Channelopathies Research Group, 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