⮝ Full datasets listing
PXD070300-1
PXD070300 is an original dataset announced via ProteomeXchange.
Dataset Summary
| Title | The clinical missense variant E282K in PPP3CA/calcineurin globally shifts substrate dephosphorylation profiles by altering active site recruitmen |
| Description | Recently, de novo heterozygous variants of Calcineurin (CN) were reported as the cause of a neurodevelopmental disorder that presents with epileptic encephalopathy and dysmorphism (DEE91), with the largest group of patients harboring the CN missense mutation E282K (glutamate to lysine). Here, we use molecular and cellular techniques to define how this mutation alters CN activity. We discovered that basophilic substrates use an arginine residue to bind to CN via a newly discovered acidic substrate recruitment pocket adjacent to the CN active site, the E282 pocket. Furthermore, we show that basic residues in the i-1 position of the substrate relative to the substrate phosphosite enhance CN-mediated dephosphorylation. While the CNE282K structure showed that the overall conformation is unchanged, the E282 pocket transformed from an acidic to basic, with pocket access blocked by the formation of a E282K-E237 salt bridge. Finally in vitro assays and in cell phosphoproteomics showed that CNE282K universally shifts CN substrate dephosphorylation profiles from basic to acidic, thereby globally altering CN-mediated dephosphorylation signaling. Together, these data define the molecular impact of the CNE282K variant in cells and development, providing a first step for developing new strategies to treat this disorder and its accompanying complications. |
| HostingRepository | MassIVE |
| AnnounceDate | 2026-01-22 |
| AnnouncementXML | Submission_2026-01-22_05:45:15.290.xml |
| DigitalObjectIdentifier | |
| ReviewLevel | Non peer-reviewed dataset |
| DatasetOrigin | Original dataset |
| RepositorySupport | Supported dataset by repository |
| PrimarySubmitter | Arminja Nadine Kettenbach |
| SpeciesList | scientific name: Mus musculus; common name: house mouse; NCBI TaxID: 10090; scientific name: Homo sapiens; common name: human; NCBI TaxID: 9606; |
| ModificationList | Phospho |
| Instrument | Orbitrap Fusion Lumos |
Dataset History
| Revision | Datetime | Status | ChangeLog Entry |
|---|---|---|---|
| 0 | 2025-11-04 08:11:06 | ID requested | |
| ⏵ 1 | 2026-01-22 05:45:15 | announced |
Publication List
| no publication |
Keyword List
| submitter keyword: intrinsically disordered protein, de-phosphorylation, protein phosphatase, calcineurin, clinical missense variant, DatasetType:Proteomics |
Contact List
| Arminja Kettenbach | |
|---|---|
| contact affiliation | The Geisel School of Medicine at Dartmouth |
| 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/v11/MSV000099747/ |
