Affinage

LSM5

U6 snRNA-associated Sm-like protein LSm5 · UniProt Q9Y4Y9

Round 2 corrected
Length
91 aa
Mass
9.9 kDa
Annotated
2026-04-28
54 papers in source corpus 14 papers cited in narrative 14 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LSM5 is a conserved Sm-fold protein that functions as a subunit of two heteroheptameric ring complexes central to RNA metabolism: the nuclear Lsm2-8 complex, which binds the 3'-terminal U-tract and 2',3'-cyclic phosphate of U6 snRNA to stabilize it and promote U4/U6 duplex formation required for pre-mRNA splicing, and the cytoplasmic Lsm1-7 complex, which localizes to P-bodies and cooperates with decapping enzymes and the 5'→3' exonuclease Xrn1 to initiate mRNA decay (PMID:10523320, PMID:12515382, PMID:32518066). Within both ring complexes, Lsm5 uniquely recognizes purine bases rather than uridylate, explaining its divergent sequence among Lsm subunits (PMID:32518066). In yeast, Lsm5 loss is lethal but is fully rescued by U6 snRNA or Prp24 overexpression, establishing that its sole essential function is support of U6 snRNA biogenesis (PMID:29615482). The Lsm1-7 complex also facilitates hepatitis C virus RNA translation and replication through direct interaction with viral 5' and 3' UTR elements (PMID:19628699).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 1999 High

    Identification of Lsm proteins including Lsm5 as components of a conserved doughnut-shaped complex that binds the U6 snRNA 3'-U-tract and promotes U4/U6 duplex formation established the biochemical framework for Lsm ring function in splicing.

    Evidence Reconstituted complex from recombinant proteins; EM imaging, in vitro RNA binding, and U4/U6 annealing assays in human and yeast systems

    PMID:10369684 PMID:10523320

    Open questions at the time
    • Subunit arrangement within the heptameric ring was unknown
    • RNA-binding contributions of individual subunits were unresolved
  2. 2001 High

    Genetic analysis in yeast revealed that Lsm5 (and the Lsm2-8 complex) acts redundantly with La protein Lhp1p to stabilize nascent U6 snRNA, linking the complex to U6 biogenesis rather than solely to mature U6 function.

    Evidence Synthetic lethality and suppressor analysis between lsm5Δ, lsm6Δ, lsm7Δ and lhp1Δ in S. cerevisiae

    PMID:11333229

    Open questions at the time
    • Direct binding of nascent U6 by Lsm2-8 was not demonstrated
    • Whether Lsm5 contributes non-redundant contacts to U6 was unclear
  3. 2002 High

    Discovery that Lsm1-7 (including Lsm5) colocalizes with Dcp1/2 and Xrn1 in cytoplasmic P-bodies established a second, spatially distinct functional context for Lsm5 in mRNA decay, separate from its nuclear U6-associated role.

    Evidence Fluorescence microscopy, FRET, and co-expression of wild-type and mutant LSm proteins in human cells

    PMID:12515382

    Open questions at the time
    • Functional requirement of Lsm5 specifically for decapping activity was not tested
    • Mechanism of Lsm1-7 recruitment to P-bodies was undefined
  4. 2009 High

    Demonstration that Lsm1-7 complexes interact with HCV RNA cis-elements and are required for viral translation and replication extended the functional scope of Lsm5-containing complexes beyond endogenous mRNA decay to viral RNA biology.

    Evidence RNAi knockdown of Lsm1, RNA co-immunoprecipitation, and in vitro translation/replication assays for HCV

    PMID:19628699

    Open questions at the time
    • Whether Lsm5 itself contacts viral RNA or whether its contribution is purely structural within the ring was unknown
    • Generality across other positive-strand RNA viruses was suggested but not fully characterized
  5. 2011 High

    Crystal and NMR structures of the Lsm5/6/7 sub-complex revealed it forms a hexameric assembly intermediate, defining the subunit order (Lsm5–Lsm6–Lsm7) and showing Lsm5 adopts a canonical Sm fold at a position analogous to SmE.

