PXD000697 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Alterations in the Interactome of Serine/Threonine Protein Phosphatase Type-1 in Atrial Fibrillation Patients |
Description | Objectives: To test the hypothesis that serine/threonine protein phosphatase type-1 (PP1) is dysregulated in paroxysmal atrial fibrillation (pAF) at the level of its regulatory subunits (R-subunits). Background: AF is the most common sustained cardiac arrhythmia yet current pharmacologic treatment is ineffective. PP1, a major phosphatase in the heart, consists of a catalytic subunit (PP1c) and a large set of R-subunits that confer localization and substrate specificity to the holoenzyme. Previous studies suggest that PP1 is dysregulated in AF but the mechanisms are unknown. Methods: Cardiac lysates were co-immunoprecipitated with anti-PP1c antibody followed by mass spectrometry-based (quantitative) profiling of associated R-subunits. Subsequently, label-free quantification was used to evaluate altered R-subunit-PP1c interactions in pAF patients. R-subunits with altered binding to PP1c in pAF were further validated using qRT-PCR, Western blotting (WB), immunocytochemistry, and co-immunoprecipitation. Results: 135 and 78 putative PP1c-interactors were captured respectively from mouse ventricles and human atria, with many previously unreported interactors with conserved PP1c-docking motifs. Increases in binding were found between PP1c and PPP1R7, CSDA, and PDE5A in pAF patients, with CSDA and PDE5A being novel interactors validated by bioinformatics, immunocytochemistry and co-immunoprecipitation. WB confirmed that these upregulated associations cannot be ascribed to changes in global protein expression alone. Conclusion: Subcellular heterogeneity in PP1 activity and downstream protein phosphorylation in AF may be attributed to alterations in PP1c-R-subunits interactions, which impair PP1 targeting to proteins involved in electrical and Ca2+-remodeling. This represents a novel concept in AF pathogenesis and provides highly-specific drug targets for treating AF. |
HostingRepository | PRIDE |
AnnounceDate | 2015-03-30 |
AnnouncementXML | Submission_2015-03-30_05:44:18.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Nicolas Lebesgue |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; scientific name: Mus musculus (Mouse); NCBI TaxID: 10090; |
ModificationList | monohydroxylated residue; acetylated residue; iodoacetamide derivatized residue |
Instrument | Q Exactive; LTQ Orbitrap Elite |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2014-01-21 03:22:40 | ID requested | |
⏵ 1 | 2015-03-30 05:44:19 | announced | |
2 | 2015-03-31 00:31:06 | announced | Updated project metadata. |
Publication List
Chiang DY, Lebesgue N, Beavers DL, Alsina KM, Damen JM, Voigt N, Dobrev D, Wehrens XH, Scholten A, Alterations in the interactome of serine/threonine protein phosphatase type-1 in atrial fibrillation patients. J Am Coll Cardiol, 65(2):163-73(2015) [pubmed] |
Keyword List
submitter keyword: protein phosphatase 1, paroxysmal atrial fibrillation, mouse, human, Q-exactive, LTQ-Orbitrap Elite, label-free quantification |
Contact List
Arjen Scholten |
contact affiliation | Biomolecular Mass Spectrometry and Proteomics Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences Utrecht University Padualaan 8 3584 CH Utrecht The Netherlands, Janssen Infectious Diseases and Vaccines, Crucell Holland B.V., Leiden, the Netherlands |
contact email | A.Scholten@uu.nl |
lab head | |
Nicolas Lebesgue |
contact affiliation | Utrecht University |
contact email | n.f.m.lebesgue@uu.nl |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
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[ - ]
- PRIDE
- PXD000697
- Label: PRIDE project
- Name: Alterations in the Interactome of Serine/Threonine Protein Phosphatase Type-1 in Atrial Fibrillation Patients