Affinage

SNAPC4

snRNA-activating protein complex subunit 4 · UniProt Q5SXM2

Length
1469 aa
Mass
159.4 kDa
Annotated
2026-06-10
30 papers in source corpus 16 papers cited in narrative 17 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SNAPC4 (SNAP190) is the largest subunit and central scaffold of the small nuclear RNA-activating protein complex (SNAPc), the factor that directs transcription of snRNA genes by both RNA polymerase II and III (PMID:9418884, PMID:9732265). It contains an unusual Myb DNA-binding domain of 4.5 repeats (Ra–Rd plus a half repeat) that directly contacts the proximal sequence element (PSE) of snRNA promoters, with multiple repeats engaging DNA simultaneously (PMID:9418884, PMID:23038247); in the assembled complex the Myb domain cooperates with SNAP50 motifs in a 'wrap-around' mode that reads both major and minor grooves of the PSE, explaining PSE sequence conservation (PMID:36369505). As scaffold, SNAPC4 makes direct contacts with SNAP43 and SNAP45 that define the minimal architecture for PSE recognition (PMID:9418884, PMID:11056176). SNAPC4 nucleates preinitiation complex assembly through several direct partner contacts: a 50-residue N-terminal region and the Myb domain recruit TBP to the adjacent TATA box and stimulate TBP–Brf2 assembly for Pol III initiation (PMID:12391172, PMID:12621023), and a defined peptide (residues 884–910) contacts the Oct-1 POU domain to mediate cooperative SNAPc binding and transcriptional activation (PMID:9418884, PMID:9832505, PMID:12414730). Its activity is constrained by CK2 phosphorylation of the N-terminal half, which allosterically inhibits the Myb domain and SNAPc DNA binding (PMID:17670747), and its productive incorporation into SNAPc depends on SUMOylation of the partner subunit SNAPC1 (PMID:40956881). Genome-wide, SNAPC4 occupancy is restricted to snRNA gene loci (PMID:22966203), and the protein is required for snRNA expression, spliceosome function, and G1 cell cycle progression (PMID:18356157, PMID:36965478). Bi-allelic loss-of-function variants in SNAPC4 reduce snRNA expression and globally dysregulate alternative splicing in patients (PMID:36965478).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1998 High

    Established that SNAPC4 is an essential scaffold of SNAPc that both binds the PSE through a novel Myb domain and is required for snRNA transcription by two polymerases.

    Evidence cDNA cloning, truncation mutagenesis and DNA-binding assays plus co-IP and transcription reconstitution in vitro

    PMID:9418884

    Open questions at the time
    • Topology of the 4.5 Myb repeats on DNA not yet resolved
    • How Pol II versus Pol III specificity is determined was not addressed
  2. 1998 High

    Showed that SNAPC4 contacts Oct-1 directly to mediate cooperative PSE binding and activation, defining how an enhancer-binding factor couples to the basal snRNA machinery.

    Evidence In vitro binding assays with switched-specificity SNAP190/Oct-1 POU mutants and transcription activation assays

    PMID:9418884 PMID:9832505

    Open questions at the time
    • Atomic interface not yet defined
    • Did not establish whether the contact operates at both Pol II and Pol III promoters
  3. 1998 High

    Demonstrated that a five-subunit recombinant SNAPc reconstitutes PSE-specific binding and directs both Pol II and Pol III transcription, proving the same core complex nucleates both initiation pathways.

    Evidence Recombinant reconstitution from defined subunits, PSE binding and in vitro transcription

    PMID:9732265

    Open questions at the time
    • Stoichiometry and quaternary arrangement of subunits not resolved
    • Determinants directing Pol II versus Pol III not identified
  4. 2000 High

    Mapped the SNAPC4 contacts to SNAP43 and SNAP45 that constitute the minimal architecture required for PSE recognition, framing SNAPC4 as the assembly hub.

    Evidence Deletion/truncation mutagenesis, co-IP and PSE binding assays

    PMID:11056176

    Open questions at the time
    • Structural basis of the minimal complex not determined
    • Role of SNAP50 in DNA contact not resolved at this stage
  5. 2002 High

    Resolved how SNAPC4 recruits TBP and Oct-1, identifying distinct N-terminal and peptide determinants for general transcription factor assembly.

