Affinage

LSM3

U6 snRNA-associated Sm-like protein LSm3 · UniProt P62310

Round 2 corrected
Length
102 aa
Mass
11.8 kDa
Annotated
2026-04-28
53 papers in source corpus 13 papers cited in narrative 13 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LSM3 is a core subunit of two distinct heptameric Sm-like (LSm) ring complexes that govern RNA metabolism: the nuclear Lsm2–8 complex, which binds and stabilizes U6 snRNA to support pre-mRNA splicing, and the cytoplasmic Lsm1–7 complex, which promotes mRNA decapping and 5′-to-3′ degradation in P-bodies. Within the Lsm2–8 ring, Lsm3 residues His36 and Arg69 directly sandwich the 3′-terminal uridine of U6 snRNA through π–π and cation–π interactions, and the Lsm3-R69A mutation is the only lethal single-residue change among Lsm2–8 RNA-contact residues, with lethality suppressible by U6 snRNA overexpression (PMID:24240276, PMID:29615482). In the cytoplasmic Lsm1–7 complex, Lsm3 together with Lsm2 bridges the interaction with the Pat1 decapping activator to stimulate mRNA decapping, and integrity of the Lsm1–7 ring is required for localization to P-bodies where decapping enzymes and the 5′-to-3′ exonuclease Xrn1 reside (PMID:24139796, PMID:24247251, PMID:12515382). Knockdown of LSM3 in human cells lengthens the circadian period, linking its splicing function to clock gene regulation (PMID:25288739).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2002 High

    Establishing where cytoplasmic LSm proteins act: demonstration that LSm1–7 (including LSm3) localizes to discrete P-body foci with decapping factors hDcp1/2 and Xrn1, and that ring integrity is required for this enrichment, defined the cellular compartment for LSm3's mRNA-decay function.

    Evidence Immunofluorescence, FRET, and co-expression of WT/mutant LSm proteins in human cells

    PMID:12515382

    Open questions at the time
    • Direct contribution of LSm3 versus other ring subunits to P-body targeting not dissected
    • Mechanism by which ring integrity controls localization unknown
  2. 2002 Medium

    Confirming LSm3 as a spliceosome component: identification of LSm proteins in affinity-purified native human C-complex spliceosomes placed LSm3 within an active catalytic spliceosome, linking it to U6-dependent splicing catalysis.

    Evidence Affinity purification of native spliceosomes, tandem MS, electron microscopy

    PMID:11991638

    Open questions at the time
    • Stoichiometry of LSm3 within the C complex not determined
    • Whether LSm3 contacts U6 snRNA within the assembled spliceosome was unresolved
  3. 2008 High

    Revealing LSm3's self-assembly properties and partner recruitment: the crystal structure of yeast Lsm3 showed it can form an octameric ring on its own and recruit Lsm6, Lsm2, and Lsm5 from lysate, suggesting Lsm3 nucleates ring assembly.

    Evidence X-ray crystallography and pulldown from yeast lysate

    PMID:18329667

    Open questions at the time
    • Whether the octameric Lsm3 ring is physiologically relevant or a crystallographic artifact
    • Kinetic order of subunit incorporation in vivo not established
  4. 2008 Medium

    Linking LSm3 to developmental mRNA decay: in C. elegans embryos, LSM-3 recruitment to P-bodies in somatic blastomeres requires LSM-1 and the CCR4-NOT subunit LET-711/Not1, tying LSm3-dependent decay to the onset of maternal mRNA degradation.

    Evidence Live imaging, fluorescent reporters, RNAi knockdown in C. elegans embryos

    PMID:18692039

    Open questions at the time
    • Which maternal mRNAs are direct LSM-3 targets is unknown
    • Whether the CCR4-NOT requirement is direct or indirect not resolved
  5. 2012 High

    Demonstrating ring-context dependence for RNA binding: S. pombe Lsm3 forms a heptamer on its own but cannot bind oligo(U) RNA; only the Lsm2/3 heterodimer binds RNA, establishing that RNA recognition requires heteromeric ring context.

