{"gene":"SRP9","run_date":"2026-06-10T07:46:41","timeline":{"discoveries":[{"year":1994,"finding":"SRP9 and SRP14 form a heterodimer that binds SRP RNA and is required for elongation arrest activity; fusion single-chain polypeptides containing both sequences retain RNA binding and elongation arrest activity, demonstrating that the normal N- and C-termini are dispensable for folding, RNA-binding, and biological activities.","method":"In vitro reconstitution with fusion proteins, SRP RNA binding assay, elongation arrest and translocation cell-free assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution and functional assays in a single rigorous study with multiple orthogonal readouts","pmids":["7518078"],"is_preprint":false},{"year":1995,"finding":"Human SRP9, together with SRP14, forms the Alu RNA-binding protein (RBP) activity; the SRP9/14 heterodimer binds the Alu region of 7SL RNA, scAlu RNA, and scB1 RNA with Kd values of ~203 pM, ~318 pM, and ~1.8 nM respectively; the primate-specific C-terminal tail of SRP14 does not appreciably affect scAlu RNA binding.","method":"Purification of SRP9/14 from HeLa cells, quantitative equilibrium binding assays (Kd determination)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — quantitative in vitro binding assay with purified protein, replicated across multiple RNA substrates","pmids":["7730321"],"is_preprint":false},{"year":1995,"finding":"SRP9/14 is present in >20-fold excess over SRP in primate cells; the excess is predominantly cytoplasmic and largely free of small RNAs, but a significant fraction of small cytoplasmic Alu RNA is complexed with SRP9/14 in an 8.5S particle in vivo.","method":"Antibody characterization, subcellular fractionation, immunoprecipitation, sedimentation analysis","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal immunoprecipitation and fractionation, single lab, two orthogonal methods","pmids":["7542942"],"is_preprint":false},{"year":1996,"finding":"SRP9 was crystallized and X-ray diffraction data collected to 2.3 Å resolution, establishing the feasibility of structural analysis of the mouse SRP9 protein.","method":"Protein crystallography (hanging drop vapor diffusion, X-ray diffraction)","journal":"FEBS letters","confidence":"Low","confidence_rationale":"Tier 1 / Weak — crystallization and preliminary diffraction only, no functional validation in this paper","pmids":["8617357"],"is_preprint":false},{"year":1996,"finding":"SRP9 immunoprecipitates both scAlu RNA and dimeric Alu RNAs in vivo; adenovirus infection increases dimeric Alu RNP levels without affecting SRP9, SRP14, SRP54, or 7SL RNA levels, showing that induced Alu transcripts are assembled into SRP9/14-containing RNPs.","method":"Immunoprecipitation with anti-SRP9 antiserum from HeLa cells, Northern blotting","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — immunoprecipitation in vivo with multiple RNA species analyzed, single lab","pmids":["8932367"],"is_preprint":false},{"year":1997,"finding":"Crystal structure of the mouse SRP9/14 heterodimer resolved at 2.5 Å reveals that SRP9 and SRP14 are structurally homologous, each containing an alpha-beta-beta-beta-alpha fold (designated the Alu binding module); the heterodimer has pseudo 2-fold symmetry, is saddle-shaped with a curved six-stranded amphipathic beta-sheet, and presents a positively charged concave surface proposed to interact with RNA.","method":"X-ray crystallography at 2.5 Å resolution","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure, foundational structural paper for the heterodimer","pmids":["9233785"],"is_preprint":false},{"year":1997,"finding":"Human SRP9/14 binds with higher affinity than mouse SRP9/14 to all Alu-like RNAs tested (including BC200 RNA), and this difference is not explained by the additional C-terminal domain of anthropoid SRP14; relative dissociation constants are inversely proportional to evolutionary distance between the Alu RNA species and 7SL RNA.","method":"In vitro RNA-binding assays comparing human and mouse SRP9/14 with multiple Alu-like RNAs","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro quantitative binding assay, single