Affinage

TXNL4A

Thioredoxin-like protein 4A · UniProt P83876

Length
142 aa
Mass
16.8 kDa
Annotated
2026-06-10
33 papers in source corpus 15 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TXNL4A (Dim1/Dib1/U5-15kD) is an essential, evolutionarily conserved thioredoxin-fold protein that functions as a core regulator of pre-mRNA splicing within the U5 snRNP and U4/U6·U5 tri-snRNP, where it acts as a checkpoint preventing premature spliceosome activation (PMID:25434003, PMID:29715471). As a temperature-sensitive Dib1 mutant stalls in vitro splicing before the first catalytic step and blocks assembly at the B complex, while exchanging dynamically in splicing extracts, TXNL4A gates the B-to-Bact transition rather than serving as a static structural subunit (PMID:29715471); its depletion reduces U4/U6·U5 tri-snRNP assembly (PMID:25434003). Structurally, the protein adopts a thioredoxin fold defining a distinct branch of that superfamily, and removal of its C-terminal extension yields a dominant-negative form that arrests cells in G2 (PMID:11015569). TXNL4A engages the spliceosome-associated factor PQBP-1 through a defined 23-residue segment of PQBP-1's C-terminal domain (PMID:10873650, PMID:20307692), and because TXNL4A lacks a classical nuclear localization signal, it is imported into the nucleus by a piggyback mechanism on PQBP-1 via karyopherin β2; disease mutations in PQBP-1 disrupt this interaction and mislocalize TXNL4A (PMID:32041777). PQBP-1's affinity for TXNL4A is allosterically reduced when PQBP-1 binds WBP11 through its WW domain, coupling TXNL4A's handling to other spliceosomal interactions (PMID:27314904). Biallelic loss-of-function mutations in TXNL4A—typically a promoter deletion reducing expression combined with a coding variant—cause Burn-McKeown syndrome by impairing splicing, with cranial neural crest cell formation as the critical developmental target (PMID:25434003, PMID:35893124). Beyond splicing, TXNL4A directly associates with c-Fos to block its binding to the NFATc1 promoter, repressing NFATc1 transcription and osteoclastogenesis (PMID:25023277), and across species its orthologs are required for mitotic entry, chromosome segregation, and APC/C function (PMID:9182666, PMID:10082519).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1999 High

    Established that the Dim1 protein is essential and functionally conserved for cell cycle progression, answering whether a thioredoxin-like protein has a defined in vivo cellular requirement.

    Evidence Fission yeast genetic deletion and temperature-sensitive mutants with heterologous mouse complementation and histone H1 kinase assays

    PMID:9182666

    Open questions at the time
    • Did not define the molecular activity producing G2 arrest
    • Link to splicing not yet identified
  2. 1999 High

    Connected dim1 function to APC/C-mediated ubiquitination, framing a possible mechanism for its mitotic phenotype.

    Evidence Synthetic-lethal screen, reciprocal Co-IP, sucrose gradient sedimentation and ubiquitination assays in S. pombe

    PMID:10082519

    Open questions at the time
    • Whether the APC/C link is direct or downstream of a splicing defect was not resolved
    • No biochemical demonstration that Dim1 acts on APC/C components enzymatically
  3. 1999 Low

    Showed the protein is amenable to crystallographic study, a prerequisite for structural mechanism.

    Evidence Recombinant expression, purification and preliminary X-ray diffraction

    PMID:10089325

    Open questions at the time
    • Preliminary crystallography only — no structure solved
    • No functional inference possible
  4. 2000 High

    Defined the thioredoxin fold and showed that a C-terminally truncated form is dominant-negative, linking structure to the cell cycle phenotype.

    Evidence NMR structural analysis, molecular modeling, alanine scanning, and overexpression cell-cycle assays

    PMID:11015569

    Open questions at the time
    • Redox or catalytic role of the thioredoxin fold not demonstrated
    • Mechanism by which the dominant-negative fragment arrests cells unresolved
  5. 2000 High

    Reoriented the protein toward splicing by identifying exclusively splicing-related interaction partners, including PQBP-1 and hnRNP F.