    Evidence X-ray crystallography at 2.5 Å, solution NMR, and pull-down assays with Lsm2/3

    PMID:22001694 PMID:22615807

    Open questions at the time
    • Full heptameric ring structure with RNA was not yet available
    • Basis for Lsm5's divergent RNA-binding specificity was unresolved
  6. 2018 High

    Systematic alanine-scanning mutagenesis and genetic suppression proved that the sole essential function of Lsm5 in yeast is to support U6 snRNA biogenesis, as lethality from Lsm5 loss is rescued by U6 or Prp24 overexpression.

    Evidence Structure-guided mutagenesis, genetic complementation, and high-copy suppressor analysis in S. cerevisiae

    PMID:29615482

    Open questions at the time
    • Whether this essentiality hierarchy extends to metazoans was not tested
    • Contributions of Lsm5 to mRNA decay in vivo could not be assessed due to lethality rescue design
  7. 2020 High

    High-resolution cryo-EM structures of RNA-bound Lsm1-7 and Lsm2-8 rings revealed that Lsm5 uniquely recognizes purine bases, explaining its sequence divergence; the structures also showed that Lsm2-8 specifically recognizes the 2',3'-cyclic phosphate end of U6 while Lsm1-7 discriminates against it, defining the molecular basis for substrate selectivity between the two complexes.

    Evidence Cryo-EM structure determination of both complexes with RNA, RNA binding assays, and Lsm1 C-terminal deletion analysis

    PMID:32518066

    Open questions at the time
    • Dynamic aspects of RNA scanning by Lsm1-7 along mRNA substrates lack time-resolved structural data
    • Whether Lsm5's purine preference contributes to mRNA target selectivity in vivo is untested
  8. 2024 Medium

    LSM5 knockdown in colon cancer cells suppressed proliferation and induced apoptosis via upregulation of p53/CDKN1A/TNFRSF10B, placing LSM5 upstream of the p53-dependent apoptotic axis in this cancer context.

    Evidence Lentiviral shRNA knockdown, proliferation and apoptosis assays, GeneChip profiling, Western blotting in colon cancer cell lines

    PMID:38994171

    Open questions at the time
    • Whether the apoptotic phenotype reflects splicing defects, mRNA decay defects, or both is undetermined
    • Single-lab finding without independent replication
    • Mechanistic link between Lsm5 loss and p53 activation is correlative

Open questions

Synthesis pass · forward-looking unresolved questions
  • Whether Lsm5's unique purine-recognition activity within the heptameric ring confers target selectivity in vivo, and whether the essential function of Lsm5 in metazoans is restricted to U6 snRNA support as in yeast, remain open questions.
  • No in vivo separation-of-function mutants distinguishing Lsm5's role in Lsm2-8 vs Lsm1-7 complexes in metazoans
  • No structural model of full spliceosomal U4/U6·U5 tri-snRNP showing Lsm5 contacts in context
  • Relationship between Lsm5 depletion phenotypes in cancer and specific RNA targets is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 3 GO:0005198 structural molecule activity 3
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-8953854 Metabolism of RNA 5 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1643685 Disease 1
Partners
DCP1ALSM1LSM2LSM3LSM4LSM6LSM7LSM8
Complex memberships
Lsm1-7 (cytoplasmic P-body-associated)Lsm2-8 (nuclear U6 snRNA-associated)