    Evidence X-ray crystallography, analytical ultracentrifugation, RNA binding assays

    PMID:22615807

    Open questions at the time
    • Minimal heteromeric complex sufficient for full RNA affinity not defined
    • Whether isolated Lsm2/3 recapitulates sequence specificity of the full ring unknown
  6. 2013 High

    Atomic-resolution view of U6 snRNA end-recognition: the Lsm2–8–U6 crystal structure showed Lsm3 His36 and Arg69 sandwich the terminal uracil via π–π and cation–π stacking, revealing the molecular basis of Lsm3's unique role in U6 3′-end recognition.

    Evidence X-ray crystallography at 2.8 Å with mutagenesis and biochemical validation

    PMID:24240276

    Open questions at the time
    • How conformational changes upon U6 binding alter the ring for downstream snRNP assembly unknown
    • Whether the same contacts are maintained in the context of the full U6 snRNP or tri-snRNP not shown
  7. 2013 High

    Defining Lsm3's role as the Pat1 bridge in mRNA decapping: crystal structures of Lsm1–7 and the Lsm2–3–Pat1C ternary complex showed Lsm2 and Lsm3 (not Lsm1) mediate Pat1 recruitment, and structure-based mutations at these interfaces impaired decapping activation in vivo.

    Evidence X-ray crystallography (2.3 Å and 3.7 Å), in vitro decapping assays, in vivo mutagenesis

    PMID:24139796 PMID:24247251

    Open questions at the time
    • Contribution of other Pat1 domains to full decapping complex assembly not assessed
    • Whether Lsm3–Pat1 interaction is regulated in response to cellular signals unknown
  8. 2015 Medium

    Extending LSm3 function to organismal physiology: C. elegans lsm-3 is required for normal development, stress-induced granule formation, and pathogen resistance regulated by the Insulin/IGF-1 signaling pathway.

    Evidence RNAi, genetic mutants, RNA-seq, DAF-16::GFP reporter in C. elegans

    PMID:26150554

    Open questions at the time
    • Whether effects are through the Lsm1–7 decay pathway, the Lsm2–8 splicing pathway, or both is unresolved
    • Direct mRNA targets mediating these phenotypes not identified
  9. 2018 High

    Proving U6 snRNA stabilization is the essential function of Lsm3: Lsm3-R69A is the sole lethal point mutation among Lsm2–8 ring RNA-contact residues, and lethality of LSM3 deletion is rescued by U6 snRNA overexpression, formally establishing U6 stabilization as the essential role.

    Evidence Alanine scanning mutagenesis, yeast growth assays, high-copy U6 suppressor analysis

    PMID:29615482

    Open questions at the time
    • Whether U6 overexpression rescues all splicing defects or only viability not tested
    • Contribution of Lsm3 to Lsm1–7-dependent decapping essentiality not separable in this assay
  10. 2024 Medium

    Revealing a chromatin-level role: ChIP-seq identified Lsm3 co-occupying 86 genes with Mediator subunits, predominantly at intron-containing ribosomal protein genes, where growth-phase-dependent Mediator repositioning to Lsm3-binding sites correlates with reduced mRNA and splicing, suggesting Lsm3 coordinates transcription and splicing of growth-regulated genes.

    Evidence ChIP-seq and RNA-seq in S. cerevisiae

    PMID:38613396

    Open questions at the time
    • Whether Lsm3 chromatin association is through the Lsm2–8 ring or independently is unknown
    • Causal directionality (Lsm3 recruits Mediator vs. Mediator recruits Lsm3) not established
    • Mechanism linking chromatin co-occupancy to splicing regulation not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open question: how Lsm3's dual roles in nuclear U6 stabilization and cytoplasmic mRNA decapping are partitioned, whether Lsm3 has regulatory functions on chromatin independent of the Lsm2–8 ring, and what controls the balance between the two complexes remain unresolved.
  • No structural data for Lsm3 within the intact human spliceosome at atomic resolution
  • Regulatory mechanisms controlling Lsm3 partitioning between nuclear and cytoplasmic complexes unknown
  • Direct mRNA targets of Lsm1–7/Pat1 in human cells not systematically identified