    Evidence Yeast two-hybrid and reiterative screening, alanine scanning with structural interface mapping, mammalian co-expression and C. elegans RNAi

    PMID:10873650 PMID:11054566

    Open questions at the time
    • Did not establish where in the splicing cycle TXNL4A acts
    • Functional consequence of each interaction not dissected
  6. 2010 Medium

    Mapped the precise PQBP-1 segment binding TXNL4A and linked its disruption to X-linked mental retardation, giving the interaction disease relevance.

    Evidence Recombinant binding assays, NMR, and deletion/mutation mapping of PQBP-1 frameshift variants

    PMID:20307692

    Open questions at the time
    • Functional readout of binding loss in cells not measured here
    • Did not address nuclear import role
  7. 2014 High

    Identified TXNL4A loss-of-function as the cause of Burn-McKeown syndrome and tied reduced expression to impaired tri-snRNP assembly, unifying genetics with splicing mechanism.

    Evidence Patient genetics, promoter reporter and in vivo expression assays, and yeast Dib1 depletion with tri-snRNP assembly analysis

    PMID:25434003

    Open questions at the time
    • Tissue specificity of the splicing defect not explained
    • Which transcripts are misspliced in patients not defined
  8. 2014 Medium

    Revealed a splicing-independent transcriptional role in which TXNL4A represses NFATc1 and osteoclastogenesis by sequestering c-Fos.

    Evidence RNAi knockdown, overexpression, ChIP, Co-IP, and osteoclast differentiation assays

    PMID:25023277

    Open questions at the time
    • Single lab; reciprocal validation of the c-Fos interaction limited
    • Relationship between nuclear splicing pool and c-Fos-bound pool unclear
  9. 2016 Medium

    Demonstrated that PQBP-1's two spliceosomal interactions are allosterically coupled, refining how TXNL4A handling is regulated.

    Evidence In vitro binding assays, NMR titration, and isothermal titration calorimetry

    PMID:27314904

    Open questions at the time
    • Physiological consequence of the allosteric coupling in cells not shown
    • Single lab in vitro system
  10. 2017 High

    Uncovered a role for the Dim1 ortholog in ribosome biogenesis, showing its release from pre-40S by the ATPase Fap7 is a translation-fidelity quality-control step.

    Evidence Genetic epistasis, biochemical ribosome assembly assays, ATPase measurements, and in vivo translation fidelity assays in yeast

    PMID:28890337

    Open questions at the time
    • Whether human TXNL4A participates in ribosome biogenesis not tested
    • Note: this ortholog activity may reflect a paralog (Dim1/DIMT1) rather than TXNL4A itself
  11. 2018 High

    Defined the precise step of action: Dib1 prevents premature spliceosome activation at the B-to-Bact transition and associates dynamically rather than statically.

    Evidence In vitro splicing with temperature-sensitive mutants, assembly assays, protein exchange experiments, and circular dichroism

    PMID:29715471

    Open questions at the time
    • Molecular trigger for Dib1 release not identified
    • Whether the thioredoxin fold has catalytic involvement in the checkpoint unresolved
  12. 2020 High

    Explained how TXNL4A reaches the nucleus, showing a piggyback import mechanism on PQBP-1 via karyopherin β2 disrupted by disease mutations.

    Evidence Recombinant binding assays, immunofluorescence in HeLa cells, and analysis of PQBP-1 P244L and other variants

    PMID:32041777

    Open questions at the time
    • Whether alternative import routes exist not addressed
    • Quantitative contribution of import defect to disease phenotypes not measured
  13. 2022 Medium

    Connected TXNL4A loss to the developmental target of Burn-McKeown syndrome by demonstrating a requirement in cranial neural crest formation.

    Evidence Morpholino knockdown in Xenopus embryos with neural crest marker and craniofacial cartilage analysis

    PMID:35893124

    Open questions at the time
    • Specific misspliced transcripts driving the neural crest defect not identified
    • Single model organism

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown whether the thioredoxin fold of TXNL4A carries an enzymatic activity relevant to its splicing checkpoint role, and what molecular signal triggers its release at the B-to-Bact transition.
  • No active-site mutagenesis tying putative catalytic residues to splicing
  • Reported peptidase/autocleavage activity remains a single unconfirmed observation
  • Trigger for Dib1 release during activation undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 1
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-8953854 Metabolism of RNA 2 R-HSA-1266738 Developmental Biology 1
Partners
C-FOSHNRNP FPQBP-1WBP11
Complex memberships
U4/U6·U5 tri-snRNPU5 snRNP

