Affinage

SNRNP40

U5 small nuclear ribonucleoprotein 40 kDa protein · UniProt Q96DI7

Round 2 corrected
Length
357 aa
Mass
39.3 kDa
Annotated
2026-04-28
41 papers in source corpus 6 papers cited in narrative 6 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SNRNP40 is a core subunit of the U5 small nuclear ribonucleoprotein (snRNP) that functions within the spliceosome to catalyze pre-mRNA splicing. Initially identified by mass spectrometry of purified spliceosomal particles (PMID:9731529), SNRNP40 was confirmed in the catalytic C complex containing U2, U5, and U6 snRNAs (PMID:11991638) and structurally resolved within the human C* spliceosome by cryo-EM (PMID:28076346). Hypomorphic loss of SNRNP40 in mice causes widespread intron retention across hundreds of transcripts, disrupting expression of immune-function proteins and producing a syndromic immunodeficiency with impaired lymphoid development and susceptibility to viral infection (PMID:31427773). Reduced SNRNP40 expression in breast cancer cells promotes metastatic colonization, linking spliceosome integrity to metastatic fitness (PMID:27138336).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 1998 High

    The composition of the human spliceosome was unknown at the single-protein level; mass spectrometry of purified spliceosomal particles identified SNRNP40 (WDR57/p40) as a spliceosome component, establishing it as a bona fide splicing factor.

    Evidence Nanoelectrospray MS of 2D-gel-separated spliceosome fractions

    PMID:9731529

    Open questions at the time
    • Specific snRNP sub-complex assignment not determined
    • No functional data on requirement for splicing
  2. 2002 High

    Whether SNRNP40 was associated with a specific spliceosomal state was unclear; its detection in purified C complex particles and in comprehensive spliceosome proteomes confirmed it as a core snRNP-associated protein present during catalytic stages of splicing.

    Evidence Affinity purification of native C complex spliceosomes followed by LC-MS/MS, replicated across two independent studies

    PMID:11991638 PMID:12226669

    Open questions at the time
    • Precise structural position within the spliceosome not resolved
    • Whether SNRNP40 is required for catalysis or is structural was unknown
  3. 2016 Medium

    Whether spliceosomal gene dosage affects cancer biology was poorly explored; engineered reduction of SNRNP40 expression in breast cancer cells promoted metastatic colonization in vivo, revealing that partial spliceosome impairment can confer metastatic fitness.

    Evidence Engineered variable expression in human breast cancer cell lines with in vivo metastasis assays and single-cell RNA-seq

    PMID:27138336

    Open questions at the time
    • Specific mis-spliced transcripts driving metastasis not fully delineated
    • Not independently replicated in a second cancer type
    • Mechanism linking partial splicing deficiency to metastatic advantage not resolved
  4. 2017 High

    The molecular architecture of SNRNP40 within the spliceosome was unknown; cryo-EM of the human C* complex placed SNRNP40 as a U5 snRNP component within the catalytic spliceosome at near-atomic resolution.

    Evidence Cryo-electron microscopy of the human spliceosomal C* complex

    PMID:28076346

    Open questions at the time
    • Contact interfaces with neighboring subunits not fully characterized
    • Structural role versus catalytic contribution not distinguished
  5. 2019 High

    Whether SNRNP40 is functionally essential in vivo and which cell types are most vulnerable to its loss was unknown; a hypomorphic mouse mutant demonstrated that reduced SNRNP40 causes widespread intron retention, disrupts immune-protein expression, and produces syndromic immunodeficiency with impaired lymphoid development.

    Evidence Viable hypomorphic mouse mutant with RNA-seq of hematopoietic stem cells and T cells plus quantitative proteomics

    PMID:31427773

    Open questions at the time
    • Why lymphoid cells are preferentially sensitive to SNRNP40 reduction is not mechanistically explained
    • Whether complete loss is embryonic lethal was not tested
    • Specific intron-retention events causally driving immunodeficiency not individually validated

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis for SNRNP40's contribution to spliceosome catalysis, the mechanism underlying cell-type-selective vulnerability to its reduction, and the specific mis-spliced transcripts that drive both immunodeficiency and metastasis remain unresolved.
  • No biochemical reconstitution of SNRNP40's catalytic contribution
  • Tissue-selective sensitivity mechanism unknown
  • No therapeutic targeting studies

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 5 GO:0005198 structural molecule activity 2
Localization
GO:0005634 nucleus 4
Pathway
R-HSA-8953854 Metabolism of RNA 5 R-HSA-1643685 Disease 2 R-HSA-168256 Immune System 1
Complex memberships
Spliceosomal C complexSpliceosomal C* complexU5 snRNP