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 LSm proteins (including LSm5) form a heteromeric complex that binds specifically to the 3'-terminal U-tract of U6 snRNA and facilitates U4/U6 RNA duplex formation in vitro; the complex exhibits a doughnut-shaped structure under electron microscopy similar to the Sm core RNP. Protein purification, EM, in vitro RNA binding assay, RNase T1 co-precipitation The EMBO journal High 10523320
1999 Sm-like proteins including LSm5 assemble into two distinct complexes of deep evolutionary origin: a nuclear complex associated with U6 snRNA (Lsm2-8) and a related complex; human LSm5 homologs associate with U6 snRNA-containing complexes. Database searches, immunoprecipitation, cDNA cloning The EMBO journal High 10369684
2000 SMN (spinal muscular atrophy disease protein) interacts with Lsm4 and Lsm6 but not directly with Lsm5; the arginine- and glycine-rich C-terminal domain of Lsm4 mediates SMN binding, suggesting SMN functions in assembly of Lsm-containing U6 snRNP complexes. Pull-down assays, domain mapping The Journal of biological chemistry Medium 10851237
2001 In Saccharomyces cerevisiae, deletion of LSM5 (along with LSM6 or LSM7) causes the La protein Lhp1p to become required for growth, indicating that the entire Lsm2-8 complex acts redundantly with Lhp1p to stabilize nascent U6 snRNA. LSM2 and LSM4 act as allele-specific suppressors of lsm8 mutations. Genetic epistasis, suppressor analysis, yeast growth assays Genetics High 11333229
2002 Human LSm1-7 complex (including LSm5) colocalizes with mRNA-degrading enzymes Dcp1/2 and Xrn1 in discrete cytoplasmic foci (P-bodies); complex formation among hLSm1-7 is required for enrichment in these foci, and hLSm8 does not localize to these cytoplasmic foci. Subcellular localization by fluorescence microscopy, FRET, co-expression of wild-type and mutant LSm proteins RNA (New York, N.Y.) High 12515382
2004 Two-hybrid mapping of human mRNA decay proteins reveals interactions between the Lsm complex (including LSm5-containing complexes), decapping factors, and 5'→3' exonucleases, providing a protein interaction framework for 5'→3' mRNA degradation. Yeast two-hybrid protein interaction mapping Genome research Medium 15231747
2008 In Trypanosoma brucei, Lsm5 was identified as a component of the heptameric Lsm2-8 complex that binds U6 snRNA; the complex localizes to the nucleus near the nucleolus and is not detected in cytoplasmic Dhh1-positive bodies, suggesting Lsm-mediated degradation in trypanosomes is not confined to cytoplasmic P-bodies. RNAi silencing, TAP-tag purification, fluorescence localization Molecular and biochemical parasitology Medium 18433897
2008 Crystal structure of yeast Lsm3 octamer reveals that Lsm6, Lsm2, and Lsm5 can be recruited directly from yeast lysate by the Lsm3 scaffold, supporting a model in which Lsm C-terminal tails and loops mediate protein-protein interactions during Lsm ring assembly. X-ray crystallography, pull-down from yeast lysate Journal of molecular biology Medium 18329667
2009 Hepatitis C virus RNA translation and replication depends on LSm1-7 complexes (which include LSm5); LSm1-7 complexes specifically interact with cis-acting HCV RNA elements in the 5' and 3' UTRs of the viral genome. RNAi knockdown, RNA co-immunoprecipitation, in vitro translation/replication assays Proceedings of the National Academy of Sciences of the United States of America High 19628699
2011 Crystal structure of the LSm5/6/7 (LSm657) assembly intermediate at 2.5 Å resolution shows that the three monomers adopt canonical Sm folds and arrange into a hexameric LSm657-657 ring; NMR confirms hexameric assembly in solution. Pull-down and NMR show LSm657 can incorporate LSm23 toward native LSm ring assembly. LSm5 uniquely positions within the ring consistent with SmE in the heptameric Sm ring. X-ray crystallography, NMR spectroscopy, pull-down assay Journal of molecular biology High 22001694
2012 Crystal structures of Lsm5/6/7 from S. pombe show Lsm5 adopts the conserved Sm fold; the Lsm5/6/7 sub-complex forms a hexamer in solution (confirmed by analytical ultracentrifugation) and binds oligo(U) RNA, revealing the inter-subunit organization order Lsm5–Lsm6–Lsm7. X-ray crystallography, analytical ultracentrifugation, RNA binding assay PloS one High 22615807
2018 Structure-guided mutational analysis of the Saccharomyces cerevisiae Lsm2-8 ring: alanine scanning of RNA-binding sites and intersubunit interfaces of Lsm5 (among others) identified that loss of Lsm5 is lethal but rescued by overexpression of U6 snRNA or Prp24, demonstrating that the only essential function of Lsm5 in yeast is to support U6 snRNA biogenesis/function. Internal genetic redundancies buffer Lsm2-8 ring function. Alanine scanning mutagenesis, genetic complementation, high-copy suppressor analysis in yeast RNA (New York, N.Y.) High 29615482
2020 High-resolution cryo-EM structures of Lsm1-7 and Lsm2-8 complexes bound to RNA reveal that Lsm5 uniquely recognizes purine bases, explaining its divergent sequence relative to other Lsm subunits. The Lsm2-8 complex specifically recognizes the 2',3'-cyclic phosphate end of U6 snRNA, while Lsm1-7 discriminates against cyclic phosphates and binds oligouridylate tracts with terminal purines. Removal of the Lsm1 C-terminal region allows Lsm1-7 to scan along RNA, suggesting a gated mechanism. Cryo-EM structure determination, RNA binding assays, domain deletion analysis RNA (New York, N.Y.) High 32518066
2024 Knockdown of LSM5 in colon cancer cells suppressed proliferation and promoted apoptosis, associated with upregulation of p53, CDKN1A, and TNFRSF10B, placing LSM5 upstream of the p53/CDKN1A/TNFRSF10B apoptotic axis in colon cancer cells. Lentiviral shRNA knockdown, proliferation and apoptosis assays, GeneChip expression profiling, Western blotting World journal of gastrointestinal oncology Medium 38994171

