Affinage

PAN3

PAN2-PAN3 deadenylation complex subunit PAN3 · UniProt Q58A45

Length
887 aa
Mass
95.6 kDa
Annotated
2026-06-10
21 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PAN3 is an essential, non-catalytic subunit of the conserved eukaryotic PAN2-PAN3 deadenylase that drives the initial, length-sensitive phase of cytoplasmic poly(A) tail shortening (PMID:8816488, PMID:31104843). Although required for poly(A) nuclease activity in vivo, PAN3 itself is catalytically inert; it functions as an asymmetric homodimer built from an N-terminal pseudokinase and a C-terminal knob domain joined by a coiled coil, with the knob providing the binding surface for the PAN2 exonuclease (PMID:23932717). PAN3 supplies substrate and architecture to the complex: it binds poly(A) RNA directly through an N-terminal zinc finger and its pseudokinase domain, engages a PAN2 linker region with 2:1 (PAN3:PAN2) stoichiometry, and orients the PAN2 nuclease active site toward the poly(A) substrate (PMID:24880344, PMID:24872509). The reconstituted complex recognizes poly(A)-PABP oligomeric ribonucleoproteins, degrading tails decorated with two or more PABP/Pab1 protomers so that PABP oligomers act as molecular rulers for tail length (PMID:31104843), a substrate-binding path that has co-evolved with the longer poly(A) tails of mammalian mRNAs (PMID:41275497). Beyond bulk PABP-dependent deadenylation, PAN3 confers transcript specificity: a tryptophan-binding pocket at its pseudokinase dimer interface engages GW182/TNRC6 proteins to recruit the complex to miRNA targets (PMID:22402495, PMID:23932717), and additional RNA-binding adaptors such as MEX3, YTHDF, and ZFP36 direct it to specific transcripts [PMID:bio_10.1101_2025.09.27.678968]. PAN3 is also a regulatory node, mediating deadenylase recruitment under oxidative stress, where its proteolytic degradation stabilizes poly(A) tails (PMID:25446091), and two human isoforms exert opposing effects on PAN2 activity and global tail length (PMID:28559491).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1996 High

    Established that PAN3 is a required subunit of the poly(A) nuclease, answering whether deadenylase activity depends on more than the catalytic subunit.

    Evidence Genetic deletion, immunodepletion, Co-IP, two-hybrid, and in vivo poly(A) measurement in yeast

    PMID:8816488

    Open questions at the time
    • Did not define which PAN3 region contacts PAN2
    • No structural basis for how PAN3 enables catalysis
    • Catalytic versus non-catalytic role of PAN3 not resolved
  2. 2002 Medium

    Linked Pan2-Pan3 to a stress-response pathway, showing the deadenylase participates in post-transcriptional control of a DNA repair transcript.

    Evidence Yeast two-hybrid (Dun1 FHA-Pan3) plus genetic epistasis and gene-expression analysis under replication stress

    PMID:11953437

    Open questions at the time
    • Direct deadenylation of RAD5 mRNA not demonstrated biochemically
    • Whether Dun1 phosphorylates Pan3 unknown
    • Single lab
  3. 2012 Medium

    Showed GW182-family recruitment of PAN2-PAN3 in miRNA silencing is evolutionarily conserved, generalizing the targeting mechanism beyond a single species.

    Evidence Co-IP and directed interaction assays of C. elegans AIN-1 with PAN3 in worm/fly contexts

    PMID:22402495

    Open questions at the time
    • Co-IP without structural mapping of the interface
    • Functional consequence for specific miRNA targets not quantified
  4. 2013 High

    Defined PAN3 domain architecture and the molecular basis of miRNA-target recruitment, explaining how a pseudokinase scaffold engages GW182.

    Evidence X-ray crystallography with mutagenesis and in vivo deadenylation and TNRC6C interaction assays

    PMID:23932717

    Open questions at the time
    • Why ATP binding is needed for deadenylation not mechanistically resolved
    • Did not capture the PAN2-bound complex
  5. 2014 High

    Resolved the assembled PAN2-PAN3 core and how PAN3 asymmetry imposes 2:1 stoichiometry, orients the nuclease, and supplies poly(A) substrate via its zinc finger.

    Evidence Crystal structures of the Pan2-Pan3 core and Pan2 linker-Pan3 complex with RNA-binding biochemistry and in vitro deadenylation

    PMID:24872509 PMID:24880344

    Open questions at the time
    • Did not show how the complex reads poly(A) tail length
    • Role of PABP in substrate engagement not yet structural
  6. 2014 Medium

    Identified PAN3 as a stress-responsive regulatory node whose degradation stabilizes poly(A) tails, connecting deadenylase recruitment to oxidative stress.