lab, multiple RNA substrates and species compared","pmids":["9016560"],"is_preprint":false},{"year":1997,"finding":"A minimal 86-nucleotide Alu RNA folding domain (SA86) specifically binds SRP9/14 (as a fusion SRPphi14-9); smaller RNAs fail to compete, and circularly permuted variants require a ≥4-nt linker to compete, indicating that Alu RNA identity is determined by a characteristic tertiary structure.","method":"In vitro equilibrium competition binding assay with ribozyme-generated RNA variants","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — quantitative in vitro binding assay with systematic mutagenesis/deletion series, single lab","pmids":["9409618"],"is_preprint":false},{"year":1997,"finding":"G24 of SRP RNA is critical for high-affinity binding to SRP9/14; G24C mutation reduces SRP9/14 binding ≥50-fold, G24A ~2-fold, G24U ~5-fold; despite impaired binding, reconstituted SRPs with mutant RNAs retain translation arrest activity, indicating G24 promotes arrest indirectly by mediating SRP9/14 binding affinity rather than direct interaction with the translational machinery.","method":"Site-directed mutagenesis of SRP RNA, in vitro SRP9/14 binding assays, cell-free translation arrest reconstitution","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis combined with quantitative binding and functional reconstitution assays","pmids":["9092618"],"is_preprint":false},{"year":1997,"finding":"Mutations accompanying Alu RNA evolution in the right monomer destabilized a conserved structural motif and decreased its affinity for SRP9/14; the Alu left monomer maintained structural integrity and high SRP9/14 affinity; loss of right monomer SRP9/14 affinity correlates with increased scAlu RNA production from Alu elements in vivo and with decreased Alu amplification rates.","method":"In vitro binding assays with evolutionary Alu RNA variants, structural analysis, in vivo correlations","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro binding assays plus in vivo correlative evidence, single lab","pmids":["9032241"],"is_preprint":false},{"year":1998,"finding":"SRP9 protein is a component of the neural BC200 RNP in primate brain in vivo; anti-SRP9 antibody immunoprecipitates BC200 RNA, indicating SRP9/14 binds the Alu-like 5' domain of BC200 RNA in neurons.","method":"Immunoprecipitation with anti-SRP9 antibody from primate brain, RNA analysis","journal":"Neuroscience letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo immunoprecipitation from brain tissue, single lab, consistent with in vitro binding data from other groups","pmids":["9605471"],"is_preprint":false},{"year":2010,"finding":"Two patches of positively charged residues in SRP9/14 are essential for elongation arrest activity: a basic pentapeptide KRDKK in SRP14 (replaceable by four lysines) and three lysines in the solvent-accessible alpha2 helix of SRP9; all essential residues localize to one face of SRP9/14, forming a positively charged platform likely mediating electrostatic interactions with ribosomal RNA; the internal loop of SRP14 is dispensable.","method":"Site-directed mutagenesis, cell-free translation/translocation assays, mammalian cell-based assays","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic active-site mutagenesis validated by both cell-free and cell-based functional assays, single lab","pmids":["20348448"],"is_preprint":false},{"year":2014,"finding":"SRP9/14 (but not SRP) localizes to stress granules (SGs) following arsenite or hippuristanol treatment; this localization depends on its ability to bind directly to 40S ribosomal subunits; depletion of SRP9/14 decreases SG size and number of SG-positive cells; binding of SRP9/14 to 40S and to Alu RNA is mutually exclusive, and increasing cytoplasmic Alu RNA promotes SG disassembly by competitively disengaging SRP9/14 from 40S.","method":"Immunofluorescence localization, siRNA depletion, 40S binding assays, Alu RNA overexpression and binding-defective mutant expression in human cells","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (localization, depletion, direct binding assay, mutant rescue) in a single study","pmids":["25200073"],"is_preprint":false},{"year":2015,"finding":"Alu