Source papers

Stage 0 corpus · 54 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
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
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2009 A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 843 19490893
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
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
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
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2014 Dynamic regulation of genome-wide pre-mRNA splicing and stress tolerance by the Sm-like protein LSm5 in Arabidopsis. Genome biology 351 24393432
2003 Splicing double: insights from the second spliceosome. Nature reviews. Molecular cell biology 329 14685174
2012 Dynamic protein-protein interaction wiring of the human spliceosome. Molecular cell 318 22365833
2002 The human LSm1-7 proteins colocalize with the mRNA-degrading enzymes Dcp1/2 and Xrnl in distinct cytoplasmic foci. RNA (New York, N.Y.) 303 12515382
1999 A doughnut-shaped heteromer of human Sm-like proteins binds to the 3'-end of U6 snRNA, thereby facilitating U4/U6 duplex formation in vitro. The EMBO journal 260 10523320
2007 hORFeome v3.1: a resource of human open reading frames representing over 10,000 human genes. Genomics 222 17207965
1999 Sm and Sm-like proteins assemble in two related complexes of deep evolutionary origin. The EMBO journal 220 10369684
2017 Cryo-EM Structure of a Pre-catalytic Human Spliceosome Primed for Activation. Cell 199 28781166
2016 Molecular architecture of the human U4/U6.U5 tri-snRNP. Science (New York, N.Y.) 167 26912367
1999 Functional interaction of a novel 15.5kD [U4/U6.U5] tri-snRNP protein with the 5' stem-loop of U4 snRNA. The EMBO journal 167 10545122
2019 H4K20me0 recognition by BRCA1-BARD1 directs homologous recombination to sister chromatids. Nature cell biology 162 30804502
2003 Human chromosome 7: DNA sequence and biology. Science (New York, N.Y.) 154 12690205
2019 Mechanism of 5' splice site transfer for human spliceosome activation. Science (New York, N.Y.) 141 30975767
2004 A protein interaction framework for human mRNA degradation. Genome research 123 15231747
2009 Translation and replication of hepatitis C virus genomic RNA depends on ancient cellular proteins that control mRNA fates. Proceedings of the National Academy of Sciences of the United States of America 116 19628699
2000 Specific sequences of the Sm and Sm-like (Lsm) proteins mediate their interaction with the spinal muscular atrophy disease gene product (SMN). The Journal of biological chemistry 115 10851237
2021 Protein interaction landscapes revealed by advanced in vivo cross-linking-mass spectrometry. Proceedings of the National Academy of Sciences of the United States of America 113 34349018
2013 Genome-wide association mapping for identification of quantitative trait loci for rectal temperature during heat stress in Holstein cattle. PloS one 83 23935954
2013 Arabidopsis thaliana LSM proteins function in mRNA splicing and degradation. Nucleic acids research 71 23620288
2001 Multiple functional interactions between components of the Lsm2-Lsm8 complex, U6 snRNA, and the yeast La protein. Genetics 65 11333229