    Evidence X-ray crystallography of the Oct-1 POU/octamer/SNAP190 peptide ternary complex and deletion/TBP-recruitment transcription assays

    PMID:12391172 PMID:12414730

    Open questions at the time
    • Full-length SNAPC4 architecture not captured
    • How CK2-regulated regions relate to these determinants not yet linked
  6. 2003 High

    Showed the SNAPC4 Myb domain itself recruits TBP and stimulates TBP–Brf2 assembly, mechanistically connecting PSE recognition to Pol III preinitiation complex formation.

    Evidence TBP recruitment assays, co-IP and in vitro transcription with truncated SNAP190 constructs

    PMID:12621023

    Open questions at the time
    • Equivalent Pol II PIC bridging not addressed here
    • Structural model of the Myb–TBP interface not available
  7. 2007 High

    Identified CK2 phosphorylation of the SNAPC4 N-terminus as a negative regulatory mechanism that allosterically inhibits the Myb DNA-binding domain.

    Evidence In vitro kinase assay, CK2-site mutagenesis, SNAPc DNA-binding and transcription assays

    PMID:17670747

    Open questions at the time
    • In vivo physiological trigger of CK2 regulation not established
    • Structural basis of the allosteric inhibition not resolved
  8. 2008 Medium

    Linked SNAPC4 function to cell proliferation by showing its specific requirement for G1 progression, distinct from SNAP45.

    Evidence siRNA knockdown and flow cytometry cell-cycle analysis

    PMID:18356157

    Open questions at the time
    • Single lab, single method
    • Causal snRNA target driving the G1 arrest not identified
  9. 2012 Medium

    Established in vivo that SNAPC4 occupancy is restricted to snRNA loci and that its loss in zebrafish disrupts snRNA expression and tissue development, defining its biological specificity.

    Evidence ChIP-seq in human cells plus forward-genetic and morpholino loss-of-function zebrafish analyses with snRNA profiling and apoptosis/organ phenotypes

    PMID:22222761 PMID:22496837 PMID:22966203

    Open questions at the time
    • Why specific tissues (biliary, exocrine pancreas) are sensitive not mechanistically explained
    • Differential SNAPC4 versus SNAPC1 genomic targeting basis unresolved
  10. 2012 Medium

    Mapped the topological arrangement of all 4.5 Myb repeats on the PSE, showing simultaneous multi-repeat DNA contacts.

    Evidence Site-specific protein–DNA photo-cross-linking of Drosophila SNAP190

    PMID:23038247

    Open questions at the time
    • Single lab using an ortholog
    • Atomic-resolution structure not yet available at this stage
  11. 2022 High

    Provided a near-atomic structural mechanism showing the SNAPC4 Myb domain cooperates with SNAP50 to wrap around and read both grooves of the PSE.

    Evidence Cryo-EM structure of human SNAPc N-terminal module bound to U6-1 PSE at 3.49 Å

    PMID:36369505

    Open questions at the time
    • Full-length SNAPc with all five subunits not resolved
    • Structural transition upon TBP/Oct-1/Pol recruitment not captured
  12. 2023 High

    Established SNAPC4 as a human disease gene by showing bi-allelic loss-of-function variants reduce snRNA and dysregulate global splicing, with CRISPR depletion recapitulating the molecular phenotype.

    Evidence Patient fibroblast analysis and CRISPR editing in HeLa cells with snRNA and alternative splicing profiling across multiple families

    PMID:36965478

    Open questions at the time
    • Genotype–phenotype relationship across affected tissues not fully defined
    • Which dysregulated splicing events drive pathology not identified
  13. 2025 Medium

    Showed that SNAPC1 SUMOylation is required for its productive interaction with SNAPC4, adding a post-translational layer controlling SNAPc assembly and basal snRNA transcription.

