GPMDB0012218OtherChiang DY, et al.InstrumentNot AvailableNot availableMus_musculus_viruses, Mousea.scholten@uu.n25593058http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014423http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014424http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014436http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014426http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014437http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014427http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014438http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014416http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014417http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014428http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014439http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014418http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014429http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014419http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014430http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014420http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014431http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014432http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014421http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014422http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014433Cardiovascular Research Institute, Baylor College of Medicine, et al.Not availableGPMDBA total of 135 and 78 putative PP1c interactors were captured from mouse and human cardiac lysates, respectively, including many previously unreported interactors with conserved PP1c docking motifs. Increases in binding were found between PP1c and PPP1R7, cold-shock domain protein A (CSDA), and phosphodiesterase type-5A (PDE5A) in PAF patients, with CSDA and PDE5A being novel interactors validated by bioinformatics, immunocytochemistry, and coimmunoprecipitation. WB confirmed that these increases in binding cannot be ascribed to their changes in global protein expression alone.Subcellular heterogeneity in PP1 activity and downstream protein phosphorylation in AF may be attributed to alterations in PP1c-R-subunit interactions, which impair PP1 targeting to proteins involved in electrical and Ca(2+) remodeling. This represents a novel concept in AF pathogenesis and may provide more specific drug targets for treating AF.Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, yet current pharmacological treatments are limited. Serine/threonine protein phosphatase type-1 (PP1), a major phosphatase in the heart, consists of a catalytic subunit (PP1c) and a large set of regulatory (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.The purpose of this study was to test the hypothesis that PP1 is dysregulated in paroxysmal atrial fibrillation (PAF) at the level of its R-subunits.Cardiac lysates were coimmunoprecipitated with anti-PP1c antibody followed by mass spectrometry-based, quantitative profiling of associated R-subunits. Subsequently, label-free quantification (LFQ) was used to evaluate altered R-subunit-PP1c interactions in PAF patients. R-subunits with altered binding to PP1c in PAF were further studied using bioinformatics, Western blotting (WB), immunocytochemistry, and coimmunoprecipitation.Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, yet current pharmacological treatments are limited. Serine/threonine protein phosphatase type-1 (PP1), a major phosphatase in the heart, consists of a catalytic subunit (PP1c) and a large set of regulatory (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.The purpose of this study was to test the hypothesis that PP1 is dysregulated in paroxysmal atrial fibrillation (PAF) at the level of its R-subunits.Cardiac lysates were coimmunoprecipitated with anti-PP1c antibody followed by mass spectrometry-based, quantitative profiling of associated R-subunits. Subsequently, label-free quantification (LFQ) was used to evaluate altered R-subunit-PP1c interactions in PAF patients. R-subunits with altered binding to PP1c in PAF were further studied using bioinformatics, Western blotting (WB), immunocytochemistry, and coimmunoprecipitation.A total of 135 and 78 putative PP1c interactors were captured from mouse and human cardiac lysates, respectively, including many previously unreported interactors with conserved PP1c docking motifs. Increases in binding were found between PP1c and PPP1R7, cold-shock domain protein A (CSDA), and phosphodiesterase type-5A (PDE5A) in PAF patients, with CSDA and PDE5A being novel interactors validated by bioinformatics, immunocytochemistry, and coimmunoprecipitation. WB confirmed that these increases in binding cannot be ascribed to their changes in global protein expression alone.Subcellular heterogeneity in PP1 activity and downstream protein phosphorylation in AF may be attributed to alterations in PP1c-R-subunit interactions, which impair PP1 targeting to proteins involved in electrical and Ca(2+) remodeling. This represents a novel concept in AF pathogenesis and may provide more specific drug targets for treating AF.<h4>Background</h4>Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, yet current pharmacological treatments are limited. Serine/threonine protein phosphatase type-1 (PP1), a major phosphatase in the heart, consists of a catalytic subunit (PP1c) and a large set of regulatory (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.<h4>Objectives</h4>The purpose of this study was to test the hypothesis that PP1 is dysregulated in paroxysmal atrial fibrillation (PAF) at the level of its R-subunits.<h4>Methods</h4>Cardiac lysates were coimmunoprecipitated with anti-PP1c antibody followed by mass spectrometry-based, quantitative profiling of associated R-subunits. Subsequently, label-free quantification (LFQ) was used to evaluate altered R-subunit-PP1c interactions in PAF patients. R-subunits with altered binding to PP1c in PAF were further studied using bioinformatics, Western blotting (WB), immunocytochemistry, and coimmunoprecipitation.<h4>Results</h4>A total of 135 and 78 putative PP1c interactors were captured from mouse and human cardiac lysates, respectively, including many previously unreported interactors with conserved PP1c docking motifs. Increases in binding were found between PP1c and PPP1R7, cold-shock domain protein A (CSDA), and phosphodiesterase type-5A (PDE5A) in PAF patients, with CSDA and PDE5A being novel interactors validated by bioinformatics, immunocytochemistry, and coimmunoprecipitation. WB confirmed that these increases in binding cannot be ascribed to their changes in global protein expression alone.<h4>Conclusions</h4>Subcellular heterogeneity in PP1 activity and downstream protein phosphorylation in AF may be attributed to alterations in PP1c-R-subunit interactions, which impair PP1 targeting to proteins involved in electrical and Ca(2+) remodeling. This represents a novel concept in AF pathogenesis and may provide more specific drug targets for treating AF.Alterations in the interactome of serine/threonine protein phosphatase type-1 in atrial fibrillation patients.Chiang David Y DY,Lebesgue Nicolas N,Beavers David L DL,Alsina Katherina M KM,Damen J Mirjam A JM,Voigt Niels N,Dobrev Dobromir D,Wehrens Xander H T XH,Scholten Arjen A,Chiang David Y DY, Lebesgue Nicolas N, Beavers David L DL, Alsina Katherina M KM, Damen J Mirjam A JM, Voigt Niels N, Dobrev Dobromir D, Wehrens Xander H T XH, Scholten Arjen AAuricular Fibrillation, DMDA1, Fibrillations, Atrial fibrillation (disorder), Auricular Fibrillations, Dual-specificity phosphatase TS-DSP1, Paroxysmal, Persistent Atrial Fibrillation, Dual-specificity protein phosphatase 19, Paroxysmal Atrial Fibrillations, A4, Fibrillation, Paroxysmal Atrial, L-Threonine, Familial, L Threonine, Familial Atrial, TYPE, Atrial Fibrillation, isoform CRA_a, LGMD2C, AFib, DAGA4, DMDA, Persistent Atrial, Auricular, Dual specificity phosphatase 19, Client., Persistent Atrial Fibrillations, Patient, Persistent, AF - Atrial fibrillation, Familial Atrial Fibrillations, Clients, SCARMD2, L Serine, Atrial Fibrillations, Familial Atrial Fibrillation, threonine, Atrial, MAM, L-Serine, Protein phosphatase, SCG3, Paroxysmal Atrial FibrillationPP, 3.4.22.-, data, Bru, Raw, PPP1G, Laboratory, Mus domesticus, mouse, number, mini-ICE, CASP-14, PP1C, B-cell receptor complex, Spectrum Analyses, antibodies, AA409629., House Mouse, Spectrum Analysis, presence, Client, mice C57BL/6xCBA/CaJ hybrid, Mus muscaris, Spectroscopy, antibody, count in organism, BCR complex, count, House, Mus, Mini-ICE, 163, PP-1G, PP1, Mass, Mus musculus domesticus, Del(8)44H, Analysis, p15(PAF), Mice, immunoglobulin complex, Mass Spectrum Analyses, Mass Spectroscopy, opsonin activity, Mass Spectrum Analysis, Svc, Mus musculus, Mass Spectrum, IOPPP, Col4a-1, IgG, Caspase-14 subunit p10, Analyses, Swiss, membrane bound, mice, ligand, Ns5atp9, Swiss Mouse, Spectrometry, House Mice, Swiss Mice, Caspase-14 subunit p19, Ns5apt9, "mouse" EXACT common_name [], MICE, free, PAF15, AA409629, SID6-8061, Laboratory Mice, domesticus, "house mouse" EXACT genbank_common_name [], "Mus muscaris" RELATED misnomer [], HEL-S-66p, immunoglobulin, B cell receptor accessory molecule complex, dis2m1, Patient, Clients, B lymphocyte receptor complex, B cell receptor activity, "mice C57BL/6xCBA/CaJ hybrid" RELATED misspelling [], Mouse, Paf, house mouse, quantitative, associated, B-lymphocyte receptor complex, mKIAA0101, Laboratory Mouse, presence or absence in organismAuricular Fibrillation, DMDA1, Fibrillations, Atrial fibrillation (disorder), Auricular Fibrillations, Dual-specificity phosphatase TS-DSP1, Paroxysmal, Persistent Atrial Fibrillation, Dual-specificity protein phosphatase 19, Paroxysmal Atrial Fibrillations, A4, Fibrillation, Paroxysmal Atrial, L-Threonine, Familial, L Threonine, Familial Atrial, TYPE, Atrial Fibrillation, isoform CRA_a, LGMD2C, AFib, DAGA4, DMDA, Persistent Atrial, Auricular, Dual specificity phosphatase 19, Client., Persistent Atrial Fibrillations, Patient, Persistent, AF - Atrial fibrillation, Familial Atrial Fibrillations, Clients, SCARMD2, L Serine, Atrial Fibrillations, Familial Atrial Fibrillation, threonine, Atrial, MAM, L-Serine, Protein phosphatase, SCG3, Paroxysmal Atrial Fibrillation3.4.22.-, MSY3, MSY4, human being, 2310014J01Rik, PPP1G, Laboratory, Circulatory, DISEASE (COPD), Chronic Airflow Obstructions, Mus domesticus, Parotid double-band protein, CAO - Chronic airflow obstruction, Pa, A4, mini-ICE, CASP-14, PP1C, CHRONIC OBSTRUCTIVE PULM DIS, Homo sapiense, Chronic obstructive pulmonary disease NOS, House Mouse, TYPE, Failure, Circulatory Collapse, Chronic obstructive pulmonary disease finding, DAGA4, Sds22, Homo spaiens, Db-s, PULMONARY DISEASE (COPD), Homo sapien, Pulmonary Disease, Yb2, House, Homo sapians, Csda, Parotid acidic protein, chronic obstructive airways disease NOS (disorder), Dbpa, Chronic irreversible airway obstruction, Mus musculus domesticus, CSDA1, Sphingolipid activator protein 2, p15(PAF), Chronic Obstructive Pulmonary Disease (COPD), MAM, Mice, SCG3, A1 activator, Shock, Salivary acidic proline-rich phosphoprotein 1|2, Pr1|Pr2, Homo sapients, COLD (chronic obstructive lung disease), Pde5a1, NEC in ICD9CM_2006, Swiss, Saposin-B-Val, ligand, Dispersin, Ns5atp9, SDS22, CAFL - Chronic airflow limitation, Swiss Mice, SAP-1, SAP-2, "mouse" EXACT common_name [], Chronic Obstructive, man, Chronic airflow limitation, Hypovolemic Shock, "Mus muscaris" RELATED misnomer [], Hypovolemic, proteins., Component C, Homo sapience, Homo sampiens, Clients, NEC, PIF-F, Chronic, "mice C57BL/6xCBA/CaJ hybrid" RELATED misspelling [], Paf, house mouse, Home