Discovery of a Cushing's syndrome protein kinase A mutant that biases signaling through type I AKAPs.

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 PKAc^W196G 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 PKAc^W196G and type II regulatory subunits (RII), but only a 395-cubic angstrom c

SUBMITTER: Omar MH 

PROVIDER: S-EPMC10881042 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature