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Adv."],"published-print":{"date-parts":[[2026,9,4]]},"abstract":"<jats:p>\n                    Thoracic aortic aneurysms and dissections (TAAD) are life-threatening conditions linked to gain-of-function mutations in cGMP-dependent protein kinase I (PKG I), a central regulator of vascular smooth muscle signaling. Among these, substitutions at Val\n                    <jats:sup>234<\/jats:sup>\n                    have been associated with kinase overactivation and early-onset disease, despite this residue being distal from the active site and cGMP binding regions. Using NMR, molecular dynamics simulations, and complementary kinase and binding assays, we show that Val\n                    <jats:sup>234<\/jats:sup>\n                    acts as a crucial allosteric hub of PKG autoinhibition. TAAD-associated variants at Val\n                    <jats:sup>234<\/jats:sup>\n                    disrupt PKG regulation through two distinct yet complementary allosteric mechanisms: by biasing the kinase toward active conformations that increase sensitivity to cGMP and by decreasing the folding stability of the regulatory domain, thereby weakening inhibitory contacts independently of cGMP control. Despite these differences, both mechanisms result in excessive PKG signaling at basal and intermediate cGMP levels, while maximal activity remains unaltered. Together, these findings explain how distal mutations can unpredictably rewire kinase allostery and drive pathogenic vascular signaling.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aeg1640","type":"journal-article","created":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T17:59:26Z","timestamp":1788371966000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Aortic disease-linked mutations reveal unexpected convergent allosteric mechanisms of protein kinase G misregulation"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1411-3383","authenticated-orcid":true,"given":"Karla","family":"Martinez Pomier","sequence":"first","affiliation":[{"name":"Department of Chemistry and Chemical Biology, McMaster University, Hamilton, ON, 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