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 3 GO:0005829 cytosol 2
Pathway
R-HSA-8953854 Metabolism of RNA 5 R-HSA-74160 Gene expression (Transcription) 2
Partners
LSM1LSM2LSM4LSM5LSM6LSM7LSM8PAT1
Complex memberships
Lsm1-7 (cytoplasmic mRNA decay)Lsm1-7-Pat1 (decapping activator complex)Lsm2-8 (U6 snRNP-associated)

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 Crystal structure of the heptameric Lsm2-8 complex bound to the 3' end of U6 snRNA revealed that Lsm3 occupies a defined position in the ring (order: Lsm3-2-8-4-7-5-6) and that Lsm3 residues His36 and Arg69 sandwich the 3'-terminal uracil base via π-π and cation-π interactions, respectively, providing the distinctive end-recognition of U6 snRNA. X-ray crystallography at 2.8 Å resolution with associated biochemical analyses Nature High 24240276
2013 Crystal structure of yeast Lsm1-7 at 2.3 Å resolution showed a heptameric ring with topology Lsm1-2-3-6-5-7-4; Pat1 recognition by the Lsm1-7 complex is mediated not by the unique Lsm1 subunit but by Lsm2 and Lsm3. X-ray crystallography (2.3 Å and 3.7 Å resolution structures), structural analysis Cell reports High 24139796
2013 Lsm2 and Lsm3 bridge the interaction between the C-terminal domain of Pat1 (Pat1C) and the Lsm1-7 complex; the Lsm2-3-Pat1C complex and the Lsm1-7-Pat1C complex stimulate mRNA decapping in vitro to a similar extent. Crystal structure of the Lsm2-3-Pat1C ternary complex revealed an asymmetric assembly with three Pat1C molecules surrounding a heptameric ring formed by Lsm2-3; structure-based mutagenesis of Lsm2-3-Pat1C interfaces impaired decapping activation in vivo. Crystal structure, in vitro decapping assay, RNA-binding assay, structure-based mutagenesis, in vivo functional analysis Cell research High 24247251
2008 Crystal structure of yeast Lsm3 revealed an octameric ring (8 subunits rather than 7), and the homomeric Lsm3 octamer recruits Lsm6, Lsm2, and Lsm5 directly from yeast lysate; C-terminal tails of Lsm3 engage in inter-ring β-sheet interactions with elongated loops of neighbouring subunits, suggesting a mechanism for Lsm3-mediated recruitment of RNA processing factors. X-ray crystallography, pulldown from yeast lysate Journal of molecular biology High 18329667
2012 Crystal structures of S. pombe Lsm3, Lsm4, and Lsm5/6/7 showed that Lsm3 forms a heptamer in solution; RNA binding assays demonstrated that Lsm2/3 binds oligo(U) RNA whereas Lsm3 alone does not, indicating that the ring context is required for RNA recognition. X-ray crystallography, analytical ultracentrifugation, RNA binding assays PloS one High 22615807
2018 Structure-guided alanine scanning of the S. cerevisiae Lsm2-8 ring identified Lsm3-R69A as the single lethal point mutation within RNA-binding/intersubunit interface residues of Lsm2, Lsm3, Lsm4, Lsm5, and Lsm8; lethal deletion of LSM3 (lsm3Δ) was rescued by overexpression of U6 snRNA, indicating that the essential function of Lsm3 within the Lsm2-8 ring is to stabilize/associate with U6 snRNA. Alanine scanning mutagenesis, yeast growth assays, high-copy suppressor (U6 snRNA overexpression), genetic epistasis RNA High 29615482