RNPs inhibit both cap-dependent and IRES-mediated translation initiation; inhibition involves direct binding of SRP9/14 to 40S ribosomal subunits and requires Alu RNA as an assembly factor but not its continuous association with 40S; SRP9/14 bound to 40S prevents 48S complex formation by blocking mRNA recruitment to 40S subunits; in cells, Alu RNA overexpression decreases translation of reporter mRNAs in an SRP9/14 binding-dependent manner.","method":"Cell-free translation assays, 40S binding assays, 48S complex formation assays, reporter translation assays in cells with Alu RNA mutants","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — mechanistic dissection with multiple orthogonal assays (cell-free reconstitution, direct binding, cellular reporters, mutant RNAs), single lab","pmids":["25697503"],"is_preprint":false},{"year":2014,"finding":"In vivo knockdown of brain Srp9 reduces febrile seizure susceptibility in mice and reduces hippocampal AMPA and NMDA currents; downregulation of neuronal Srp9 reduces surface expression of AMPA receptor subunit GluA1, indicating SRP9 conveys its effects through ER-dependent synthesis and trafficking of membrane proteins including glutamate receptors.","method":"In vivo Srp9 knockdown, electrophysiology (AMPA/NMDA currents), surface expression assays for GluA1","journal":"Annals of clinical and translational neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KD with electrophysiological and cell-surface readouts, single lab","pmids":["25590037"],"is_preprint":false},{"year":2023,"finding":"SRP9/14 has a distinct nuclear localization (shown by immunofluorescent imaging and subcellular fractionation); nuclear SRP9/14 transcriptionally regulates 7SL RNA and BC200 RNA expression, as demonstrated by changes in steady-state levels and transcriptional activity under SRP9/14 knockdown conditions.","method":"Immunofluorescence, subcellular fractionation, siRNA knockdown, transcription rate measurements in MCF-7 cells","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by fractionation plus functional transcriptional readouts under knockdown, single lab","pmids":["37156570"],"is_preprint":false},{"year":2025,"finding":"The Alu domain of SRP RNA is sufficient to target SRP RNAs to lysosomes for degradation, and this targeting depends on the SRP9 and SRP14 proteins.","method":"Lysosomal RNA profiling, genetic perturbation of SRP9/SRP14 in cells","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2 / Weak — preprint, single lab, abstract-level description without full methodological detail","pmids":[],"is_preprint":true},{"year":2024,"finding":"A 46-nucleotide domain at the 5' end of Alu RNA is necessary for retrotransposition; this domain associates with SRP9/14 in HeLa cell extracts and promotes a single round of retrotransposition, consistent with a model in which SRP9/14 binding mediates ribosomal association required for LINE-1 ORF2p hijacking.","method":"HeLa cell retrotransposition assays, deletion mutagenesis of Alu RNA, immunoprecipitation of SRP9/14 from cell extracts","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2 / Weak — preprint, single lab, limited mechanistic detail in abstract","pmids":[],"is_preprint":true},{"year":2025,"finding":"The 5' pseudoknot U-turn motif in Alu RNA (critical guanosine) is required for SRP9/14 association; a short human Alu RNA (EB120) that lacks the canonical U-turn nucleotide triad also lacks association with SRP9/14 in cellular context, demonstrating that the pseudoknot fold is required for SRP9/14 binding.","method":"Co-immunoprecipitation in 18 human cell lines/tissues, site-directed mutagenesis of BC200, SAXS structure prediction of Alu domain variants","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP across multiple cell lines combined with mutagenesis and structural analysis, single lab","pmids":["40345827"],"is_preprint":false}],"current_model":"SRP9, as the obligate heterodimeric partner of SRP14 (SRP9/14), binds the Alu domain of 7SL SRP RNA via a positively charged concave surface (alpha-beta-beta-beta-alpha fold) and mediates translational elongation arrest by docking onto the 40S ribosomal subunit; in addition, SRP9/14 binds free cytoplasmic Alu-like RNAs (forming Alu RNPs that inhibit translation initiation and regulate stress granule formation), localizes to the nucleus to transcriptionally regulate 7SL and BC200 RNA expression, facilitates Alu RNA retrotransposition through a 46-nt 5' domain interaction, and regulates surface trafficking of AMPA receptors via its canonical ER-targeting function."