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 SNRNP40 (WDR57/p40) was identified as a component of the human spliceosome complex through mass spectrometry and EST-database searching of purified spliceosomal particles. Nanoelectrospray mass spectrometry of purified spliceosome fractions separated by 2D gel electrophoresis Nature genetics High 9731529
2002 SNRNP40 was confirmed as a component of functional human spliceosomes, specifically detected in purified C complex spliceosomal particles containing U2, U5, and U6 snRNAs. Affinity purification of native spliceosomes followed by tandem mass spectrometry RNA (New York, N.Y.) High 11991638
2002 SNRNP40 was catalogued as a component of the human spliceosome in a comprehensive proteomic analysis identifying ~145 distinct spliceosomal proteins, confirming its role as a core snRNP-associated protein. Maltose-binding protein affinity chromatography purification of spliceosomes followed by nanoscale LC-MS/MS Nature High 12226669
2017 SNRNP40 was structurally localized within the human C* spliceosome (activated for step 2 of splicing) by cryo-EM, placing it as part of the U5 snRNP component of the catalytic spliceosome. Cryo-electron microscopy of human spliceosomal C* complex at near-atomic resolution Nature High 28076346
2019 SNRNP40 is an essential subunit of the U5 snRNP complex of the spliceosome; hypomorphic loss-of-function mutation in mice causes increased splicing errors (predominantly intron retention) in hundreds of mRNAs in hematopoietic stem cells, T cells, and EL4 cells, leading to altered expression of immune-function proteins and a syndromic immunodeficiency phenotype including hypersusceptibility to murine cytomegalovirus and defects in lymphoid development. Viable hypomorphic mouse mutant; RNA-seq of primary hematopoietic stem cells and T cells; quantitative proteomics of mutant cells Nature immunology High 31427773
2016 Engineered variable (low) expression of SNRNP40 in breast cancer cells promotes metastatic colonization, identifying SNRNP40 as a spliceosomal gene whose reduced expression confers increased metastatic fitness. Engineered variable expression in human breast cancer cell lines; in vivo metastasis assays; single-cell RNA-sequencing Nature communications Medium 27138336

Source papers

Stage 0 corpus · 41 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2009 Defining the human deubiquitinating enzyme interaction landscape. Cell 1282 19615732
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2007 Large-scale mapping of human protein-protein interactions by mass spectrometry. Molecular systems biology 733 17353931
2002 Comprehensive proteomic analysis of the human spliceosome. Nature 725 12226669
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2018 High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. Molecular cell 580 29395067
2017 Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science (New York, N.Y.) 533 28302793
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2010 Systematic analysis of human protein complexes identifies chromosome segregation proteins. Science (New York, N.Y.) 421 20360068
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
1998 Mass spectrometry and EST-database searching allows characterization of the multi-protein spliceosome complex. Nature genetics 404 9731529
2006 CUL4-DDB1 ubiquitin ligase interacts with multiple WD40-repeat proteins and regulates histone methylation. Nature cell biology 371 17041588
2015 Proteome-wide profiling of protein assemblies by cross-linking mass spectrometry. Nature methods 370 26414014
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2006 Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy. Nature genetics 317 16429158
2002 Purification and characterization of native spliceosomes suitable for three-dimensional structural analysis. RNA (New York, N.Y.) 301 11991638
2012 The cellular EJC interactome reveals higher-order mRNP structure and an EJC-SR protein nexus. Cell 272 23084401
2011 A function for cyclin D1 in DNA repair uncovered by protein interactome analyses in human cancers. Nature 269 21654808
2017 Cryo-EM structure of a human spliceosome activated for step 2 of splicing. Nature 204 28076346
2013 PRP19 transforms into a sensor of RPA-ssDNA after DNA damage and drives ATR activation via a ubiquitin-mediated circuitry. Molecular cell 204 24332808
2015 A deep proteomics perspective on CRM1-mediated nuclear export and nucleocytoplasmic partitioning. eLife 198 26673895
2016 Highly variable cancer subpopulations that exhibit enhanced transcriptome variability and metastatic fitness. Nature communications 109 27138336
2021 The Role of the U5 snRNP in Genetic Disorders and Cancer. Frontiers in genetics 42 33584830
2020 Analysis of testis metabolome and transcriptome from the oriental river prawn (Macrobrachium nipponense) in response to different temperatures and illumination times. Comparative biochemistry and physiology. Part D, Genomics & proteomics 35 32114312
2021 Identification of biomarkers for acute leukemia via machine learning-based stemness index. Gene 21 34411647
2018 CINP is a novel cofactor of KLF5 required for its role in the promotion of cell proliferation, survival and tumor growth. International journal of cancer 15 30289973
2021 The Role of Hemoglobin Subunit Delta in the Immunopathy of Multiple Sclerosis: Mitochondria Matters. Frontiers in immunology 13 34504491
2019 Syndromic immune disorder caused by a viable hypomorphic allele of spliceosome component Snrnp40. Nature immunology 13 31427773
2022 Analysis of genomic alterations in cancer associated human pancreatic stellate cells. Scientific reports 4 35941161
2022 Tandem Mass Tag-Based Quantitative Proteomics Analysis of Gonads Reveals New Insight into Sexual Reversal Mechanism in Chinese Soft-Shelled Turtles. Biology 4 36101459
2023 Novel genetic variants linked to prelabor rupture of membranes among Chinese pregnant women. Placenta 1 37054626
2026 Proteomic Profiling of Non-Muscle Invasive Bladder Cancer Reveals Potential Biomarkers for Recurrence and Progression Risk. Journal of proteome research 0 41587934