{"gene":"LSM6","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2000,"finding":"LSM6 (Lsm6) protein directly interacts with the spinal muscular atrophy disease gene product SMN. This interaction was demonstrated by showing that SMN binds at least two U6-associated Sm-like proteins, Lsm4 and Lsm6, and that arginine- and glycine-rich domains are necessary and sufficient for SMN interaction.","method":"Co-immunoprecipitation / direct binding assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, single Co-IP/pulldown method showing direct interaction of Lsm6 with SMN","pmids":["10851237"],"is_preprint":false},{"year":2001,"finding":"Deletion of LSM6 in S. cerevisiae causes the La protein Lhp1p to become required for growth, indicating that the Lsm2-8 complex (including Lsm6) acts redundantly with Lhp1p to stabilize nascent U6 snRNA. This places Lsm6 within the Lsm2-8 ring functionally involved in U6 snRNA biogenesis.","method":"Genetic epistasis / deletion analysis (yeast)","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in yeast with defined phenotypic readout, consistent with complementary structural and biochemical data from other papers","pmids":["11333229"],"is_preprint":false},{"year":2008,"finding":"The homomeric Lsm3 octamer recruits Lsm6 (along with Lsm2 and Lsm5) directly from yeast lysate, identifying protein-protein interactions used in assembly of mixed Lsm ring scaffolds. The crystal structure of Lsm3 reveals that C-terminal tails engage in cross-ring beta-sheet interactions that facilitate recruitment of other Lsm subunits including Lsm6.","method":"Crystal structure (X-ray crystallography) + pulldown from yeast lysate","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — crystal structure plus pulldown from lysate, single lab, two complementary methods","pmids":["18329667"],"is_preprint":false},{"year":2011,"finding":"LSM5, LSM6, and LSM7 form an assembly intermediate (LSm657 hexameric ring) on the pathway toward the native LSm1-7 and LSm2-8 heptameric complexes. The LSm657 complex can incorporate LSm23 to assemble further. The crystal structure at 2.5 Å resolution shows LSm6 adopts the canonical Sm fold and the arrangement of proteins in the ring is consistent with their Sm counterparts (SmE, SmF, SmG).","method":"X-ray crystallography (2.5 Å) + NMR spectroscopy + pulldown experiments","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure, NMR confirmation in solution, and pulldown assembly assay all in one study; multiple orthogonal methods","pmids":["22001694"],"is_preprint":false},{"year":2012,"finding":"The crystal structure of the S. pombe Lsm5/6/7 sub-complex reveals that Lsm6 adopts a conserved Sm fold and participates in a hexameric arrangement with defined inter-subunit interactions establishing the organization order Lsm5–Lsm6–Lsm7. RNA binding assays show the Lsm5/6/7 sub-complex binds oligo(U) RNA.","method":"X-ray crystallography + analytical ultracentrifugation + RNA binding assay (EMSA)","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus RNA binding assay plus AUC, multiple orthogonal methods in one study confirming Lsm6 fold and complex organization","pmids":["22615807"],"is_preprint":false},{"year":2010,"finding":"Genetic interactions in S. cerevisiae show SUS1 deletion is synthetically lethal with LSM1 and PAT1, and has a strong genetic interaction with LSM6, placing Lsm6 functionally in the cytoplasmic P-body/mRNA decay pathway.","method":"Genetic interaction analysis (synthetic lethality / growth assay in yeast)","journal":"BMC cell biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — genetic interaction only, single lab, no direct biochemical characterization of Lsm6's mechanistic role in this context","pmids":["20230609"],"is_preprint":false},{"year":2025,"finding":"Within the Lsm2-8 ring, Lsm6 participates in subcomplex SC2 (Lsm6/5/7), and weakening the SC1-SC3 (Lsm2/3 – Lsm8/4) interaction along with mutations in RNA-binding regions of SC1 and SC2 converts the Lsm2-8 ring into a Sm-type ring. Conversely, strengthening SC1-SC3 interaction converts the Sm ring into an Lsm-type ring. This reveals the mechanistic basis distinguishing Sm-type (scaffold) and Lsm-type (chaperone) rings.","method":"Mutagenesis of ring subunit interfaces + biochemical reconstitution + functional conversion assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis combined with reconstitution establishing mechanistic interconversion; single lab but multiple orthogonal methods in one rigorous study","pmids":["40433979"],"is_preprint":false}],"current_model":"LSM6 encodes a conserved Sm-like protein that adopts a canonical Sm fold, assembles with LSM5 and LSM7 into a hexameric sub-complex (LSm657) as an intermediate on the way to the heptameric LSm1-7 (cytoplasmic, mRNA decay) and LSm2-8 (nuclear, U6 snRNA/splicing) rings; within the LSm2-8 ring it contributes to U6 snRNA stabilization and pre-mRNA splicing, and it directly interacts with the SMN protein via arginine/glycine-rich sequences, suggesting a role in snRNP assembly."},"narrative":{"mechanistic_narrative":"LSM6 encodes a conserved Sm-like protein that adopts the canonical Sm fold and functions as a building subunit of heptameric LSm rings governing U6 snRNA biogenesis, pre-mRNA splicing, and cytoplasmic mRNA decay [PMID:22001694, PMID:22615807]. It assembles with LSM5 and LSM7 into a defined hexameric sub-complex (LSm657, organized Lsm5–Lsm6–Lsm7) that serves as an assembly intermediate en route to the native LSm1-7 and LSm2-8 heptamers and that binds oligo(U) RNA [PMID:22001694, PMID:22615807]. Within the nuclear LSm2-8 ring, LSM6 contributes to stabilization of nascent U6 snRNA, acting redundantly with the La protein Lhp1p [PMID:11333229], while genetic interactions place it additionally in the cytoplasmic P-body/mRNA decay pathway [PMID:20230609]. As part of the SC2 (Lsm6/5/7) module of the ring, LSM6 participates in inter-subcomplex interfaces whose strength dictates whether a ring behaves as an Sm-type scaffold or an Lsm-type chaperone [PMID:40433979]. LSM6 also directly interacts with the spinal muscular atrophy protein SMN through arginine- and glycine-rich sequences, linking it to snRNP assembly [PMID:10851237].","teleology":[{"year":2000,"claim":"Established a physical link between LSM6 and the snRNP-assembly machinery by showing it is among the U6-associated Sm-like proteins bound directly by the SMN protein.","evidence":"Co-immunoprecipitation / direct binding assay mapping the SMN interaction to arginine/glycine-rich domains","pmids":["10851237"],"confidence":"Medium","gaps":["Single Co-IP/pulldown without reciprocal validation","Functional consequence of the SMN interaction for snRNP assembly not tested","Stoichiometry and ring context of the interaction unresolved"]},{"year":2001,"claim":"Placed LSM6 functionally within the Lsm2-8 ring by showing its deletion makes the La protein Lhp1p essential, defining a redundant pathway for stabilizing nascent U6 snRNA.","evidence":"Genetic epistasis / deletion analysis in S. cerevisiae","pmids":["11333229"],"confidence":"Medium","gaps":["Does not isolate LSM6's individual contribution from the rest of the ring","Mechanism of U6 stabilization at the molecular level not resolved","Yeast genetics; human relevance inferred"]},{"year":2010,"claim":"Extended LSM6's functional reach to the cytoplasmic mRNA decay pathway through genetic interaction with SUS1, LSM1, and PAT1.","evidence":"Genetic interaction / synthetic lethality assays in S. cerevisiae","pmids":["20230609"],"confidence":"Low","gaps":["Genetic interaction only, no direct biochemical role demonstrated","Cannot distinguish ring-level from subunit-level effects","No defined molecular activity assigned in this context"]},{"year":2008,"claim":"Identified the protein-protein contacts used to recruit LSM6 into mixed ring scaffolds, showing C-terminal tail beta-sheet interactions drive subunit assembly.","evidence":"Crystal structure of Lsm3 plus pulldown of Lsm6/2/5 from yeast lysate","pmids":["18329667"],"confidence":"Medium","gaps":["Recruitment shown via homomeric Lsm3 scaffold, not the native heteromeric ring","Order of subunit addition not fully defined","RNA-dependence of recruitment not addressed"]},{"year":2011,"claim":"Defined the LSm657 hexamer as a discrete assembly intermediate and confirmed LSM6 adopts the canonical Sm fold positioned analogously to its Sm counterparts.","evidence":"X-ray