2002 Human LSm1-7 proteins (including LSm3) co-localize in discrete cytoplasmic foci with the mRNA-decapping enzymes hDcp1/2 and the 5'-to-3' exonuclease hXrn1 (P-bodies); FRET studies and co-expression of wild-type and mutant LSm proteins demonstrated that formation of the hLSm1-7 complex is required for enrichment in these cytoplasmic foci, whereas hLSm8 is excluded. Subcellular localization (immunofluorescence), FRET, co-expression of wild-type and mutant proteins RNA High 12515382
2002 LSm proteins (Sm and Lsm core proteins including LSm3) are components of affinity-purified native human spliceosomal C complexes containing U2, U5, and U6 snRNAs, confirming their presence in the assembled spliceosome. Affinity purification of native spliceosomes, tandem mass spectrometry, electron microscopy RNA Medium 11991638
2008 In C. elegans embryos, LSM-3 is recruited to P-bodies in somatic blastomeres in an LSM-1-dependent manner; this recruitment requires the LET-711/Not1 subunit of the CCR4-NOT deadenylase complex and correlates with the onset of maternal mRNA degradation. In germline blastomeres, P-bodies are maintained without LSM-1 and LSM-3. Live imaging, fluorescent reporter localization, RNAi knockdown, genetic analysis Developmental biology Medium 18692039
2015 In C. elegans, lsm-3 (along with lsm-1) is required for normal development, reproduction, and motility; lsm-1 and lsm-3 are needed for stress-induced aggregation of cytoplasmic LSm proteins into granules and for processes regulated by the Insulin/IGF-1 signaling pathway (aging, pathogen resistance), with lsm-1 mutant RNA-seq analysis implicating impaired DAF-16/FOXO nuclear translocation. RNAi knockdown, genetic mutants, RNA-seq, DAF-16::GFP reporter, phenotypic analysis RNA Medium 26150554
2014 Down-regulation of LSM3 (as well as LSM5 and LSM7) expression in human cells lengthens the circadian period, placing LSM3 as a component of the spliceosomal machinery that contributes to circadian rhythm regulation, likely through effects on alternative splicing of clock gene transcripts. siRNA knockdown in human cells, circadian period measurement Proceedings of the National Academy of Sciences of the United States of America Medium 25288739
2024 ChIP-seq in S. cerevisiae identified 86 genes co-occupied by Lsm3 and Mediator subunits (Med1/Med15), predominantly intron-containing ribosomal protein genes; during late exponential growth, Mediator transitions from promoters to 3'-exon positions overlapping Lsm3 binding sites ~250 bp downstream of the last intron-exon boundary, and this transition correlates with reduced mRNA levels and splicing ratios, indicating Lsm3 and Mediator cooperate to control growth-regulated transcription and splicing of ribosomal protein genes. ChIP-seq, RNA-seq, chromatin immunoprecipitation Nucleic acids research Medium 38613396
2010 In Leishmania tarentolae, Lsm3-associated complexes purified to homogeneity by affinity purification and analyzed by mass spectrometry contained 39 proteins; notably, no mRNA degradation factors were detected in the Lsm3 complex, in contrast to Lsm complexes from other eukaryotes, suggesting divergence in the cytoplasmic Lsm3 complex composition in trypanosomatids. Affinity purification to homogeneity, mass spectrometry Journal of biological chemistry Medium 20592024