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 Fission yeast dim1p is required for entry into mitosis and chromosome segregation; deletion causes lethal G2 arrest, and this lethality is rescued by overexpression of the mouse dim1 homolog (mdim1), demonstrating functional conservation. dim1-35 temperature-sensitive cells arrest with low histone H1 kinase activity and show sensitivity to the microtubule-destabilizing drug thiabendazole. Genetic deletion, temperature-sensitive mutant analysis, heterologous complementation, histone H1 kinase assay, drug sensitivity assay The Journal of cell biology High 9182666
1999 S. pombe dim1p maintains the steady-state level of the APC/C component lid1p. In dim1 mutants, lid1p abundance and the 20S APC/C complex decline significantly, and ubiquitination of the APC/C target cut2p is abolished. Genetic synthetic-lethal interaction places dim1 upstream of APC/C function. Synthetic lethal screen, co-immunoprecipitation, sucrose gradient sedimentation, ubiquitination assay, epitope tagging Molecular and cellular biology High 10082519
1999 Human Dim1 (hDim1/U5-15kD/TXNL4A) adopts a thioredoxin fold structure as determined by NMR and molecular modeling. The ~125 of 142 amino acids define a novel sixth branch of the thioredoxin superfamily. Removal of the C-terminal extension (residues 129–142) generates a dominant-negative form that induces G2 cell cycle arrest when overproduced, via altered interactions with partner molecules. NMR structural analysis, molecular modeling, alanine scanning mutagenesis, cell cycle analysis by overexpression Physiological genomics High 11015569
2000 Human U5-15kD (TXNL4A) interacts with PQBP-1 (polyglutamine tract-binding protein-1) through PQBP-1's C-terminal domain (CTD), placing TXNL4A in a complex with a protein implicated in splicing and the polyglutamine disease pathway. Two-hybrid screen, co-immunoprecipitation, domain-deletion mapping Biochemical and biophysical research communications Medium 10873650
2000 Dim1 (hDim1/TXNL4A) interacts with pre-mRNA splicing factors hnRNP F and Npw38/PQBP-1. Two-hybrid reiterative screening identified exclusively splicing-related partners. Saturating alanine scanning mutagenesis of Dim1 mapped residues essential for these interactions to a defined surface sector on the thioredoxin fold. Co-expression of one partner induced synthetic growth arrest in mammalian cells. Yeast two-hybrid screening, alanine scanning mutagenesis, structural mapping, mammalian co-expression phenotypic assay, C. elegans RNAi (embryonic lethality upon DML-1 depletion) Gene High 11054566
1999 Human U5-15kD (TXNL4A) was overexpressed in E. coli, purified, and crystallized in space group P21212, diffracting to at least 3.0 Å, establishing the protein is amenable to crystallographic structure determination. Recombinant protein expression, purification, X-ray crystallography (preliminary diffraction) Acta crystallographica. Section D, Biological crystallography Low 10089325
2010 PQBP-1 binds to U5-15kD (TXNL4A) via a continuous 23-residue segment within PQBP-1's C-terminal domain. Frameshift mutations in PQBP-1 associated with X-linked mental retardation truncate this segment and abolish binding to U5-15kD. Recombinant protein binding assays, NMR, deletion/mutation mapping Biochimica et biophysica acta Medium 20307692