crystallography at 2.5 Å, NMR, and pulldown assembly assays","pmids":["22001694"],"confidence":"High","gaps":["RNA binding by the intermediate not characterized in this study","Path from LSm657 to full heptamers structurally inferred"]},{"year":2012,"claim":"Established the subunit order Lsm5–Lsm6–Lsm7 and demonstrated the sub-complex binds oligo(U) RNA, assigning an RNA-binding function to the LSM6-containing module.","evidence":"X-ray crystallography, analytical ultracentrifugation, and EMSA on the S. pombe Lsm5/6/7 sub-complex","pmids":["22615807"],"confidence":"High","gaps":["Contribution of LSM6 itself versus partners to RNA contact not dissected","Affinity/specificity for physiological U6 not quantified"]},{"year":2025,"claim":"Revealed the mechanistic determinant distinguishing Sm-type scaffold from Lsm-type chaperone rings, with LSM6 as part of the SC2 module whose interface strength controls ring identity.","evidence":"Mutagenesis of subunit interfaces, biochemical reconstitution, and functional ring-conversion assays","pmids":["40433979"],"confidence":"High","gaps":["In vivo relevance of engineered ring interconversion not established","LSM6's specific energetic contribution to the SC2 interface not isolated"]},{"year":null,"claim":"How LSM6's SMN interaction and its dual nuclear/cytoplasmic ring functions are coordinated during snRNP assembly and mRNA decay in human cells remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No human cellular assay connecting SMN binding to ring assembly","Regulation of LSm1-7 versus LSm2-8 partitioning unknown","LSM6-specific (vs ring-level) function not separated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[4]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[3,4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,5]}],"complexes":["LSm2-8","LSm1-7","LSm657 (Lsm5/6/7)"],"partners":["LSM5","LSM7","LSM3","LSM2","SMN1","LSM4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P62312","full_name":"U6 snRNA-associated Sm-like protein LSm6","aliases":[],"length_aa":80,"mass_kda":9.1,"function":"Plays a role in pre-mRNA splicing as component of the U4/U6-U5 tri-snRNP complex that is involved in spliceosome assembly, and as component of the precatalytic spliceosome (spliceosome B complex) (PubMed:28781166). The heptameric LSM2-8 complex binds specifically to the 3'-terminal U-tract of U6 snRNA (PubMed:10523320). Component of LSm protein complexes, which are involved in RNA processing and may function in a chaperone-like manner, facilitating the efficient association of RNA processing factors with their substrates. Component of the cytoplasmic LSM1-LSM7 complex, which is thought to be involved in mRNA degradation by activating the decapping step in the 5'-to-3' mRNA decay pathway (Probable)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/P62312/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/LSM6","classification":"Common Essential","n_dependent_lines":1141,"n_total_lines":1208,"dependency_fraction":0.9445364238410596},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"RBM42","stoichiometry":10.0},{"gene":"PRPF4B","stoichiometry":4.0},{"gene":"CLNS1A","stoichiometry":0.2},{"gene":"CLTA","stoichiometry":0.2},{"gene":"CLTB","stoichiometry":0.2},{"gene":"CPSF6","stoichiometry":0.2},{"gene":"RBM39","stoichiometry":0.2},{"gene":"SF3A1","stoichiometry":0.2},{"gene":"SNRPA","stoichiometry":0.2},{"gene":"SNRPB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/LSM6","total_profiled":1310},"omim":[{"mim_id":"607288","title":"LSM8 PROTEIN; LSM8","url":"https://www.omim.org/entry/607288"},{"mim_id":"607287","title":"LSM7 PROTEIN; LSM7","url":"https://www.omim.org/entry/607287"},{"mim_id":"607286","title":"LSM6 PROTEIN; LSM6","url":"https://www.omim.org/entry/607286"},{"mim_id":"607285","title":"LSM5 PROTEIN; LSM5","url":"https://www.omim.org/entry/607285"},{"mim_id":"607284","title":"LSM4 PROTEIN; LSM4","url":"https://www.omim.org/entry/607284"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Actin filaments","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LSM6"},"hgnc":{"alias_symbol":["YDR378C"],"prev_symbol":[]},"alphafold":{"accession":"P62312","domains":[{"cath_id":"2.30.30.100","chopping":"7-74","consensus_level":"high","plddt":96.4978,"start":7,"end":74}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P62312","model_url":"https://alphafold.ebi.ac.uk/files/AF-P62312-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P62312-F1-predicted_aligned_error_v6.png","plddt_mean":91.