    Evidence CRISPR/dCas9-SENP1 deSUMOylation, degron depletion, SUMO-deficient mutant rescue and co-IP of tagged SNAPC3/SNAPC4 with snRNA assays

    PMID:40956881

    Open questions at the time
    • Single lab, not yet independently replicated
    • Whether SNAPC4 itself is SUMO-regulated not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how the same SNAPC4-containing core is differentially directed to assemble Pol II versus Pol III preinitiation complexes and how its regulatory phosphorylation and partner SUMOylation are integrated with cell-cycle and developmental signals.
  • No structure of full-length SNAPC4 within an intact PIC
  • Signaling inputs controlling CK2/SUMO regulation in vivo unknown
  • Tissue-specific vulnerability to SNAPC4 loss unexplained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 3 GO:0060090 molecular adaptor activity 3 GO:0140110 transcription regulator activity 3 GO:0140223 general transcription initiation factor activity 2
Localization
GO:0000228 nuclear chromosome 1 GO:0005634 nucleus 1
Pathway
R-HSA-74160 Gene expression (Transcription) 2 R-HSA-1640170 Cell Cycle 1 R-HSA-8953854 Metabolism of RNA 1
Partners
BRF2POU2F1SNAP43SNAP45SNAP50SNAPC1SNAPC2TBP
Complex memberships
SNAPc

