{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T18:10:43Z","timestamp":1785607843755,"version":"3.56.0"},"reference-count":80,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"8","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2024,2,23]]},"abstract":"<jats:p>\n            Adrenal Cushing\u2019s syndrome is a disease of cortisol hypersecretion often caused by mutations in protein kinase A catalytic subunit (PKAc). Using a personalized medicine screening platform, we discovered a Cushing\u2019s driver mutation, PKAc-W196G, in ~20% of patient samples analyzed. Proximity proteomics and photokinetic imaging reveal that PKAc\n            <jats:sup>W196G<\/jats:sup>\n            is unexpectedly distinct from other described Cushing\u2019s variants, exhibiting retained association with type I regulatory subunits (RI) and their corresponding A kinase anchoring proteins (AKAPs). Molecular dynamics simulations predict that substitution of tryptophan-196 with glycine creates a 653\u2013cubic angstrom cleft between the catalytic core of PKAc\n            <jats:sup>W196G<\/jats:sup>\n            and type II regulatory subunits (RII), but only a 395\u2013cubic angstrom cleft with RI. Endocrine measurements show that overexpression of RI\u03b1 or redistribution of PKAc\n            <jats:sup>W196G<\/jats:sup>\n            via AKAP recruitment counteracts stress hormone overproduction. We conclude that a W196G mutation in the kinase catalytic core skews R subunit selectivity and biases AKAP association to drive Cushing\u2019s syndrome.\n          <\/jats:p>","DOI":"10.1126\/sciadv.adl1258","type":"journal-article","created":{"date-parts":[[2024,2,21]],"date-time":"2024-02-21T18:58:22Z","timestamp":1708541902000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":14,"title":["Discovery of a Cushing\u2019s syndrome protein kinase A mutant that biases signaling through type I AKAPs"],"prefix":"10.1126","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1713-4473","authenticated-orcid":true,"given":"Mitchell H.","family":"Omar","sequence":"first","affiliation":[{"name":"Department of Pharmacology, University of Washington, Seattle, WA 98195, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominic P.","family":"Byrne","sequence":"additional","affiliation":[{"name":"Department of 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