    Evidence Arsenite treatment, siRNA knockdown, and poly(A) tail length and protein-degradation assays

    PMID:25446091

    Open questions at the time
    • Protease responsible for PAN3 degradation not identified
    • Single lab
  7. 2017 Medium

    Showed two human PAN3 isoforms exert opposing control over PAN2 activity and global tail length, revealing isoform-level tuning of the first deadenylation phase.

    Evidence Isoform-specific knockdown, transcriptome-wide poly(A) and stability profiling, PABP-interaction and P-body imaging

    PMID:28559491

    Open questions at the time
    • Structural basis for opposing isoform activities unknown
    • How isoform ratio is set physiologically unclear
  8. 2019 High

    Provided the structural mechanism for length-sensitive deadenylation, showing PABP/Pab1 oligomers serve as rulers recognized by the complex.

    Evidence Cryo-EM of Pan2-Pan3 bound to a poly(A)-Pab1 RNP with in vitro reconstitution and activity assays

    PMID:31104843

    Open questions at the time
    • How the complex transitions from initial to processive trimming not fully defined
    • Cross-talk with Ccr4-Not at the same substrate unresolved
  9. 2021 Low

    Suggested metabolic regulation of the deadenylase, detecting Pan2/Pan3 phosphorylation upon carbon-source shift and cooperation with Ccr4-Not.

    Evidence Genetic deletion, growth assays on non-fermentable media, suppressor screen, and phosphorylation detection in yeast

    PMID:34280615

    Open questions at the time
    • Kinase/phosphatase acting on Pan3 not identified
    • Functional consequence of phosphorylation not demonstrated
    • Single lab, single method for phospho-claim
  10. 2025 High

    Demonstrated co-evolution of human deadenylase substrate-binding architecture with longer mammalian poly(A) tails.

    Evidence Cryo-EM of human PAN2-PAN3 with poly(A)-PABPC1 RNPs and comparative in vitro deadenylation on long substrates

    PMID:41275497

    Open questions at the time
    • In-cell relevance of the longer substrate path not tested
    • Regulation of human-specific features unknown
  11. 2025 Medium

    Expanded targeting logic beyond PABP, showing diverse RBP adaptors recruit PAN2-PAN3 for transcript-specific decay.

    Evidence Biochemical reconstitution with MEX3/YTHDF/ZFP36 and cell-based interaction assays (preprint)

    PMID:bio_10.1101_2025.09.27.678968

    Open questions at the time
    • Preprint, not yet peer-reviewed
    • Which PAN3 surfaces engage each adaptor not mapped
    • Transcript-level decay consequences not fully quantified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PAN3 phosphorylation, isoform balance, and competing adaptor inputs are integrated to control deadenylase activity and target selection in vivo remains open.
  • No identified PAN3 kinase/phosphatase
  • Mechanism coordinating PABP-dependent versus adaptor-dependent recruitment unknown
  • In-cell dynamics of isoform-specific regulation undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 2 GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 1 GO:0140657 ATP-dependent activity 1
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-8953854 Metabolism of RNA 2
Partners
AIN-1DUN1MEX3PABPC1PAN2TNRC6CYTHDFZFP36
Complex memberships
PAN2-PAN3 deadenylase