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 SNAP190 (SNAPC4) contains an unusual Myb DNA binding domain consisting of four complete repeats (Ra–Rd) and a half repeat (Rh); a truncated protein with only the last two Myb repeats (Rc and Rd) can bind to the PSE, indicating the Myb domain directly contributes to PSE recognition by the SNAP complex. cDNA cloning, truncation mutagenesis, and DNA binding assays in vitro Molecular and cellular biology High 9418884
1998 SNAP190 (SNAPC4) is required for snRNA gene transcription by both RNA polymerase II and III and interacts directly with SNAP45, establishing its role as an essential scaffold subunit of SNAPc. Co-immunoprecipitation, transcription reconstitution assays Molecular and cellular biology High 9418884
1998 SNAP190 (SNAPC4) directly interacts with Oct-1, and this interaction mediates cooperative binding of SNAPc to the PSE; a switched-specificity SNAP190 mutant that interacts with Oct-1 POU E7R but not wild-type Oct-1 POU demonstrates the interaction is a direct protein–protein contact that results in transcriptional activation. In vitro binding assays, switched-specificity mutagenesis, transcription activation assays Genes & development High 9418884 9832505
1998 A functional five-subunit recombinant SNAPc (SNAP43, SNAP45, SNAP50, SNAP190, and newly identified SNAP19) can be reconstituted from recombinant proteins; this complex binds specifically to the PSE and directs both RNA polymerase II and III snRNA gene transcription, establishing that the same core SNAPc nucleates both initiation complexes. Recombinant protein reconstitution, PSE DNA binding assay, in vitro transcription Genes & development High 9732265
2000 Detailed subunit–subunit interaction mapping within SNAPc showed that SNAP190 (SNAPC4) makes direct contacts with SNAP43 and SNAP45, and complexes containing little more than these interaction domains retain specific PSE binding, defining the minimal architecture required for DNA recognition. Deletion/truncation mutagenesis, co-immunoprecipitation, PSE binding assays The Journal of biological chemistry High 11056176
2002 X-ray crystal structure of the Oct-1 POU domain/U1 octamer/SNAP190 peptide ternary complex revealed that the SNAP190 peptide (residues 884–910) makes extensive contacts with the Oct-1 POU-specific domain and with the DNA phosphate backbone, and that this interface is distinct from that used by OCA-B. X-ray crystallography at 2.3 Å resolution Genes & development High 12414730
2002 A 50-amino-acid region within the N-terminal third of SNAP190 (SNAPC4) is required for cooperative binding with TBP in the context of mini-SNAPc and is sufficient for TBP cooperative binding when fused to a heterologous DNA binding domain, identifying this region as a TBP recruitment determinant in U6 transcription. Deletion mutagenesis, TBP recruitment assay, in vitro transcription Molecular and cellular biology High 12391172
2003 The SNAP190 Myb DNA binding domain directly interacts with the TBP DNA binding domain and is sufficient for recruiting TBP to the U6 TATA box; SNAP190 Myb domain also stimulates assembly of TBP–Brf2 complex, thereby facilitating RNA polymerase III preinitiation complex assembly. TBP recruitment assays, co-immunoprecipitation, in vitro transcription with truncated SNAP190 constructs The Journal of biological chemistry High 12621023
2007 Protein kinase CK2 phosphorylates the N-terminal half of SNAP190 (SNAPC4) at two regions (amino acids 20–63 and 514–545), and this phosphorylation inhibits SNAPc DNA binding and U6 transcription activity through allosteric inhibition of the SNAP190 Myb DNA binding domain. In vitro kinase assay, site-directed mutagenesis of CK2 consensus sites, SNAPc DNA binding assay, in vitro transcription The Journal of biological chemistry High 17670747
2008 Down-regulation of SNAP190 (SNAPC4), distinct from SNAP45, leads to an accumulation of cells with G0/G1 DNA content, indicating SNAP190 is specifically required for cell cycle progression at G1 rather than mitosis. siRNA knockdown, flow cytometry cell cycle analysis The Journal of biological chemistry Medium 18356157
2012 In zebrafish, the snapc4(s445) mutation truncates the C-terminus of Snapc4, deleting the domain required for interaction with Snapc2 (a vertebrate-specific SNAPc subunit); this hypomorphic allele alters expression of a subset of snRNAs and causes apoptosis of biliary epithelial cells and loss of the intrahepatic biliary network. Forward genetic screen, whole-genome sequencing, loss-of-function zebrafish mutant analysis, apoptosis assay, snRNA expression profiling Developmental biology High 22222761
2012 Chromatin immunoprecipitation sequencing showed that SNAPC4 occupancy is limited to snRNA gene loci genome-wide, whereas SNAPC1 occupancy extends broadly to protein-coding genes, establishing that SNAPC4 function is restricted to snRNA promoters in vivo. ChIP-seq with SNAPC4 and SNAPC1 antibodies Molecular and cellular biology Medium 22966203
2012 In zebrafish, a loss-of-function nonsense mutation in snapc4 causes severe hypoplasia of the exocrine pancreas; morpholino knockdown confirmed that loss of snapc4 is causally responsible for this phenotype. Whole-genome sequencing for mutation identification, morpholino knockdown in zebrafish PloS one Medium 22496837
2012 Drosophila melanogaster SNAP190 Myb repeats were mapped by site-specific protein–DNA photo-cross-linking to specific nucleotides of the U1 snRNA gene PSE, revealing the topological arrangement of all 4.5 Myb repeats on DNA and showing that multiple repeats contact DNA simultaneously. Site-specific protein–DNA photo-cross-linking assay The Journal of biological chemistry Medium 23038247
2022 Cryo-EM structure of human SNAPc (N-terminal domain of SNAP190/SNAPC4, SNAP50, and SNAP43) bound to the U6-1 PSE at 3.49 Å resolution revealed a 'wrap-around' DNA binding mode; the SNAP190 Myb domain cooperates with three SNAP50 motifs to recognize both major and minor grooves of the PSE, explaining PSE sequence conservation. Cryo-electron microscopy structure determination at 3.49 Å Nature communications High 36369505
2023 Bi-allelic loss-of-function variants in SNAPC4 in human patients reduce SNAPC4 protein abundance, decrease snRNA expression, and cause global dysregulation of alternative splicing; CRISPR-mediated depletion of SNAPC4 in HeLa cells recapitulated decreased snRNA expression and splicing dysregulation, establishing SNAPC4 as essential for normal snRNA-dependent spliceosome function. Patient fibroblast analysis, CRISPR genomic editing in HeLa cells, snRNA expression profiling, global alternative splicing analysis American journal of human genetics High 36965478
2025 SUMOylation-deficient SNAPC1 (2KR mutant) fails to maintain basal snRNA transcription and shows impaired interaction with SNAPC4, despite still being recruited to the PSE, indicating that SNAPC1 SUMOylation is required for its productive interaction with SNAPC4 within the SNAPc complex. CRISPR/dCas9-SENP1 targeted deSUMOylation, inducible degron depletion of endogenous SNAPC1, SUMOylation-deficient mutant rescue, co-immunoprecipitation of tagged SNAPC3 and SNAPC4, snRNA expression assay Proceedings of the National Academy of Sciences of the United States of America Medium 40956881