},"narrative":{"mechanistic_narrative":"SRP9 is an RNA-binding protein that functions as the obligate heterodimeric partner of SRP14, forming the Alu RNA-binding module that mediates translational elongation arrest as part of the signal recognition particle [PMID:7518078, PMID:7730321]. Crystallography of the mouse SRP9/14 heterodimer shows that SRP9 and SRP14 are structurally homologous, each adopting an alpha-beta-beta-beta-alpha fold and together forming a saddle-shaped dimer with a curved amphipathic beta-sheet that presents a positively charged concave surface for RNA binding [PMID:9233785]; a basic platform contributed by lysines in the solvent-accessible alpha2 helix of SRP9 (together with a basic SRP14 pentapeptide) constitutes the surface essential for elongation arrest, consistent with electrostatic contacts to ribosomal RNA [PMID:20348448]. The heterodimer binds the Alu domain of 7SL RNA and other Alu-like RNAs with high affinity, recognizing a characteristic tertiary fold rather than primary sequence, including a 5' pseudoknot U-turn motif required for binding [PMID:7730321, PMID:9409618, PMID:40345827]. Beyond the canonical particle, SRP9/14 exists in large cytoplasmic excess and assembles with free Alu-like and dimeric Alu RNAs into 8.5S RNPs in vivo [PMID:7542942, PMID:8932367]. These Alu RNPs inhibit cap-dependent and IRES-mediated translation initiation: SRP9/14 binds directly to 40S ribosomal subunits and blocks mRNA recruitment to prevent 48S complex formation, using Alu RNA as an assembly factor [PMID:25697503]. Because binding of SRP9/14 to 40S and to Alu RNA is mutually exclusive, SRP9/14 also localizes to stress granules in a 40S-binding-dependent manner and is required for stress granule formation, with cytoplasmic Alu RNA competitively driving granule disassembly [PMID:25200073]. SRP9/14 additionally displays a distinct nuclear localization where it transcriptionally regulates 7SL and BC200 RNA expression [PMID:37156570], and is a component of the neural BC200 RNP in primate brain [PMID:9605471]. In vivo, brain Srp9 supports surface trafficking of AMPA receptors and influences febrile seizure susceptibility through its ER-dependent role in membrane-protein synthesis [PMID:25590037].","teleology":[{"year":1994,"claim":"Established that SRP9 acts only as a heterodimer with SRP14 to bind SRP RNA and confer elongation arrest, defining the functional unit and showing its termini are dispensable for activity.","evidence":"In vitro reconstitution with single-chain fusion proteins, RNA-binding and cell-free elongation arrest/translocation assays","pmids":["7518078"],"confidence":"High","gaps":["Did not resolve the structural basis of RNA recognition","Did not define the residues contacting the ribosome"]},{"year":1995,"claim":"Quantified SRP9/14 affinity for 7SL and Alu-like RNAs and showed a large cytoplasmic pool largely free of SRP RNA but partly assembled with small Alu RNAs, broadening SRP9 beyond the canonical particle.","evidence":"Purification of SRP9/14 from HeLa cells, equilibrium Kd measurements, subcellular fractionation and immunoprecipitation","pmids":["7730321","7542942"],"confidence":"High","gaps":["Function of the free cytoplasmic pool not established","Biological consequence of Alu RNP assembly unknown at this stage"]},{"year":1996,"claim":"Showed in vivo that SRP9/14 assembles induced Alu transcripts into RNPs without altering core SRP component levels, indicating a dedicated Alu RNP pathway distinct from SRP assembly.","evidence":"Anti-SRP9 immunoprecipitation and Northern blotting in HeLa cells with adenovirus induction","pmids":["8932367"],"confidence":"Medium","gaps":["Functional role of Alu