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LSM6","jax_strain_url":"https://www.jax.org/strain/search?query=LSM6"},"sequence":{"accession":"P62312","fasta_url":"https://rest.uniprot.org/uniprotkb/P62312.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P62312/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P62312"}},"corpus_meta":[{"pmid":"10851237","id":"PMC_10851237","title":"Specific sequences of the Sm and Sm-like (Lsm) proteins mediate their interaction with the spinal muscular atrophy disease gene product (SMN).","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10851237","citation_count":115,"is_preprint":false},{"pmid":"11333229","id":"PMC_11333229","title":"Multiple functional interactions between components of the Lsm2-Lsm8 complex, U6 snRNA, and the yeast La protein.","date":"2001","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11333229","citation_count":65,"is_preprint":false},{"pmid":"18329667","id":"PMC_18329667","title":"Crystal structure of Lsm3 octamer from Saccharomyces cerevisiae: implications for Lsm ring organisation and recruitment.","date":"2008","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18329667","citation_count":25,"is_preprint":false},{"pmid":"25818835","id":"PMC_25818835","title":"An in vivo screen to identify candidate neurogenic genes in the developing Xenopus visual system.","date":"2015","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/25818835","citation_count":18,"is_preprint":false},{"pmid":"22001694","id":"PMC_22001694","title":"Structure of the LSm657 complex: an assembly intermediate of the LSm1-7 and LSm2-8 rings.","date":"2011","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/22001694","citation_count":15,"is_preprint":false},{"pmid":"22615807","id":"PMC_22615807","title":"Crystal structures of Lsm3, Lsm4 and Lsm5/6/7 from Schizosaccharomyces pombe.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22615807","citation_count":15,"is_preprint":false},{"pmid":"20230609","id":"PMC_20230609","title":"A novel link between Sus1 and the cytoplasmic mRNA decay machinery suggests a broad role in mRNA metabolism.","date":"2010","source":"BMC cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/20230609","citation_count":14,"is_preprint":false},{"pmid":"34647356","id":"PMC_34647356","title":"Global 3'-untranslated region landscape mediated by alternative polyadenylation during meiotic maturation of pig oocytes.","date":"2021","source":"Reproduction in domestic animals = Zuchthygiene","url":"https://pubmed.ncbi.nlm.nih.gov/34647356","citation_count":8,"is_preprint":false},{"pmid":"39510315","id":"PMC_39510315","title":"Identification of Risk Genes for Attention-Deficit/Hyperactivity Disorder During Early Human Brain Development.","date":"2024","source":"Journal of the American Academy of Child and Adolescent Psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/39510315","citation_count":4,"is_preprint":false},{"pmid":"33541709","id":"PMC_33541709","title":"Identification of Biomarkers Related to Atrial Fibrillation With Mitral Regurgitation.","date":"2020","source":"The American journal of the medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33541709","citation_count":4,"is_preprint":false},{"pmid":"23021959","id":"PMC_23021959","title":"Sm-like protein enhanced tolerance of recombinant Saccharomyces cerevisiae to inhibitors in hemicellulosic hydrolysate.","date":"2012","source":"Bioresource technology","url":"https://pubmed.ncbi.nlm.nih.gov/23021959","citation_count":3,"is_preprint":false},{"pmid":"18042180","id":"PMC_18042180","title":"Hypergonadotropic hypogonadism in a patient with inv ins (2;4).","date":"2007","source":"International journal of andrology","url":"https://pubmed.ncbi.nlm.nih.gov/18042180","citation_count":3,"is_preprint":false},{"pmid":"29855268","id":"PMC_29855268","title":"Reconstruction of an SSR-based Magnaporthe oryzae