{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T08:01:13Z","timestamp":1774944073962,"version":"3.50.1"},"reference-count":59,"publisher":"Proceedings of the National Academy of Sciences","issue":"18","license":[{"start":{"date-parts":[[2024,4,23]],"date-time":"2024-04-23T00:00:00Z","timestamp":1713830400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"MEC | Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["PTDC\/BIA-BQM\/29863\/2017"],"award-info":[{"award-number":["PTDC\/BIA-BQM\/29863\/2017"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007472","name":"Funda\u00e7\u00e3o Luso-Americana para o Desenvolvimento","doi-asserted-by":"publisher","award":["FLAD Life Science 2020"],"award-info":[{"award-number":["FLAD Life Science 2020"]}],"id":[{"id":"10.13039\/501100007472","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010434","name":"'la Caixa' Foundation","doi-asserted-by":"publisher","award":["LCF\/PR\/HR22\/52420004"],"award-info":[{"award-number":["LCF\/PR\/HR22\/52420004"]}],"id":[{"id":"10.13039\/100010434","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["Priority Program SPP1879 (Stu 214-16)"],"award-info":[{"award-number":["Priority Program SPP1879 (Stu 214-16)"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,4,30]]},"abstract":"<jats:p>\n                    In bacteria, intracellular K\n                    <jats:sup>+<\/jats:sup>\n                    is involved in the regulation of membrane potential, cytosolic pH, and cell turgor as well as in spore germination, environmental adaptation, cell-to-cell communication in biofilms, antibiotic sensitivity, and infectivity. The second messenger cyclic-di-AMP (c-di-AMP) has a central role in modulating the intracellular K\n                    <jats:sup>+<\/jats:sup>\n                    concentration in many bacterial species, controlling transcription and function of K\n                    <jats:sup>+<\/jats:sup>\n                    channels and transporters. However, our understanding of how this regulatory network responds to c-di-AMP remains poor. We used the RCK (Regulator of Conductance of K\n                    <jats:sup>+<\/jats:sup>\n                    ) proteins that control the activity of Ktr channels in\n                    <jats:italic>Bacillus subtilis<\/jats:italic>\n                    as a model system to analyze the regulatory function of c-di-AMP with a combination of in vivo and in vitro functional and structural characterization. We determined that the two RCK proteins (KtrA and KtrC) are neither physiologically redundant or functionally equivalent. KtrC is the physiologically dominant RCK protein in the regulation of Ktr channel activity. In explaining this hierarchical organization, we found that, unlike KtrA, KtrC is very sensitive to c-di-AMP inactivation and lack of c-di-AMP regulation results in RCK protein toxicity, most likely due to unregulated K\n                    <jats:sup>+<\/jats:sup>\n                    flux. We also found that KtrC can assemble with KtrA, conferring c-di-AMP regulation to the functional KtrA\/KtrC heteromers and potentially compensating KtrA toxicity. Altogether, we propose that the central role of c-di-AMP in the control of the K\n                    <jats:sup>+<\/jats:sup>\n                    machinery, by modulating protein levels through gene transcription and by regulating protein activity, has determined the evolutionary selection of KtrC as the dominant RCK protein, shaping the hierarchical organization of regulatory components of the K\n                    <jats:sup>+<\/jats:sup>\n                    machinery.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2318666121","type":"journal-article","created":{"date-parts":[[2024,4,23]],"date-time":"2024-04-23T13:42:38Z","timestamp":1713879758000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":6,"title":["c-di-AMP determines the hierarchical organization of bacterial RCK proteins"],"prefix":"10.1073","volume":"121","author":[{"given":"Rita","family":"Rocha","sequence":"first","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, Porto 4200-135, Portugal"},{"name":"Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto 4200-135, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7075-5589","authenticated-orcid":false,"given":"Jo\u00e3o M. P.","family":"Jorge","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, Porto 4200-135, Portugal"},{"name":"Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto 4200-135, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8036-7069","authenticated-orcid":false,"given":"Celso M.","family":"Teixeira-Duarte","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, Porto 4200-135, Portugal"},{"name":"Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto 4200-135, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5567-4928","authenticated-orcid":false,"given":"In\u00eas R.","family":"Figueiredo-Costa","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, Porto 4200-135, Portugal"}]},{"given":"Tatiana B.","family":"Cereija","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, Porto 4200-135, Portugal"}]},{"given":"Paula F.","family":"Ferreira-Teixeira","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, Porto 4200-135, Portugal"}]},{"given":"Christina","family":"Herzberg","sequence":"additional","affiliation":[{"name":"Department of General Microbiology, Institute for Microbiology and Genetics, Georg-August-University G\u00f6ttingen, G\u00f6ttingen 37073, Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5881-5390","authenticated-orcid":false,"given":"J\u00f6rg","family":"St\u00fclke","sequence":"additional","affiliation":[{"name":"Department of General Microbiology, Institute for Microbiology and Genetics, Georg-August-University G\u00f6ttingen, G\u00f6ttingen 37073, Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4461-9716","authenticated-orcid":false,"given":"Jo\u00e3o H.","family":"Morais-Cabral","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, Porto 4200-135, Portugal"},{"name":"Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto 4200-135, Portugal"}]}],"member":"341","published-online":{"date-parts":[[2024,4,23]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1134\/S0006297915050016"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0079-6603(03)75008-9"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro2549"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1099\/mic.0.2007\/007450-0"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1985.tb09148.x"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1099\/00221287-136-12-2521"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2021.166968"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.185.4.1289-1298.2003"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1099\/00221287-136-12-2527"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature15709"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.12.014"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1099\/mic.0.068700-0"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1111\/mmi.12312"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.3390\/antibiotics11040509"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.03.039"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.00691-19"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1111\/mmi.13277"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2011.07953.x"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2016.00804"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2014.12.007"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0073512"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002217"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0069425"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-micro-020518-115943"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aal3011"},{"key":"e_1_3_4_26_2","doi-asserted-by":"crossref","DOI":"10.1128\/mbio.00092-22","article-title":"A central role for magnesium homeostasis during adaptation to osmotic stress","volume":"13","author":"Wendel B. 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