2014 Biallelic mutations in TXNL4A cause Burn-McKeown syndrome (BMKS). Promoter deletions reduce TXNL4A expression (shown by reporter gene and in vivo assays). Depletion of TXNL4A (Dib1) in yeast reduces assembly of the U4/U6·U5 tri-snRNP complex. Patient genetics, reporter gene assays, in vivo expression assays, yeast Dib1 depletion with tri-snRNP assembly analysis American journal of human genetics High 25434003
2014 Dim1 (TXNL4A) negatively regulates osteoclastogenesis by directly associating with c-Fos and preventing c-Fos from binding to the NFATc1 promoter, thereby repressing NFATc1 transcription. RNAi knockdown of Dim1 enhanced NFATc1 expression and osteoclast differentiation; ectopic Dim1 overexpression suppressed it. RNAi knockdown, ectopic overexpression, ChIP assay, co-immunoprecipitation, osteoclast differentiation assay (TRAP staining, bone resorption) The Journal of biological chemistry Medium 25023277
2016 Binding of PQBP-1 to WBP11 (via PQBP-1's WW domain) allosterically reduces the binding affinity of PQBP-1 for U5-15kD (TXNL4A), demonstrating that PQBP-1's interactions with two spliceosomal partners are allosterically coupled. In vitro binding assays, NMR titration, isothermal titration calorimetry FEBS letters Medium 27314904
2018 Yeast Dib1 (TXNL4A ortholog) functions to prevent premature spliceosome activation at the B-to-Bact transition. Temperature-sensitive dib1 mutants stall in vitro splicing prior to the first catalytic step and block assembly at the B complex. Dib1 exchanges readily in splicing extracts despite being a U5 snRNP component, indicating dynamic rather than static association. In vitro splicing assay with temperature-sensitive mutants, spliceosome assembly assay, protein exchange experiments in splicing extracts, circular dichroism Journal of molecular biology High 29715471
2020 TXNL4A lacks a classical nuclear localization signal and relies on PQBP-1 for nuclear import via a piggyback mechanism through the karyopherin β2 receptor. The PQBP-1 P244L missense mutation (X-linked intellectual disability) disrupts the PQBP-1–TXNL4A interaction and mislocalizes TXNL4A. Recombinant protein expression, in vitro binding assays, immunofluorescence microscopy in HeLa cells, PQBP-1 mutant analysis The Journal of biological chemistry High 32041777
2022 Knockdown of Txnl4a in Xenopus embryos causes defects in cranial neural crest cell formation, establishing a direct role for TXNL4A in neural crest development underlying mandibulofacial dysostosis (Burn-McKeown syndrome). This parallels phenotypes from EFTUD2 and SNRPB knockdowns, pointing to a common spliceosomopathy mechanism. Morpholino-mediated knockdown in Xenopus embryos, neural crest marker analysis, craniofacial cartilage staining Journal of developmental biology Medium 35893124
2006 Human Dim1 (TXNL4A) has peptidase activity with autocleavage, generating a thioredoxin-like core fragment. This truncated form retains peptidase activity. The autocleavage product corresponds to the dominant-negative fragment previously shown to cause G2 arrest. In vitro biochemical peptidase assay, autocleavage detection by SDS-PAGE/mass spectrometry Chemical biology & drug design Low 17177886
2017 The ATPase Fap7 promotes formation of the rotated state of pre-40S ribosomes and releases Dim1 (TXNL4A ortholog) from nascent 40S subunits during ribosome maturation. This quality-control step links ribosome assembly to translocation competence; bypassing it causes reading-frame maintenance defects. Genetic epistasis, biochemical ribosome assembly assays, ATPase activity measurements, in vivo translation fidelity assay Molecular cell High 28890337