2014 Role for LSM genes in the regulation of circadian rhythms. Proceedings of the National Academy of Sciences of the United States of America 56 25288739
2020 Molecular basis for the distinct cellular functions of the Lsm1-7 and Lsm2-8 complexes. RNA (New York, N.Y.) 31 32518066
2008 Crystal structure of Lsm3 octamer from Saccharomyces cerevisiae: implications for Lsm ring organisation and recruitment. Journal of molecular biology 25 18329667
2008 Identification of the heptameric Lsm complex that binds U6 snRNA in Trypanosoma brucei. Molecular and biochemical parasitology 25 18433897
2022 Identification of LSM Family Members as Novel Unfavorable Biomarkers in Hepatocellular Carcinoma. Frontiers in oncology 24 35646684
2017 Strong association of SLC1A1 and DPF3 gene variants with idiopathic male infertility in Han Chinese. Asian journal of andrology 23 27232852
2016 Sm-Like Protein-Mediated RNA Metabolism Is Required for Heat Stress Tolerance in Arabidopsis. Frontiers in plant science 20 27493656
2003 Identification of differentially expressed genes like cofilin2 in growing collateral arteries. Biochemical and biophysical research communications 18 12507514
2012 Crystal structures of Lsm3, Lsm4 and Lsm5/6/7 from Schizosaccharomyces pombe. PloS one 15 22615807
2011 Structure of the LSm657 complex: an assembly intermediate of the LSm1-7 and LSm2-8 rings. Journal of molecular biology 15 22001694
2023 Identification of LSM family members as potential chemoresistance predictive and therapeutic biomarkers for gastric cancer. Frontiers in oncology 13 37007092
2018 Defining essential elements and genetic interactions of the yeast Lsm2-8 ring and demonstration that essentiality of Lsm2-8 is bypassed via overexpression of U6 snRNA or the U6 snRNP subunit Prp24. RNA (New York, N.Y.) 8 29615482
2023 A MACHINE LEARNING MODEL DERIVED FROM ANALYSIS OF TIME-COURSE GENE-EXPRESSION DATASETS REVEALS TEMPORALLY STABLE GENE MARKERS PREDICTIVE OF SEPSIS MORTALITY. Shock (Augusta, Ga.) 7 37752077
2022 CBX3 is associated with metastasis and glutathione/glycosphingolipid metabolism in colon adenocarcinoma. Journal of gastrointestinal oncology 7 35284119
2024 Sm-like 5 knockdown inhibits proliferation and promotes apoptosis of colon cancer cells by upregulating p53, CDKN1A and TNFRSF10B. World journal of gastrointestinal oncology 5 38994171
2024 Transcriptomics data integration and analysis to uncover hallmark genes in hypertrophic cardiomyopathy. American journal of translational research 4 38463581
2025 Integrated Single-cell RNA-seq and Bulk RNA-seq Identify Diagnostic Biomarkers for Postmenopausal Osteoporosis. Current medicinal chemistry 3 39364870
2024 Peripheral Blood CD8+ T-Lymphocyte Immune Response in Benign and Subpopulations of Breast Cancer Patients. International journal of molecular sciences 2 38928129
2025 Identification of RNA processing factor LSM5 as a new adverse biomarker in nasopharyngeal carcinoma. Scientific reports 1 40121338
2022 Effect of Different Irrigants on the Adhesive Interface and Influence on the Push Out Strength of Fiber Posts. Operative dentistry 1 36121721