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 Pan3p (76-kDa subunit) is required for PAN (poly(A) nuclease) enzymatic activity in yeast; deletion of PAN3 abolishes PAN activity in cell extracts, immunodepletion of Pan3p from purified PAN fractions eliminates activity, and Pan2p and Pan3p physically interact by coimmunoprecipitation and two-hybrid assay. Both subunits are required for in vivo poly(A) tail shortening. Genetic deletion, enzymatic activity assay in yeast extracts, immunodepletion, coimmunoprecipitation, two-hybrid assay, in vivo poly(A) tail length analysis Molecular and cellular biology High 8816488
2002 The Dun1 kinase forkhead-associated domain interacts with the Pan3 subunit of the poly(A)-nuclease complex; dun1/pan2 and dun1/pan3 double mutants are hypersensitive to replication stress, and Dun1 and Pan2-Pan3 cooperate to regulate posttranscriptional control of the RAD5 DNA repair gene, which is specifically up-regulated in dun1/pan2 double mutants. Yeast two-hybrid (Dun1 FHA domain–Pan3 interaction), genetic double-mutant phenotypic analysis, replication stress sensitivity assay, gene expression analysis The Journal of biological chemistry Medium 11953437
2012 C. elegans AIN-1 (GW182 homolog) interacts with PAN3 (as well as PAB-1 and NOT1/NOT2), demonstrating that GW182-family recruitment of the PAN2-PAN3 deadenylase complex is evolutionarily conserved in C. elegans miRNA-mediated silencing. Coimmunoprecipitation, directed protein interaction assays in C. elegans and Drosophila cell contexts Nucleic acids research Medium 22402495
2013 Crystal structure of PAN3 reveals it forms asymmetric homodimers via a coiled coil linking an N-terminal pseudokinase to a C-terminal knob domain. The knob domain contains the binding surface for PAN2. A tryptophan-binding pocket at the dimer interface mediates binding to TNRC6C (GW182), enabling PAN2-PAN3 recruitment to miRNA targets. PAN3 pseudokinase binds ATP, and this ATP-binding function is required for mRNA deadenylation in vivo. X-ray crystallography, in vivo deadenylation assay, mutagenesis of binding surfaces, cell-based interaction assays with TNRC6C Molecular cell High 23932717
2014 Crystal structure of the Pan2-Pan3 core complex (~200 kDa) shows a 1:2 (Pan2:Pan3) stoichiometry imposed by the asymmetric Pan3 homodimer. An extended region of Pan2 wraps around Pan3 as the major anchoring point. A Pan2 module formed by the pseudo-ubiquitin-hydrolase and RNase domains latches onto the Pan3 pseudokinase, orienting the deadenylase active site toward the A-binding site of Pan3. Recombinant yeast Pan2-Pan3 can deadenylate RNA in vitro without Pab1. X-ray crystallography of recombinant complex, in vitro deadenylation assay Nature structural & molecular biology High 24880344
2014 Pan3 directly binds poly(A) RNA through two regions: an N-terminal zinc finger that binds poly(A) specifically, and its pseudokinase/C-terminal domain. Isolated Pan2 cannot bind RNA. Pan3 binds the linker region of Pan2 connecting its WD40 domain to the exonuclease domain with 2:1 (Pan3:Pan2) stoichiometry. Crystal structure of the Pan2 linker–Pan3 homodimer complex shows how Pan3 asymmetry creates a high-affinity interaction, enabling Pan3 to supply Pan2 with poly(A) substrate. RNA-binding assays, crystal structure of Pan2 linker–Pan3 complex, stoichiometry determination, in vitro deadenylation assays The EMBO journal High 24872509
2014 Arsenite-induced oxidative stress inhibits mRNA deadenylation through proteolytic degradation of Pan3 (and Tob). siRNA knockdown of Pan3 alone recapitulates global poly(A) tail stabilization seen during arsenite stress, establishing Pan3 as an essential mediator of deadenylase recruitment under stress conditions. Arsenite treatment, siRNA knockdown, poly(A) tail length analysis, protein degradation assays Biochemical and biophysical research communications Medium 25446091
2017 Two human PAN3 isoforms (Pan3S and Pan3L) have opposing activities: Pan3S interacts more strongly with PABP and enhances Pan2 deadenylase activity, while Pan3L suppresses Pan2 activity. Knockdown of individual isoforms has opposing effects on global poly(A) tail length, P-body formation, and mRNA decay pathways, revealing that the two isoforms coordinate the first phase of biphasic deadenylation. Isoform-specific knockdown, global poly(A) tail profiling, transcriptome-wide mRNA stability analysis, PABP interaction assays, P-body imaging RNA (New York, N.Y.) Medium 28559491
2019 Cryo-EM structure of Pan2-Pan3 in complex with a poly(A) RNP (90 adenosines + three Pab1 protomers) shows that Pan2-Pan3 recognizes the oligomerization interfaces of Pab1 via conserved features of the deadenylase and threads the poly(A) RNA substrate into the nuclease active site. Pan2-Pan3 associates with and degrades poly(A) RNPs containing two or more Pab1 molecules. This reveals how Pab1 oligomers act as rulers for poly(A) tail length. Cryo-EM structure determination, in vitro reconstitution with recombinant proteins, deadenylation activity assays Cell High 31104843
2021 Pan2 and Pan3 are phosphorylated when yeast are switched to non-fermentable carbon sources (glycerol-lactate), suggesting their activities are regulated by phosphorylation in response to carbon source changes. The Pan2-Pan3 complex cooperates with Ccr4-Not for growth on non-fermentable carbon sources. Genetic deletion analysis, growth assays on non-fermentable carbon media, multicopy suppressor screen, phosphorylation detection Biochemical and biophysical research communications Low 34280615
2025 Cryo-EM structures of human PAN2-PAN3 bound to poly(A)-PABPC1 ribonucleoproteins reveal a longer substrate-binding path in the human deadenylase compared to the fungal ortholog, providing structural basis for the co-evolution of deadenylase properties with the longer poly(A) tails characteristic of mammalian mRNAs. Human PAN2-PAN3 shows greater deadenylation activity on long poly(A)-PABPC1 substrates in vitro. Cryo-EM structure determination, in vitro deadenylation assays with poly(A) RNAs up to 240 nt, comparative structural analysis Cell reports High 41275497
2025 PAN2-PAN3 can be recruited to specific mRNAs via RNA-binding protein (RBP) adaptors, including MEX3, YTHDF, and ZFP36 proteins, as demonstrated by biochemical reconstitution. In cells, a diverse range of RNA adaptors interact with both PAN2-PAN3 and CCR4-NOT, indicating PAN2-PAN3 contributes to transcript-specific mRNA degradation beyond general PABP-dependent recruitment. Biochemical reconstitution, affinity pulldown/interaction assays in cells bioRxiv (preprint)preprint Medium bio_10.1101_2025.09.27.678968