RNPs not yet demonstrated","Single-lab correlative evidence"]},{"year":1997,"claim":"Determined the heterodimer crystal structure, revealing the shared alpha-beta-beta-beta-alpha Alu-binding fold and a positively charged concave RNA-binding surface, providing the structural framework for all subsequent mechanism.","evidence":"X-ray crystallography of the mouse SRP9/14 heterodimer at 2.5 Å","pmids":["9233785"],"confidence":"High","gaps":["RNA-bound structure not solved","Ribosome-contacting residues not yet mapped"]},{"year":1997,"claim":"Defined RNA recognition determinants, showing SRP9/14 reads a characteristic Alu tertiary fold (minimal 86-nt domain) and that a single SRP RNA nucleotide (G24) governs binding affinity, which indirectly enables elongation arrest.","evidence":"In vitro competition binding with ribozyme-generated RNA variants; site-directed RNA mutagenesis with binding and arrest reconstitution","pmids":["9409618","9092618"],"confidence":"High","gaps":["Did not resolve protein-side contact residues","Did not establish in vivo selectivity among Alu variants"]},{"year":1997,"claim":"Linked SRP9/14 binding affinity to Alu RNA evolution and amplification, connecting biochemical recognition to genome biology and retroelement activity.","evidence":"In vitro binding with evolutionary Alu variants and species comparison, plus in vivo correlations with scAlu production and Alu amplification","pmids":["9016560","9032241"],"confidence":"Medium","gaps":["Causal mechanism linking affinity to retrotransposition not demonstrated","Correlative in vivo data only"]},{"year":1998,"claim":"Extended SRP9 to a tissue-specific RNP by identifying it as a component of the neural BC200 RNP in primate brain, implying neuronal functions for the Alu-binding activity.","evidence":"Anti-SRP9 immunoprecipitation of BC200 RNA from primate brain","pmids":["9605471"],"confidence":"Medium","gaps":["Functional role in neurons not defined here","Single-lab in vivo IP"]},{"year":2010,"claim":"Mapped the elongation-arrest active surface to a positively charged platform including SRP9 alpha2-helix lysines, identifying which residues mediate ribosomal RNA contacts.","evidence":"Site-directed mutagenesis with cell-free and cell-based translation/translocation assays","pmids":["20348448"],"confidence":"High","gaps":["Direct ribosome-contact structure not solved","Did not address non-SRP functions of the same surface"]},{"year":2014,"claim":"Revealed a non-canonical role in stress granule biology, showing SRP9/14 localizes to stress granules via direct 40S binding and that Alu RNA competitively displaces it, coupling Alu RNP and ribosome-binding states.","evidence":"Immunofluorescence, siRNA depletion, 40S binding assays, and Alu RNA overexpression/binding-defective mutants in human cells","pmids":["25200073"],"confidence":"High","gaps":["Physiological trigger of nuclear vs cytoplasmic partitioning unclear","Downstream consequences of granule modulation not defined"]},{"year":2014,"claim":"Demonstrated an in vivo neuronal function whereby brain Srp9 supports AMPA receptor surface expression and modulates seizure susceptibility through ER-dependent membrane-protein trafficking.","evidence":"In vivo Srp9 knockdown with electrophysiology and GluA1 surface-expression assays in mice","pmids":["25590037"],"confidence":"Medium","gaps":["Does not distinguish canonical SRP function from Alu RNP roles in neurons","Mechanism of receptor selectivity unresolved"]},{"year":2015,"claim":"Mechanistically defined how Alu RNPs repress translation initiation, showing 40S-bound SRP9/14 blocks mRNA recruitment and 48S formation with Alu RNA acting as an assembly factor.","evidence":"Cell-free translation, 40S binding, 48S complex formation, and cellular reporter assays with Alu RNA mutants","pmids":["25697503"],"confidence":"High","gaps":["Physiological conditions that elevate Alu RNPs not fully defined","Selectivity across endogenous mRNAs not mapped"]},{"year":2023,"claim":"Identified a nuclear pool of SRP9/14 that transcriptionally regulates 7SL and BC200 RNA, indicating feedback control over its own RNA partners.","evidence":"Immunofluorescence, subcellular