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Five of the 13 PDEs feature a periplasmic CSS domain with two conserved cysteines, flanked by transmembrane (TM) regions, and an enzymatically active cytoplasmic EAL domain. One of these (PdeC) was previously shown to be redox-regulated by DsbA\/DsbB-mediated disulfide bond (DSB) formation in the cysteine serine serine (CSS) domain. Comparing all five CSS domain PDEs, we found them to fall into two groups with similar biochemical features, resulting in different consequences for PDE activity. PdeB, PdeC, and PdeG are more active when lacking the periplasmic DSB, resulting in diminished biofilm formation, while PdeN and PdeD are active in their oxidized forms. Using PdeB and PdeN as prototypes for the two groups, not only the periplasmic DSB but also differently charged amino acid motifs close to the transmembrane (TM) domains and a putative additional DSB in PdeN were identified as important for transmembrane signaling. All these elements, including its stable structural DSB in the periplasm, which can form independently of DsbA, maintain PdeN in a rigid, proteolysis-resistant active conformation. By contrast, for PdeB, the more rigid DSB-containing conformation is inactive, with mutations in the stabilizing elements leading to a structurally less constrained, more active enzyme. Notably, low PdeN levels are post-transcriptionally upregulated at acidic pH, resulting in less biofilm formation. Overall, the five CSS domain PDEs enable\n                      <jats:italic toggle=\"yes\">E. coli<\/jats:italic>\n                      to adapt to diverse environmental niches.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        Sensing environmental cues and transmembrane signal transduction via membrane-embedded proteins is a process of key importance in all living cells. To investigate the molecular mechanisms involved, we performed a systematic functional comparison of the five CSS domain phosphodiesterases of\n                        <jats:italic toggle=\"yes\">Escherichia coli<\/jats:italic>\n                        , which degrade the bacterial second messenger c-di-GMP in response to redox and other signals. With a sensory domain in the periplasm linked to a cytoplasmic enzymatic domain, these proteins represent minimal devices for transmembrane signaling. We demonstrate that these signal-transducing enzymes fall into two functional classes with a similar periplasmic redox biochemistry resulting in opposite states of cytoplasmic enzymatic activity. Several characteristic sequence elements convey redox and structural information in the periplasmic and transmembrane protein segments to their ability to dimerize into an enzymatically active form in the cytoplasm. Comparing the five enzymes also shows that evolution has played with these elements to facilitate adaptation to various environmental niches.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.01325-26","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T13:01:11Z","timestamp":1788267671000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Redox control and mechanisms of transmembrane signaling in CSS domain c-di-GMP phosphodiesterases that control biofilm formation in\n                    <i>Escherichia coli<\/i>"],"prefix":"10.1128","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8162-3178","authenticated-orcid":false,"given":"Katharina","family":"Pressler","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01hcx6992","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Biology\/Microbiology, Humboldt-Universit\u00e4t zu Berlin","place":["Berlin, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Lorkowski","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01hcx6992","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Biology\/Microbiology, Humboldt-Universit\u00e4t zu Berlin","place":["Berlin, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3969-8018","authenticated-orcid":true,"given":"Regine","family":"Hengge","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01hcx6992","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Biology\/Microbiology, Humboldt-Universit\u00e4t zu Berlin","place":["Berlin, Germany"]},{"id":[{"id":"https:\/\/ror.org\/01hcx6992","id-type":"ROR","asserted-by":"publisher"}],"name":"Excellence Cluster Matters of Activity. 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