Source papers

Stage 0 corpus · 21 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 RNA decay machines: deadenylation by the Ccr4-not and Pan2-Pan3 complexes. Biochimica et biophysica acta 197 23337855
1996 PAN3 encodes a subunit of the Pab1p-dependent poly(A) nuclease in Saccharomyces cerevisiae. Molecular and cellular biology 133 8816488
2013 Structure of the PAN3 pseudokinase reveals the basis for interactions with the PAN2 deadenylase and the GW182 proteins. Molecular cell 84 23932717
2019 Molecular Basis for poly(A) RNP Architecture and Recognition by the Pan2-Pan3 Deadenylase. Cell 82 31104843
2014 Structural basis for Pan3 binding to Pan2 and its function in mRNA recruitment and deadenylation. The EMBO journal 55 24872509
2020 MicroRNA-31-5p attenuates doxorubicin-induced cardiotoxicity via quaking and circular RNA Pan3. Journal of molecular and cellular cardiology 50 32135167
2014 mRNA deadenylation by Pan2-Pan3. Biochemical Society transactions 49 24450649
2014 The structure of the Pan2-Pan3 core complex reveals cross-talk between deadenylase and pseudokinase. Nature structural & molecular biology 46 24880344
2012 The Caenorhabditis elegans GW182 protein AIN-1 interacts with PAB-1 and subunits of the PAN2-PAN3 and CCR4-NOT deadenylase complexes. Nucleic acids research 44 22402495
2002 Posttranscriptional regulation of the RAD5 DNA repair gene by the Dun1 kinase and the Pan2-Pan3 poly(A)-nuclease complex contributes to survival of replication blocks. The Journal of biological chemistry 33 11953437
2023 Sevoflurane exerts protection against myocardial ischemia-reperfusion injury and pyroptosis through the circular RNA PAN3/microRNA-29b-3p/stromal cell-derived factor 4 axis. International immunopharmacology 23 37270931
2017 Antagonistic actions of two human Pan3 isoforms on global mRNA turnover. RNA (New York, N.Y.) 13 28559491
2018 PAN3-PSMA2 fusion resulting from a novel t(7;13)(p14;q12) chromosome translocation in a myelodysplastic syndrome that evolved into acute myeloid leukemia. Experimental hematology & oncology 11 29560286
2014 Arsenite inhibits mRNA deadenylation through proteolytic degradation of Tob and Pan3. Biochemical and biophysical research communications 11 25446091
2025 Circ-PAN3 facilitates hepatocellular carcinoma growth via sponging miR-153 and upregulating cyclin D1. Oncology research 2 39866238
2021 Pan2-Pan3 complex, together with Ccr4-Not complex, has a role in the cell growth on non-fermentable carbon sources. Biochemical and biophysical research communications 2 34280615
2025 lncRNA PAN3-AS1 Modulates Cilium Assemble Signaling Pathway Through Regulation of RPGR as a Potential MS Diagnostic Biomarker: Integrated Systems Biology Investigation. Journal of molecular neuroscience : MN 1 40227518
2026 Pan2-Pan3 Complex-Mediated Deadenylation Enforces mRNA Quality Control for Infection of the Rice Blast Fungus. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 0 41556236
2025 Mechanisms governing poly(A)-tail-length specificity of the human PAN2-PAN3 deadenylase complex. Cell reports 0 41275497
2025 Cryo-EM structure of cyanopodophage Pan3 reveals a modular tail architecture for host recognition. Structure (London, England : 1993) 0 41380677
2025 Pan-Cancer Analysis of Enhancer-Induced PAN3-AS1 and Experimental Validation as a WFDC13-Promoting Factor in Colon Cancer. Oncology research 0 41502505

Missed literature

Know a paper Affinage missed for PAN3? Flag it for the maintainers and the community.

No submissions yet.