⮝ Full datasets listing
PXD064473-1
PXD064473 is an original dataset announced via ProteomeXchange.
Dataset Summary
| Title | The clinical missense variant E282K in PPP3CA globally shifts substrate dephosphorylation profiles by altering active site recruitment |
| Description | Whole exome sequencing led to the discovery that de novo heterozygous variants of Calcineurin are present in patients with a distinct neurodevelopmental disorder that presents with epileptic encephalopathy and dysmorphism. The largest group of patients harbor the CN missense mutation E282K. Defining how this mutation alters CN activity in vitro and in cells is essential for developing novel strategies to treat this disorder and its accompanying complications. Here, by integrating x-ray crystallography, NMR spectroscopy, biophysics and substrate-based activity assays, we identified a novel phosphosite interaction pocket on CN that is critical for enhancing the dephosphorylation of CN substrates. We then showed that this enhancement is due to a specific interaction between CN E282 and an arginine residue that immediately precedes the substrate phosphosite, and, more importantly, that this enhancement is abolished in the E282K variant. Finally, using a cellular phosphoproteomics approach, we show that the CN E282K variant shifts CN substrate dephosphorylation profiles, thereby globally altering signaling. Together, these data provide the key mechanistic insights to understand the impact of the CN E282K variant in cells and development and to identify disrupted signaling pathways that may lead to treatments for this disorder. |
| HostingRepository | MassIVE |
| AnnounceDate | 2026-01-23 |
| AnnouncementXML | Submission_2026-01-23_11:59:22.421.xml |
| DigitalObjectIdentifier | |
| ReviewLevel | Non peer-reviewed dataset |
| DatasetOrigin | Original dataset |
| RepositorySupport | Supported dataset by repository |
| PrimarySubmitter | Arminja Nadine Kettenbach |
| SpeciesList | scientific name: Human; |
| ModificationList | Phospho |
| Instrument | Orbitrap Fusion Lumos |
Dataset History
| Revision | Datetime | Status | ChangeLog Entry |
|---|---|---|---|
| 0 | 2025-05-31 08:49:54 | ID requested | |
| ⏵ 1 | 2026-01-23 11:59:23 | announced |
Publication List
| no publication |
Keyword List
| submitter keyword: Calcineurin, Phosphorylation, substrate specificity, DatasetType:Proteomics |
Contact List
| Arminja Kettenbach | |
|---|---|
| contact affiliation | Dartmouth College |
| contact email | arminja.n.kettenbach@dartmouth.edu |
| lab head | |
| Arminja Nadine Kettenbach | |
| contact affiliation | Dartmouth |
| contact email | Arminja.N.Kettenbach@Dartmouth.edu |
| dataset submitter | |
Full Dataset Link List
| MassIVE dataset URI |
| Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://massive-ftp.ucsd.edu/v10/MSV000098060/ |
