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Discovery of a Cushing's syndrome protein kinase A mutant that biases signaling through type I AKAPs.
Omar, Mitchell H; Byrne, Dominic P; Shrestha, Safal; Lakey, Tyler M; Lee, Kyung-Soon; Lauer, Sophia M; Collins, Kerrie B; Daly, Leonard A; Eyers, Claire E; Baird, Geoffrey S; Ong, Shao-En; Kannan, Natarajan; Eyers, Patrick A; Scott, John D.
Afiliación
  • Omar MH; Department of Pharmacology, University of Washington, Seattle, WA 98195, USA.
  • Byrne DP; Department of Biochemistry, Cell and Systems Biology, University of Liverpool, Liverpool L69 7ZB, UK.
  • Shrestha S; Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA.
  • Lakey TM; Department of Pharmacology, University of Washington, Seattle, WA 98195, USA.
  • Lee KS; Department of Pharmacology, University of Washington, Seattle, WA 98195, USA.
  • Lauer SM; Department of Pharmacology, University of Washington, Seattle, WA 98195, USA.
  • Collins KB; Department of Pharmacology, University of Washington, Seattle, WA 98195, USA.
  • Daly LA; Centre for Proteome Research, Department of Biochemistry, Cell and Systems Biology, University of Liverpool, Liverpool L69 7ZB, UK.
  • Eyers CE; Centre for Proteome Research, Department of Biochemistry, Cell and Systems Biology, University of Liverpool, Liverpool L69 7ZB, UK.
  • Baird GS; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA.
  • Ong SE; Department of Pharmacology, University of Washington, Seattle, WA 98195, USA.
  • Kannan N; Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA.
  • Eyers PA; Department of Biochemistry, Cell and Systems Biology, University of Liverpool, Liverpool L69 7ZB, UK.
  • Scott JD; Department of Pharmacology, University of Washington, Seattle, WA 98195, USA.
Sci Adv ; 10(8): eadl1258, 2024 Feb 23.
Article en En | MEDLINE | ID: mdl-38381834
ABSTRACT
Adrenal Cushing's 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's driver mutation, PKAc-W196G, in ~20% of patient samples analyzed. Proximity proteomics and photokinetic imaging reveal that PKAcW196G is unexpectedly distinct from other described Cushing's 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-cubic angstrom cleft between the catalytic core of PKAcW196G and type II regulatory subunits (RII), but only a 395-cubic angstrom cleft with RI. Endocrine measurements show that overexpression of RIα or redistribution of PKAcW196G 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's syndrome.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Síndrome de Cushing Límite: Humans Idioma: En Revista: Sci Adv Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Síndrome de Cushing Límite: Humans Idioma: En Revista: Sci Adv Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos