Affinage

POPDC2

Popeye domain-containing protein 2 · UniProt Q9HBU9

Length
364 aa
Mass
40.4 kDa
Annotated
2026-04-28
30 papers in source corpus 6 papers cited in narrative 6 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

POPDC2 is a transmembrane, striated-muscle-enriched cAMP-effector protein essential for cardiac conduction system function. It is expressed from early cardiogenesis under sequential regulation by MEIS1 and NKX2-5 (PMID:26411676), with highest abundance in the atrioventricular node and bundle (PMID:40409267). POPDC2 upregulates TREK-1 two-pore domain potassium channel current density in a cAMP-dependent manner; loss-of-function variants abolish this modulation and cause sinus bradycardia, atrioventricular conduction block, and arrhythmia in zebrafish, mouse, and human (PMID:22290329, PMID:32535041, PMID:40409267). POPDC2 forms a complex with POPDC1, and pathogenic variants in either gene reduce abundance and membrane trafficking of both proteins, establishing bi-allelic POPDC2 loss-of-function as a cause of hereditary cardiac conduction disease (PMID:40409267).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2004 Medium

    Before any functional data existed, expression profiling established that Popdc2 encodes a transmembrane protein with striking restriction to myocardium and skeletal muscle during embryogenesis, framing it as a candidate striated-muscle regulator.

    Evidence Northern blot and whole-mount in situ hybridization in chick embryos

    PMID:14991725

    Open questions at the time
    • Expression data only; no functional manipulation or loss-of-function phenotype
    • Mammalian expression pattern not yet mapped from endogenous locus
  2. 2008 Medium

    A LacZ knock-in at the endogenous Popdc2 locus confirmed cardiac and somitic expression beginning at E7.5 and revealed postnatal expression in smooth muscle and visceral organs, extending the known expression domains to mammalian development.

    Evidence LacZ reporter knock-in mouse with whole-mount and section staining across embryonic and postnatal stages

    PMID:18189275

    Open questions at the time
    • Reporter knock-in disrupts one allele but heterozygous phenotype was not assessed
    • No functional consequence of loss tested
  3. 2012 High

    The first loss-of-function study showed that popdc2 is required for cardiac conduction and striated muscle development: morpholino knockdown in zebrafish produced AV block, arrhythmia, and skeletal muscle disorganization, establishing a direct role in cardiac rhythm.

    Evidence Morpholino knockdown in zebrafish with optical contractility mapping and calcium transient imaging (Tg(cmlc2:gCaMP))

    PMID:22290329

    Open questions at the time
    • Morpholino off-target effects not fully excluded; genetic mutant confirmation not yet available
    • Molecular mechanism (channel target, cAMP dependence) not identified
  4. 2015 High

    Transcriptional control of Popdc2 was resolved: MEIS1 and NKX2-5 bind its enhancer in a mutually exclusive manner, providing a competitive switch that times Popdc2 activation as cardiac progenitors differentiate.

    Evidence ChIP, enhancer reporter assays, and binding-site competition experiments in cardiac differentiation models

    PMID:26411676

    Open questions at the time
    • Upstream signals controlling the MEIS1-to-NKX2-5 transition are not defined
    • Whether this enhancer logic applies to POPDC1 or POPDC3 is unknown
  5. 2020 High

    The molecular mechanism was identified: POPDC2 upregulates TREK-1 potassium channel current in a cAMP-dependent manner, and a human disease-causing nonsense variant (W188*) that truncates the cAMP-binding domain abolishes this modulation and causes stress-induced sinus bradycardia in knock-in mice.

    Evidence Xenopus oocyte two-electrode voltage clamp co-expressing POPDC2 and TREK-1; W188* knock-in mouse with ECG telemetry

    PMID:32535041

    Open questions at the time
    • Direct cAMP-binding affinity of POPDC2 was not measured in this study
    • Whether POPDC2 interacts physically with TREK-1 or acts indirectly was not resolved
    • Contribution of other K2P channels not tested
  6. 2025 High

    Bi-allelic POPDC2 variants were confirmed as a cause of human cardiac conduction disease; pathogenic mutations abolish TREK-1 modulation and destabilize the POPDC1–POPDC2 complex, with both proteins reduced in patient muscle biopsies and co-expression enriched in AV node cells.

    Evidence Xenopus oocyte electrophysiology; protein quantification from patient muscle biopsy; homology modeling; single-cell RNA-seq of human hearts

    PMID:40409267

    Open questions at the time
    • Stoichiometry and structural basis of the POPDC1–POPDC2 complex remain undetermined
    • Whether POPDC2 loss affects channels other than TREK-1 in human conduction tissue is unknown
    • No rescue or gene-therapy experiments have been reported

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of cAMP binding and TREK-1 modulation by POPDC2, whether POPDC2 directly contacts TREK-1, and whether additional effectors beyond TREK-1 contribute to conduction phenotypes.
  • No crystal or cryo-EM structure of POPDC2 or the POPDC1–POPDC2 complex
  • Direct physical interaction between POPDC2 and TREK-1 not demonstrated
  • Role of POPDC2 in skeletal muscle disease beyond cardiac conduction not mechanistically defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 2
Pathway
GO:0005886 plasma membrane 1
Partners
POPDC1TREK-1
Complex memberships
POPDC1-POPDC2 complex

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 Morpholino oligonucleotide-mediated knockdown of popdc2 in zebrafish causes aberrant skeletal muscle development, cardiac morphogenesis defects (pericardial edema, abnormal looping), and cardiac arrhythmia with 2:1 or 3:1 atrial/ventricular conduction block, identifying popdc2 as required for striated muscle differentiation and cardiac conduction system development. Morpholino knockdown in zebrafish; optical recording of cardiac contractility; calcium transient imaging via transgenic calcium indicator (Tg(cmlc2:gCaMP)) and SPIM microscopy Developmental biology High 22290329
2015 MEIS1 and NKX2-5 bind overlapping sites on the Popdc2 gene enhancer in a mutually exclusive manner; as cardiac progenitors differentiate, sequential high MEIS1 then increasing NKX2-5 levels provide spatiotemporal transcriptional regulation of Popdc2 expression during cardiogenesis. ChIP, reporter assays, in vivo cardiac differentiation models; binding site competition assays Cell reports High 26411676
2020 A loss-of-function nonsense mutation in POPDC2 (W188*, deleting part of the cAMP-binding domain) impairs TREK-1 potassium channel modulation; co-expression of POPDC2W188* with TREK-1 in Xenopus oocytes fails to increase TREK-1 current density, and knock-in mice display stress-induced sinus bradycardia and pauses, establishing POPDC2 as a cAMP-dependent regulator of TREK-1 required for normal cardiac conduction. Xenopus oocyte electrophysiology (co-expression); knock-in mouse model; quantitative PCR for expression profiling Journal of molecular and cellular cardiology High 32535041
2025 Bi-allelic loss-of-function variants in POPDC2 abolish TREK-1 current upregulation in vitro; patient muscle biopsies show reduced abundance of both POPDC1 and POPDC2, indicating that pathogenic variants in either protein impair stability and/or membrane trafficking of the POPDC1-POPDC2 complex; single-cell RNA-seq shows co-expression of POPDC1 and POPDC2 is highest in AV node, AV node pacemaker, and AV bundle cells. In vitro electrophysiology (Xenopus oocyte co-expression); protein quantification from patient muscle biopsy; homology modeling; single-cell RNA sequencing of human hearts American journal of human genetics High 40409267
2004 Popdc2 is a transmembrane plasma membrane protein expressed predominantly in myocardium and skeletal muscle during chick embryogenesis, with distinct spatial patterns across cardiac chambers and muscle-forming fields, identifying it as a myocyte-specific differentiation marker. Northern blot; whole-mount in situ hybridization; cDNA cloning of alternatively spliced isoforms Developmental dynamics Medium 14991725
2008 LacZ reporter knock-in into the Popdc2 locus shows expression in cardiac and extraembryonic mesoderm from E7.5, then heart, somites, coelomic mesothelium, skeletal muscle, bladder, gut, and smooth muscle postnatally, establishing the in vivo expression pattern linked to the Popdc2 locus. LacZ reporter gene knock-in; embryonic and postnatal whole-mount and section staining Developmental dynamics Medium 18189275

Source papers

Stage 0 corpus · 30 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Pollen tube growth and guidance is regulated by POP2, an Arabidopsis gene that controls GABA levels. Cell 366 12859897
2005 Smaug recruits the CCR4/POP2/NOT deadenylase complex to trigger maternal transcript localization in the early Drosophila embryo. Current biology : CB 210 15723788
2010 The Arabidopsis pop2-1 mutant reveals the involvement of GABA transaminase in salt stress tolerance. BMC plant biology 179 20122158
2001 The yeast POP2 gene encodes a nuclease involved in mRNA deadenylation. Nucleic acids research 176 11410650
2010 Cell wall integrity is linked to mitochondria and phospholipid homeostasis in Candida albicans through the activity of the post-transcriptional regulator Ccr4-Pop2. Molecular microbiology 113 21299651
2003 X-ray structure and activity of the yeast Pop2 protein: a nuclease subunit of the mRNA deadenylase complex. EMBO reports 101 14618157
1998 Two F-box/WD-repeat proteins Pop1 and Pop2 form hetero- and homo-complexes together with cullin-1 in the fission yeast SCF (Skp1-Cullin-1-F-box) ubiquitin ligase. Genes to cells : devoted to molecular & cellular mechanisms 93 9990507
2008 Mutants of GABA transaminase (POP2) suppress the severe phenotype of succinic semialdehyde dehydrogenase (ssadh) mutants in Arabidopsis. PloS one 64 18846220
2012 The Popeye domain containing 2 (popdc2) gene in zebrafish is required for heart and skeletal muscle development. Developmental biology 59 22290329
2017 The PYRIN domain-only protein POP2 inhibits inflammasome priming and activation. Nature communications 54 28580931
2015 Sequential Binding of MEIS1 and NKX2-5 on the Popdc2 Gene: A Mechanism for Spatiotemporal Regulation of Enhancers during Cardiogenesis. Cell reports 47 26411676
2011 Uncoupling of Pyrin-only protein 2 (POP2)-mediated dual regulation of NF-κB and the inflammasome. The Journal of biological chemistry 32 21976665
2006 In vivo targeting of the yeast Pop2 deadenylase subunit to reporter transcripts induces their rapid degradation and generates new decay intermediates. The Journal of biological chemistry 30 16793769
2004 Popeye domain containing gene 2 (Popdc2) is a myocyte-specific differentiation marker during chick heart development. Developmental dynamics : an official publication of the American Association of Anatomists 27 14991725
2011 Recent evolution of the NF-κB and inflammasome regulating protein POP2 in primates. BMC evolutionary biology 22 21362197
2009 The Ccr4-Pop2-NOT mRNA deadenylase contributes to septin organization in Saccharomyces cerevisiae. Genetics 22 19487562
2008 Expression pattern of Popdc2 during mouse embryogenesis and in the adult. Developmental dynamics : an official publication of the American Association of Anatomists 21 18189275
2020 POPDC2 a novel susceptibility gene for conduction disorders. Journal of molecular and cellular cardiology 20 32535041
2016 Different Regulations of ROM2 and LRG1 Expression by Ccr4, Pop2, and Dhh1 in the Saccharomyces cerevisiae Cell Wall Integrity Pathway. mSphere 16 27704052
2004 Requirement of the SCFPop1/Pop2 Ubiquitin Ligase for Degradation of the Fission Yeast S Phase Cyclin Cig2. The Journal of biological chemistry 16 14970237
1995 The DNA sequence of a 7941 bp fragment of the left arm of chromosome VII of Saccharomyces cerevisiae contains four open reading frames including the multicopy suppressor gene of the pop2 mutation and a putative serine/threonine protein kinase gene. Yeast (Chichester, England) 11 7668046
2010 The yeast PUF protein Puf5 has Pop2-independent roles in response to DNA replication stress. PloS one 10 20498834
2008 Biophysical and biochemical characterization of recombinant human Pop2 deadenylase. Protein expression and purification 8 18430587
1999 Mouse CAF1, a mouse homologue of the yeast POP2 gene, complements the yeast pop2 null mutation. Yeast (Chichester, England) 8 10509017
2021 Pbp1 mediates the aberrant expression of genes involved in growth defect of ccr4∆ and pop2∆ mutants in yeast Saccharomyces cerevisiae. Genes to cells : devoted to molecular & cellular mechanisms 7 33764672
2019 Pop2 phosphorylation at S39 contributes to the glucose repression of stress response genes, HSP12 and HSP26. PloS one 7 30973945
2011 Comparative transcriptome analysis of yeast strains carrying slt2, rlm1, and pop2 deletions. Genome 3 21326366
2025 Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy. American journal of human genetics 1 40409267
2025 A Novel POPDC2 Pathogenic Variant in a Young Patient With Cardiac Conduction Disease and Hypertrophic Cardiomyopathy. Clinical genetics 0 41456958
2024 Biallelic variants in POPDC2 cause a novel autosomal recessive syndrome presenting with cardiac conduction defects and variable hypertrophic cardiomyopathy. medRxiv : the preprint server for health sciences 0 39006410