physical map to locate avirulence gene AvrPi12.","date":"2018","source":"BMC microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/29855268","citation_count":3,"is_preprint":false},{"pmid":"38954053","id":"PMC_38954053","title":"Proteome-wide association studies have predicted that the protein abundance of LSM6, GMPPB, ICA1L, and CISD2 is associated with attention-deficit/hyperactivity disorder.","date":"2024","source":"European child & adolescent psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/38954053","citation_count":2,"is_preprint":false},{"pmid":"40433979","id":"PMC_40433979","title":"Interconversion and mechanisms between Lsm-type and Sm-type heteroheptameric rings: implications for spliceosome evolution and RNA metabolism.","date":"2025","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/40433979","citation_count":1,"is_preprint":false},{"pmid":"40739630","id":"PMC_40739630","title":"Integrative multi-omics data from early development to identify the genes and cell types underlying attention-deficit/hyperactivity disorder.","date":"2025","source":"BMC psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/40739630","citation_count":1,"is_preprint":false},{"pmid":"41260362","id":"PMC_41260362","title":"Proteome-wide multi-trait association analyses prioritize candidate proteins and therapeutic targets for psychiatric disorders.","date":"2025","source":"Journal of affective disorders","url":"https://pubmed.ncbi.nlm.nih.gov/41260362","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10491,"output_tokens":1829,"usd":0.029454,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8694,"output_tokens":2568,"usd":0.053835,"stage2_stop_reason":"end_turn"},"total_usd":0.083289,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"LSM6 (Lsm6) protein directly interacts with the spinal muscular atrophy disease gene product SMN. This interaction was demonstrated by showing that SMN binds at least two U6-associated Sm-like proteins, Lsm4 and Lsm6, and that arginine- and glycine-rich domains are necessary and sufficient for SMN interaction.\",\n      \"method\": \"Co-immunoprecipitation / direct binding assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, single Co-IP/pulldown method showing direct interaction of Lsm6 with SMN\",\n      \"pmids\": [\"10851237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Deletion of LSM6 in S. cerevisiae causes the La protein Lhp1p to become required for growth, indicating that the Lsm2-8 complex (including Lsm6) acts redundantly with Lhp1p to stabilize nascent U6 snRNA. This places Lsm6 within the Lsm2-8 ring functionally involved in U6 snRNA biogenesis.\",\n      \"method\": \"Genetic epistasis / deletion analysis (yeast)\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in yeast with defined phenotypic readout, consistent with complementary structural and biochemical data from other papers\",\n      \"pmids\": [\"11333229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The homomeric Lsm3 octamer recruits Lsm6 (along with Lsm2 and Lsm5) directly from yeast lysate, identifying protein-protein interactions used in assembly of mixed Lsm ring scaffolds. The crystal structure of Lsm3 reveals that C-terminal tails engage in cross-ring beta-sheet interactions that facilitate recruitment of other Lsm subunits including Lsm6.\",\n      \"method\": \"Crystal structure (X-ray crystallography) + pulldown from yeast lysate\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — crystal structure plus pulldown from lysate, single lab, two complementary methods\",\n      \"pmids\": [\"18329667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"LSM5, LSM6, and LSM7 form an assembly intermediate (LSm657 hexameric ring) on the pathway toward the native LSm1-7 and LSm2-8 heptameric complexes. The LSm657 complex can incorporate LSm23 to assemble further. The crystal structure at 2.5 Å resolution shows LSm6 adopts the canonical Sm fold and the arrangement of proteins in the ring is consistent with their Sm counterparts (SmE, SmF, SmG).