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Likewise, how stimulatory compounds enhance sGC activity is poorly understood, hampering development of new treatments for cardiovascular disease. NO binding to ferrous heme near the N\u2010terminus in sGC activates cyclase activity near the C\u2010terminus, yielding cGMP production and physiological response. CO binding can also stimulate sGC, but only weakly in the absence of stimulatory small\u2010molecule compounds, which together lead to full activation. How ligand binding enhances catalysis, however, has yet to be discovered. Here, using a truncated version of sGC from <jats:italic>Manduca sexta<\/jats:italic>, we demonstrate that the central coiled\u2010coil domain, the most highly conserved region of the ~150,000\u2009Da protein, not only provides stability to the heterodimer but is also conformationally active in signal transduction. Sequence conservation in the coiled coil includes the expected heptad\u2010repeating pattern for coiled\u2010coil motifs, but also invariant positions that disfavor coiled\u2010coil stability. Full\u2010length coiled coil dampens CO affinity for heme, while shortening of the coiled coil leads to enhanced CO binding. Introducing double mutation \u03b1E447L\/\u03b2E377L, predicted to replace two destabilizing glutamates with leucines, lowers CO binding affinity while increasing overall protein stability. Likewise, introduction of a disulfide bond into the coiled coil results in reduced CO affinity. Taken together, we demonstrate that the heme domain is greatly influenced by coiled\u2010coil conformation, suggesting communication between heme and catalytic domains is through the coiled coil. Highly conserved structural imperfections in the coiled coil provide needed flexibility for signal transduction.<\/jats:p>","DOI":"10.1002\/pro.3707","type":"journal-article","created":{"date-parts":[[2019,8,14]],"date-time":"2019-08-14T15:59:47Z","timestamp":1565798387000},"page":"1830-1839","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Instability in a coiled\u2010coil signaling helix is conserved for signal transduction in soluble guanylyl cyclase"],"prefix":"10.1002","volume":"28","author":[{"given":"Andrzej","family":"Weichsel","sequence":"first","affiliation":[{"name":"Department of Chemistry and Biochemistry University of Arizona  Tucson Arizona"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica A.","family":"Kievenaar","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry University of Arizona  Tucson Arizona"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roslyn","family":"Curry","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry University of Arizona  Tucson Arizona"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacob T.","family":"Croft","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry University of Arizona  Tucson Arizona"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5776-2530","authenticated-orcid":false,"given":"William R.","family":"Montfort","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry University of Arizona  Tucson 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