PXD045556

PXD045556 is an original dataset announced via ProteomeXchange.

Title	Discovery of a new Cushing’s syndrome PKAc mutant that is retained within anchored type I holoenzymes
Description	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 new Cushing’s driver mutation, PKAc-W196G, in ~20% of patient samples analyzed. Proximity proteomics and photokinetic imaging reveal that PKAcW196G is distinct from other Cushing’s variants. This mutant surprisingly retains association with type I regulatory subunits (RI) and their corresponding A kinase anchoring proteins (AKAPs). Molecular dynamics simulations predict that substitution of glycine for tryptophan 196 creates a 653 Å3 cleft between the catalytic core of PKAcW196G and type II regulatory subunits (RII), but only a 395 Å3 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.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:29:01.442.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD045556
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	leonard daly
SpeciesList	scientific name: Escherichia coli; NCBI TaxID: 562; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos; Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2023-09-21 04:57:47	ID requested
1	2024-02-10 09:19:46	announced
⏵ 2	2024-10-22 06:29:01	announced	2024-10-22: Updated project metadata.

10.6019/PXD045556;

submitter keyword: Cushing's syndrome,PKA

Prof Claire E Eyers
contact affiliation	Centre for Proteome Research, Department of Biochemistry & Systems Biology, University of Liverpool, Liverpool L69 7ZB, UK
contact email	ceyers@liverpool.ac.uk
lab head
leonard daly
contact affiliation	University of Liverpool
contact email	leonard.daly@liverpool.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD045556
     1. Label: PRIDE project
     2. Name: Discovery of a new Cushing’s syndrome PKAc mutant that is retained within anchored type I holoenzymes