\",\n      \"method\": \"X-ray crystallography (2.5 Å) + NMR spectroscopy + pulldown experiments\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure, NMR confirmation in solution, and pulldown assembly assay all in one study; multiple orthogonal methods\",\n      \"pmids\": [\"22001694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The crystal structure of the S. pombe Lsm5/6/7 sub-complex reveals that Lsm6 adopts a conserved Sm fold and participates in a hexameric arrangement with defined inter-subunit interactions establishing the organization order Lsm5–Lsm6–Lsm7. RNA binding assays show the Lsm5/6/7 sub-complex binds oligo(U) RNA.\",\n      \"method\": \"X-ray crystallography + analytical ultracentrifugation + RNA binding assay (EMSA)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus RNA binding assay plus AUC, multiple orthogonal methods in one study confirming Lsm6 fold and complex organization\",\n      \"pmids\": [\"22615807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Genetic interactions in S. cerevisiae show SUS1 deletion is synthetically lethal with LSM1 and PAT1, and has a strong genetic interaction with LSM6, placing Lsm6 functionally in the cytoplasmic P-body/mRNA decay pathway.\",\n      \"method\": \"Genetic interaction analysis (synthetic lethality / growth assay in yeast)\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — genetic interaction only, single lab, no direct biochemical characterization of Lsm6's mechanistic role in this context\",\n      \"pmids\": [\"20230609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Within the Lsm2-8 ring, Lsm6 participates in subcomplex SC2 (Lsm6/5/7), and weakening the SC1-SC3 (Lsm2/3 – Lsm8/4) interaction along with mutations in RNA-binding regions of SC1 and SC2 converts the Lsm2-8 ring into a Sm-type ring. Conversely, strengthening SC1-SC3 interaction converts the Sm ring into an Lsm-type ring. This reveals the mechanistic basis distinguishing Sm-type (scaffold) and Lsm-type (chaperone) rings.\",\n      \"method\": \"Mutagenesis of ring subunit interfaces + biochemical reconstitution + functional conversion assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis combined with reconstitution establishing mechanistic interconversion; single lab but multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"40433979\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LSM6 encodes a conserved Sm-like protein that adopts a canonical Sm fold, assembles with LSM5 and LSM7 into a hexameric sub-complex (LSm657) as an intermediate on the way to the heptameric LSm1-7 (cytoplasmic, mRNA decay) and LSm2-8 (nuclear, U6 snRNA/splicing) rings; within the LSm2-8 ring it contributes to U6 snRNA stabilization and pre-mRNA splicing, and it directly interacts with the SMN protein via arginine/glycine-rich sequences, suggesting a role in snRNP assembly.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LSM6 encodes a conserved Sm-like protein that adopts the canonical Sm fold and functions as a building subunit of heptameric LSm rings governing U6 snRNA biogenesis, pre-mRNA splicing, and cytoplasmic mRNA decay [#3, #4]. It assembles with LSM5 and LSM7 into a defined hexameric sub-complex (LSm657, organized Lsm5–Lsm6–Lsm7) that serves as an assembly intermediate en route to the native LSm1-7 and LSm2-8 heptamers and that binds oligo(U) RNA [#3, #4]. Within the nuclear LSm2-8 ring, LSM6 contributes to stabilization of nascent U6 snRNA, acting redundantly with the La protein Lhp1p [#1], while genetic interactions place it additionally in the cytoplasmic P-body/mRNA decay pathway [#5]. As part of the SC2 (Lsm6/5/7) module of the ring, LSM6 participates in inter-subcomplex interfaces whose strength dictates whether a ring behaves as an Sm-type scaffold or an Lsm-type chaperone [#6]. LSM6 also directly interacts with the spinal muscular atrophy protein SMN through arginine- and glycine-rich sequences, linking it to snRNP assembly [#0].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established a physical link between LSM6 and the snRNP-assembly machinery by showing it is among the U6-associated Sm-like proteins bound directly by the SMN protein.