Omar, Mitchell H, Byrne, Dominic P, Shrestha, Safal, Lakey, Tyler M, Lee, Kyung-Soon, Lauer, Sophia M, Collins, Kerrie B, Daly, Leonard A 
ORCID: 0000-0001-9712-9676, Eyers, Claire E ORCID: 0000-0002-3223-5926, Baird, Geoffrey S et al (show 4 more authors)
(2024)
Discovery of a Cushing’s syndrome protein kinase A mutant that biases signaling through type I AKAPs.
Science Advances, 10 (8).
eadl1258-.
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Abstract
<jats:p> 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 <jats:sup>W196G</jats:sup> 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 <jats:sup>W196G</jats:sup> 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 PKAc <jats:sup>W196G</jats:sup> 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. </jats:p>
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Humans, Cushing Syndrome, Signal Transduction, Catalytic Domain, A Kinase Anchor Proteins, Bias |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 29 Feb 2024 08:14 |
| Last Modified: | 01 Mar 2024 18:06 |
| DOI: | 10.1126/sciadv.adl1258 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3178979 |
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