Source papers

Stage 0 corpus · 53 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Towards a proteome-scale map of the human protein-protein interaction network. Nature 2090 16189514
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
2016 ATPase-Modulated Stress Granules Contain a Diverse Proteome and Substructure. Cell 1233 26777405
2008 Identification of host proteins required for HIV infection through a functional genomic screen. Science (New York, N.Y.) 1165 18187620
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
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2012 The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. Molecular cell 973 22681889
2020 A reference map of the human binary protein interactome. Nature 849 32296183
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
2008 An empirical framework for binary interactome mapping. Nature methods 652 19060904
2018 High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. Molecular cell 580 29395067
2020 Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms. Science (New York, N.Y.) 564 33060197
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
2016 Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing. Cell 423 26871637
2013 The intracellular interactome of tetraspanin-enriched microdomains reveals their function as sorting machineries toward exosomes. The Journal of biological chemistry 413 23463506
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
2018 DNA Repair Network Analysis Reveals Shieldin as a Key Regulator of NHEJ and PARP Inhibitor Sensitivity. Cell 379 29656893
2007 Systematic analysis of the protein interaction network for the human transcription machinery reveals the identity of the 7SK capping enzyme. Molecular cell 367 17643375
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
2002 Purification and characterization of native spliceosomes suitable for three-dimensional structural analysis. RNA (New York, N.Y.) 301 11991638
2008 Processing bodies and germ granules are distinct RNA granules that interact in C. elegans embryos. Developmental biology 121 18692039
2012 LSM proteins provide accurate splicing and decay of selected transcripts to ensure normal Arabidopsis development. The Plant cell 94 23221597
2013 Crystal structures of the Lsm complex bound to the 3' end sequence of U6 small nuclear RNA. Nature 83 24240276
2013 Architecture of the Lsm1-7-Pat1 complex: a conserved assembly in eukaryotic mRNA turnover. Cell reports 65 24139796
2020 The Predicted Key Molecules, Functions, and Pathways That Bridge Mild Cognitive Impairment (MCI) and Alzheimer's Disease (AD). Frontiers in neurology 62 32308643
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
2010 Analysis of spliceosomal proteins in Trypanosomatids reveals novel functions in mRNA processing. The Journal of biological chemistry 38 20592024
2013 Lsm2 and Lsm3 bridge the interaction of the Lsm1-7 complex with Pat1 for decapping activation. Cell research 35 24247251
2008 Crystal structure of Lsm3 octamer from Saccharomyces cerevisiae: implications for Lsm ring organisation and recruitment. Journal of molecular biology 25 18329667
2021 Immune-Omics Networks of CD27, PD1, and PDL1 in Non-Small Cell Lung Cancer. Cancers 17 34503105
2017 Next-generation sequencing reveals lymph node metastasis associated genetic markers in colorectal cancer. Experimental and therapeutic medicine 15 28672935
2015 Cytoplasmic LSM-1 protein regulates stress responses through the insulin/IGF-1 signaling pathway in Caenorhabditis elegans. RNA (New York, N.Y.) 15 26150554
2012 Crystal structures of Lsm3, Lsm4 and Lsm5/6/7 from Schizosaccharomyces pombe. PloS one 15 22615807
2021 Characterization and comparative genomic analysis of gamma-aminobutyric acid (GABA)-producing lactic acid bacteria from Thai fermented foods. Biotechnology letters 12 33999363
2025 Unsupervised Classification of the Host Response Identifies Dominant Pathobiological Signatures of Sepsis in Sub-Saharan Africa. American journal of respiratory and critical care medicine 9 39514831
2021 Mechanical stretching of cells and lipid nanoparticles for nucleic acid delivery. Journal of controlled release : official journal of the Controlled Release Society 9 34563590
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
2010 Antigen-subtracted 2-DE/MS strategy, a novel proteomic analysis platform. Archives of toxicology 4 20407759
2025 Interfacial properties and stability of Pickering emulsion stabilized by silkworm pupa protein and preparation of emulsion-filled hydrogel with high hardness: Effect of sodium alginate and ultrasonication. International journal of biological macromolecules 2 40446995
2024 Growth-regulated co-occupancy of Mediator and Lsm3 at intronic ribosomal protein genes. Nucleic acids research 2 38613396
2024 Peripheral Blood CD8+ T-Lymphocyte Immune Response in Benign and Subpopulations of Breast Cancer Patients. International journal of molecular sciences 2 38928129
2020 Species and tissue specific analysis based on quantitative proteomics from allotetraploid and the parents. Journal of proteomics 2 33309926
2025 Continuous Engineering of Phenylalanine Ammonia Lyase from Lettuce (Lactuca sativa L.) for Efficient Synthesis of 3,4-Substituted Phenylalanine. Journal of agricultural and food chemistry 1 40254840