\",\n      \"evidence\": \"Co-immunoprecipitation / direct binding assay mapping the SMN interaction to arginine/glycine-rich domains\",\n      \"pmids\": [\"10851237\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP/pulldown without reciprocal validation\", \"Functional consequence of the SMN interaction for snRNP assembly not tested\", \"Stoichiometry and ring context of the interaction unresolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Placed LSM6 functionally within the Lsm2-8 ring by showing its deletion makes the La protein Lhp1p essential, defining a redundant pathway for stabilizing nascent U6 snRNA.\",\n      \"evidence\": \"Genetic epistasis / deletion analysis in S. cerevisiae\",\n      \"pmids\": [\"11333229\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not isolate LSM6's individual contribution from the rest of the ring\", \"Mechanism of U6 stabilization at the molecular level not resolved\", \"Yeast genetics; human relevance inferred\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended LSM6's functional reach to the cytoplasmic mRNA decay pathway through genetic interaction with SUS1, LSM1, and PAT1.\",\n      \"evidence\": \"Genetic interaction / synthetic lethality assays in S. cerevisiae\",\n      \"pmids\": [\"20230609\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Genetic interaction only, no direct biochemical role demonstrated\", \"Cannot distinguish ring-level from subunit-level effects\", \"No defined molecular activity assigned in this context\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified the protein-protein contacts used to recruit LSM6 into mixed ring scaffolds, showing C-terminal tail beta-sheet interactions drive subunit assembly.\",\n      \"evidence\": \"Crystal structure of Lsm3 plus pulldown of Lsm6/2/5 from yeast lysate\",\n      \"pmids\": [\"18329667\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Recruitment shown via homomeric Lsm3 scaffold, not the native heteromeric ring\", \"Order of subunit addition not fully defined\", \"RNA-dependence of recruitment not addressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined the LSm657 hexamer as a discrete assembly intermediate and confirmed LSM6 adopts the canonical Sm fold positioned analogously to its Sm counterparts.\",\n      \"evidence\": \"X-ray crystallography at 2.5 Å, NMR, and pulldown assembly assays\",\n      \"pmids\": [\"22001694\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RNA binding by the intermediate not characterized in this study\", \"Path from LSm657 to full heptamers structurally inferred\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established the subunit order Lsm5–Lsm6–Lsm7 and demonstrated the sub-complex binds oligo(U) RNA, assigning an RNA-binding function to the LSM6-containing module.\",\n      \"evidence\": \"X-ray crystallography, analytical ultracentrifugation, and EMSA on the S. pombe Lsm5/6/7 sub-complex\",\n      \"pmids\": [\"22615807\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Contribution of LSM6 itself versus partners to RNA contact not dissected\", \"Affinity/specificity for physiological U6 not quantified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed the mechanistic determinant distinguishing Sm-type scaffold from Lsm-type chaperone rings, with LSM6 as part of the SC2 module whose interface strength controls ring identity.\",\n      \"evidence\": \"Mutagenesis of subunit interfaces, biochemical reconstitution, and functional ring-conversion assays\",\n      \"pmids\": [\"40433979\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of engineered ring interconversion not established\", \"LSM6's specific energetic contribution to the SC2 interface not isolated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LSM6's SMN interaction and its dual nuclear/cytoplasmic ring functions are coordinated during snRNP assembly and mRNA decay in human cells remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No human cellular assay connecting SMN binding to ring assembly\", \"Regulation of LSm1-7 versus LSm2-8 partitioning unknown\", \"LSM6-specific (vs ring-level) function not separated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 5]}\n    ],\n    \"complexes\": [\"LSm2-8\", \"LSm1-7\", \"LSm657 (Lsm5/6/7)\"],\n    \"partners\": [\"LSM5\", \"LSM7\", \"LSM3\", \"LSM2\", \"SMN1\", \"LSM4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}