Source papers

Stage 0 corpus · 30 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 The large subunit of basal transcription factor SNAPc is a Myb domain protein that interacts with Oct-1. Molecular and cellular biology 82 9418884
2003 STAT5 and Oct-1 form a stable complex that modulates cyclin D1 expression. Molecular and cellular biology 76 14645506
1998 SNAP19 mediates the assembly of a functional core promoter complex (SNAPc) shared by RNA polymerases II and III. Genes & development 73 9732265
2010 Elucidating the chromosome 9 association with AS; CARD9 is a candidate gene. Genes and immunity 60 20463747
1998 The Oct-1 POU domain activates snRNA gene transcription by contacting a region in the SNAPc largest subunit that bears sequence similarities to the Oct-1 coactivator OBF-1. Genes & development 50 9832505
2000 A map of protein-protein contacts within the small nuclear RNA-activating protein complex SNAPc. The Journal of biological chemistry 41 11056176
2002 Redundant cooperative interactions for assembly of a human U6 transcription initiation complex. Molecular and cellular biology 34 12391172
2012 Fast homozygosity mapping and identification of a zebrafish ENU-induced mutation by whole-genome sequencing. PloS one 31 22496837
2020 Implication of m6A mRNA Methylation in Susceptibility to Inflammatory Bowel Disease. Epigenomes 29 34968289
2003 Inhibition of p53, p21 and Bax by pifithrin-alpha does not affect UV induced apoptotic response in CS-B cells. DNA repair 29 12893085
2003 The small nuclear RNA-activating protein 190 Myb DNA binding domain stimulates TATA box-binding protein-TATA box recognition. The Journal of biological chemistry 22 12621023
2015 Determination of IL1 R2, ANTXR2, CARD9, and SNAPC4 single nucleotide polymorphisms in Iranian patients with ankylosing spondylitis. Rheumatology international 20 26590821
2011 Mutation of zebrafish Snapc4 is associated with loss of the intrahepatic biliary network. Developmental biology 18 22222761
2013 Evidence for genetic association of CARD9 and SNAPC4 with ankylosing spondylitis in a Chinese Han population. The Journal of rheumatology 17 24334645
2006 The unorthodox SNAP50 zinc finger domain contributes to cooperative promoter recognition by human SNAPC. The Journal of biological chemistry 16 16901896
2002 Activator recruitment by the general transcription machinery: X-ray structural analysis of the Oct-1 POU domain/human U1 octamer/SNAP190 peptide ternary complex. Genes & development 16 12414730
2012 Requirement for SNAPC1 in transcriptional responsiveness to diverse extracellular signals. Molecular and cellular biology 15 22966203
2002 Recruitment of the priming protein pTP and DNA binding occur by overlapping Oct-1 POU homeodomain surfaces. The EMBO journal 15 11847120
2007 The protein kinase CK2 phosphorylates SNAP190 to negatively regulate SNAPC DNA binding and human U6 transcription by RNA polymerase III. The Journal of biological chemistry 13 17670747
2022 Structural basis of human SNAPc recognizing proximal sequence element of snRNA promoter. Nature communications 12 36369505
2022 Identification of the hub genes related to adipose tissue metabolism of bovine. Frontiers in veterinary science 12 36439361
2023 Bi-allelic SNAPC4 variants dysregulate global alternative splicing and lead to neuroregression and progressive spastic paraparesis. American journal of human genetics 8 36965478
2006 Co-expression of multiple subunits enables recombinant SNAPC assembly and function for transcription by human RNA polymerases II and III. Protein expression and purification 6 16603380
2012 Architectural arrangement of the small nuclear RNA (snRNA)-activating protein complex 190 subunit (SNAP190) on U1 snRNA gene promoter DNA. The Journal of biological chemistry 5 23038247
2008 Mitotic functions for SNAP45, a subunit of the small nuclear RNA-activating protein complex SNAPc. The Journal of biological chemistry 5 18356157
2024 Genetic overlap between inflammatory bowel disease and iridocyclitis: insights from a genome-wide association study in a European population. BMC genomic data 2 39472800
2002 Crystallization of the Oct-1/SNAP190 peptide/DNA complex. Acta crystallographica. Section D, Biological crystallography 1 11856838
2025 UBE3C promotes pancreatic ductal adenocarcinoma progression by catalysing p53 ubiquitination. Molecular biology reports 0 40553397
2025 SUMO conjugation to promoter-proximal sequence elements-associated proteins impacts on snRNA transcription. Proceedings of the National Academy of Sciences of the United States of America 0 40956881
2024 Multiregion exome sequencing indicates a monoclonal origin of esophageal spindle-cell squamous cell carcinoma. The Journal of pathology 0 39022845

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