sapiens, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, PIF-S, mKIAA0101, phosphodiesterase, COPD, CHRONIC, ZONAB, COAD - Chronic obstructive airways disease, Cn5n, chronic obstructive lung disease [Ambiguous], chronic obstructive airways disease NOS, Peptide P-C, Proactivator polypeptide, not elsewhere classified, COAD, mouse, Saposin-A, Parotid isoelectric focusing variant protein, oxyR, Circulatory Failure, PRP-3|PRP-4, Co-beta-glucosidase, COLD - Chronic obstructive lung disease, Client, Airflow Obstructions, PULM DIS CHRONIC OBSTRUCTIVE, mice C57BL/6xCBA/CaJ hybrid, Mus muscaris, Chronic obstructive pulmonary disease finding (finding), LGMD2C, Pde5, CHRONIC OBSTRUCTIVE AIRWAY DIS, polypeptide, Mus, Homo sapian, low temperature, CHRONIC OBSTRUCTIVE, Mini-ICE, PP-1G, chronic obstructive pulmonary disease and allied conditions, Chronic airway disease, NOS, (COPD), Homo sapeins, chronic airway obstruction, Airflow Obstruction, CAL - Chronic airflow limitation, COPD NOS, CHRONIC OBSTRUCTIVE LUNG DIS, chronic obstructive airway disease, Chronic Obstructive Airways Disease, Mus musculus, Chronic airway obstruction, Chronic obstructive lung disease, PRP-1|PRP-2, Salivary acidic proline-rich phosphoprotein 3|4, Caspase-14 subunit p10, Sphingolipid activator protein 1, DMDA1, cold, Dpba, Parotid proline-rich protein 1|2, mice, Dops, Swiss Mouse, Humo sapiens, CSAct, House Mice, Caspase-14 subunit p19, Ns5apt9, MICE, Homo sapines, PAF15, AA409629, human, Laboratory Mice, domesticus, Collapse, "house mouse" EXACT genbank_common_name [], dbpA, Chronic Airflow Obstruction, Cerebroside sulfate activator, Homo spiens, "human" EXACT genbank_common_name [], DMDA, Protein C, Saposin-D, Patient, OBSTRUCTIVE PULMONARY DISEASE (COPD), Saposin-C, COPD - Chronic obstructive pulmonary disease, Protein A, Saposin-B, chronic obstructive lung disease (disorder), SCARMD2, DBPA, Sulfatide|GM1 activator, CSDA, Mouse, Chronic Obstructive Lung Disease, Db-F, Laboratory Mouse, COLD, Glucosylceramidase activator, Cgbpde120218http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014437dbgap_ncbi~0patentfamilies~0intact~213rfam~0merops~0complex-portal~0uniprot~0wormbaseparasite~0embl-covid19~0reactome~0emdb~0wgs_masters~0ebiweb_resources~0opentargets_genetics~0biomodels_all~0ipd-mhc~0ebiweb_teams~0taxonomy~0genome_assembly~0sc-experiments~0ebiweb_people~0enzymeportal_enzymes~0ipd-nhkir~0cellosaurus~0pdbe~0chebi~0patentproteins~0interpro7~0uniref~0chembl~0pdbekb~0gpcrdb~0hgnc~0sc-genes~0rhea~0ebiweb_training~0alphafold~0imgt-hla~0patentnucleotides~0ensemblroot~0eva_studies~0non-coding~0europepmc~0pubmed~1identifiers_registry~0pdbechem~0hpa-covid19~0eva-variants-covid19~0biosamples~0gwas_catalog~0biotools~0tls_masters~0mesh~0coding~0sra~0opentargets~0efo~0embl-pathogen~0project~0pride~1human_diseases~0geo_datasets~0embl~0treefam~0uniparc~0ols~0dgva~0intenz~0go~0tsa_masters~0biosamples-covid19~0ebiweb_corporate~0omim~0lrg~0earlycause-molecular-sequences~0ipd-kir~0empiar~0rnacentral~0orcid_data_claims~0gpmdb~2lineage-covid19~0metagenomics~0pfam~0pride archive~1varsite~00Resource Reanalysis0.00.00.0037014188772362741.00.0falseAlterations in the interactome of serine/threonine protein phosphatase type-1 in atrial fibrillation patients.Data from ProteomeXchange, PXD ID: PXD000697. Exiperiment: PP1_Mouse_raw_IgG, file: OR8_121211_NL_DC_PP1_Gel4_B_labelfree2.mzml. Published as part of J Am Coll Cardiol. 2015 Jan 20;65(2):163-73 . From the Abstract: {{i}} Cardiac lysates were coimmunoprecipitated with anti-PP1c antibody followed by mass spectrometry-based, quantitative profiling of associated R-subunits. Subsequently, label-free quantification (LFQ) was used to evaluate altered R-subunit-PP1c interactions in PAF patients. R-subunits with altered binding to PP1c in PAF were further studied using bioinformatics, Western blotting (WB), immunocytochemistry, and coimmunoprecipitation. {{/i}}2015-04-03GPM3232001443725593058PXD000697PXD000697