Source papers

Stage 0 corpus · 33 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 The DIM1 gene responsible for the conserved m6(2)Am6(2)A dimethylation in the 3'-terminal loop of 18 S rRNA is essential in yeast. Journal of molecular biology 144 8064863
2000 PQBP-1/Npw38, a nuclear protein binding to the polyglutamine tract, interacts with U5-15kD/dim1p via the carboxyl-terminal domain. Biochemical and biophysical research communications 75 10873650
2000 Evidence that dim1 associates with proteins involved in pre-mRNA splicing, and delineation of residues essential for dim1 interactions with hnRNP F and Npw38/PQBP-1. Gene 68 11054566
2010 Characterization of DIM-1, an integron-encoded metallo-beta-lactamase from a Pseudomonas stutzeri clinical isolate in the Netherlands. Antimicrobial agents and chemotherapy 65 20308383
2014 Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in TXNL4A causes Burn-McKeown syndrome. American journal of human genetics 62 25434003
1999 The schizosaccharomyces pombe dim1(+) gene interacts with the anaphase-promoting complex or cyclosome (APC/C) component lid1(+) and is required for APC/C function. Molecular and cellular biology 43 10082519
2017 The ATPase Fap7 Tests the Ability to Carry Out Translocation-like Conformational Changes and Releases Dim1 during 40S Ribosome Maturation. Molecular cell 39 28890337
1997 Fission yeast dim1(+) encodes a functionally conserved polypeptide essential for mitosis. The Journal of cell biology 39 9182666
2003 DIM-1, a novel immunoglobulin superfamily protein in Caenorhabditis elegans, is necessary for maintaining bodywall muscle integrity. Genetics 38 12663531
1999 The evolutionarily conserved Dim1 protein defines a novel branch of the thioredoxin fold superfamily. Physiological genomics 28 11015569
2013 Vaccination of goats with DNA vaccine encoding Dim-1 induced partial protection against Haemonchus contortus: a preliminary experimental study. Research in veterinary science 23 23545480
2022 The Core Splicing Factors EFTUD2, SNRPB and TXNL4A Are Essential for Neural Crest and Craniofacial Development. Journal of developmental biology 22 35893124
2004 DLP, a novel Dim1 family protein implicated in pre-mRNA splicing and cell cycle progression. The Journal of biological chemistry 20 15161931
2021 Insights into synthesis and function of KsgA/Dim1-dependent rRNA modifications in archaea. Nucleic acids research 18 33434266
2014 Defective entry into mitosis 1 (Dim1) negatively regulates osteoclastogenesis by inhibiting the expression of nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1). The Journal of biological chemistry 17 25023277
2010 Polyglutamine tract-binding protein-1 binds to U5-15kD via a continuous 23-residue segment of the C-terminal domain. Biochimica et biophysica acta 17 20307692
2008 Sequence and structural evolution of the KsgA/Dim1 methyltransferase family. BMC research notes 15 18959795
1998 Mutations in the dim-1 gene of Neurospora crassa reduce the level of DNA methylation. Molecular & general genetics : MGG 14 9738881
2014 Disorganized muscle protein-1 (DIM-1) of filarial parasite Brugia malayi: cDNA cloning, expression, purification, structural modeling and its potential as vaccine candidate for human filarial infection. Vaccine 13 24513011
2018 Functional and Biochemical Characterization of Dib1's Role in Pre-Messenger RNA Splicing. Journal of molecular biology 11 29715471
2013 Retrospective molecular analysis of DIM-1 metallo-β-lactamase discovered in Pseudomonas stutzeri from India in 2000. Antimicrobial agents and chemotherapy 11 24145536
2005 Biochemical characterization and crystal structure of a Dim1 family associated protein: Dim2. Biochemistry 11 16142897
2020 The Renpenning syndrome-associated protein PQBP1 facilitates the nuclear import of splicing factor TXNL4A through the karyopherin β2 receptor. The Journal of biological chemistry 10 32041777
2016 Allosteric modulation of the binding affinity between PQBP1 and the spliceosomal protein U5-15kD. FEBS letters 9 27314904
2021 Expanding the genotypic spectrum of TXNL4A variants in Burn-McKeown syndrome. Clinical genetics 8 34713892
1999 Overproduction, purification, crystallization and preliminary x-ray diffraction studies of the human spliceosomal protein U5-15kD. Acta crystallographica. Section D, Biological crystallography 7 10089325
2006 Identification of human dim1 as a peptidase with autocleavage activity. Chemical biology & drug design 5 17177886
2016 Gene silencing of Dim-1, a member of the disorganized muscle family, in Haemonchus contortus. Molecular and biochemical parasitology 4 27984072
2015 Crystal Structure of DIM-1, an Acquired Subclass B1 Metallo-β-Lactamase from Pseudomonas stutzeri. PloS one 4 26451836
2023 Combined bulk RNA and single-cell RNA analyses reveal TXNL4A as a new biomarker for hepatocellular carcinoma. Frontiers in oncology 3 37305572
2013 Cloning and characterization of a Dim1-like mitosis gene of Spodoptera frugiperda cells (Sf9) induced by Autographa californica multiple nucleopolyhedrovirus. Journal of invertebrate pathology 2 23473738
2023 Immune Response Profiling of Cocktails of Brugia malayi Vaccine Candidates DIM-1, Calponin and Troponin 1 in BALB/c Mice. Acta parasitologica 1 37935895
2019 1H, 13C, 15N backbone NMR resonance assignments for the rRNA methyltransferase Dim1 from the hyperthermophilic archaeon Pyrococcus horikoshii. Biomolecular NMR assignments 0 31069720

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