biostudies-literatureWalker CAmerican Heart AssociationNational Natural Science Foundation of ChinaNational Institutes of HealthNIH HHSNIGMS NIH HHS167123https://www.ebi.ac.uk/biostudies/studies/S-EPMC8409435biostudies-literatureUnknown433(18)Somatic mutations in the PRKACA gene encoding the catalytic α subunit of protein kinase A (PKA-C) are responsible for cortisol-producing adrenocortical adenomas. These benign neoplasms contribute to the development of Cushing's syndrome. The majority of these mutations occur at the interface between the two lobes of PKA-C and interfere with the enzyme's ability to recognize substrates and regulatory (R) subunits, leading to aberrant phosphorylation patterns and activation. Rarely, patients with similar phenotypes carry an allosteric mutation, E31V, located at the C-terminal end of the αA-helix and adjacent to the αC-helix, but structurally distinct from the PKA-C/R subunit interface mutations. Using a combination of solution NMR, thermodynamics, kinetic assays, and molecular dynamics simulJournal of molecular biologyIs Disrupted Nucleotide-Substrate Cooperativity a Common Trait for Cushing's Syndrome Driving Mutations of Protein Kinase A?PMC8409435R01 GM10031022007069R35 GM13038920PRE35120253S10 OD021536GM100310R01 GM046736GM046736Bernlohr DAVeglia GOlivieri CWalker CGao JTaylor SSWang YCalebiro DV S MfalseIs Disrupted Nucleotide-Substrate Cooperativity a Common Trait for Cushing's Syndrome Driving Mutations of Protein Kinase A?Somatic mutations in the PRKACA gene encoding the catalytic α subunit of protein kinase A (PKA-C) are responsible for cortisol-producing adrenocortical adenomas. These benign neoplasms contribute to the development of Cushing's syndrome. The majority of these mutations occur at the interface between the two lobes of PKA-C and interfere with the enzyme's ability to recognize substrates and regulatory (R) subunits, leading to aberrant phosphorylation patterns and activation. Rarely, patients with similar phenotypes carry an allosteric mutation, E31V, located at the C-terminal end of the αA-helix and adjacent to the αC-helix, but structurally distinct from the PKA-C/R subunit interface mutations. Using a combination of solution NMR, thermodynamics, kinetic assays, and molecular dynamics simul2021-01-01T00:00:00Z2021 Sep2026-05-31T02:17:53.561Z2024-10-16T04:17:31.343ZS-EPMC84094353422474810.1016/j.jmb.2021.167123