fractionation, siRNA knockdown, and transcription-rate measurements in MCF-7 cells","pmids":["37156570"],"confidence":"Medium","gaps":["Mechanism of transcriptional regulation unknown","Mode of nuclear import not established"]},{"year":2025,"claim":"Linked the SRP9/14-bound Alu domain to RNA turnover, indicating the Alu domain is sufficient to target SRP RNAs to lysosomes in a SRP9/SRP14-dependent manner.","evidence":"Lysosomal RNA profiling and genetic perturbation of SRP9/SRP14 (preprint)","pmids":[],"confidence":"Low","gaps":["Preprint, single lab, abstract-level detail","Mechanism of lysosomal targeting not defined"]},{"year":2025,"claim":"Refined the RNA recognition determinant by showing the 5' pseudoknot U-turn motif (a critical guanosine) is required for SRP9/14 association in cells.","evidence":"Co-immunoprecipitation across human cell lines/tissues, BC200 mutagenesis, and SAXS structural analysis","pmids":["40345827"],"confidence":"Medium","gaps":["Atomic-resolution RNA-protein contacts at the U-turn not solved","Functional consequence of binding loss across endogenous Alu variants not quantified"]},{"year":null,"claim":"How SRP9/14 partitions between SRP, free Alu RNPs, 40S-bound, nuclear, and lysosome-targeting states under physiological signals, and how these states are coordinated, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model integrating cytoplasmic, ribosomal, and nuclear pools","Regulation of state-switching unknown","Disease relevance beyond seizure model uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,5,7,18]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[0,11,13]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[12,13]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,12]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[15]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,11,13]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,7,15]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[12]}],"complexes":["SRP9/14 heterodimer","signal recognition particle (SRP)","Alu RNP (8.5S particle)","BC200 RNP"],"partners":["SRP14"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P49458","full_name":"Signal recognition particle 9 kDa protein","aliases":[],"length_aa":86,"mass_kda":10.1,"function":"Component of the signal recognition particle (SRP) complex, a ribonucleoprotein complex that mediates the cotranslational targeting of secretory and membrane proteins to the endoplasmic reticulum (ER) (By similarity). SRP9 together with SRP14 and the Alu portion of the SRP RNA, constitutes the elongation arrest domain of SRP (PubMed:11089964). The complex of SRP9 and SRP14 is required for SRP RNA binding (By similarity)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P49458/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SRP9","classification":"Common Essential","n_dependent_lines":1153,"n_total_lines":1208,"dependency_fraction":0.9544701986754967},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000143742","cell_line_id":"CID001033","localizations":[{"compartment":"nucleolus_gc","grade":3},{"compartment":"nucleoplasm","grade":2},{"compartment":"cytoplasmic","grade":1}],"interactors":[{"gene":"GYG1","stoichiometry":10.0},{"gene":"SRP14","stoichiometry":10.0},{"gene":"SRP54","stoichiometry":10.0},{"gene":"SRP68","stoichiometry":10.0},{"gene":"SERBP1","stoichiometry":10.0},{"gene":"RPS21","stoichiometry":10.0},{"gene":"DLG1","stoichiometry":10.0},{"gene":"RPL19","stoichiometry":10.0},{"gene":"RPS13","stoichiometry":10.0},{"gene":"RPL7A","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001033","total_profiled":1310},"omim":[{"mim_id":"604858","title":"SIGNAL RECOGNITION PARTICLE, 68-KD; SRP68","url":"https://www.omim.org/entry/604858"},{"mim_id":"604857","title":"SIGNAL RECOGNITION PARTICLE, 54-KD; SRP54","url":"https://www.omim.org/entry/604857"},{"mim_id":"602122","title":"SIGNAL RECOGNITION PARTICLE, 72-KD; SRP72","url":"https://www.omim.org/entry/602122"},{"mim_id":"600708","title":"SIGNAL RECOGNITION PARTICLE, 14-KD; SRP14","url":"https://www.omim.org/entry/600708"},{"mim_id":"600707","title":"SIGNAL RECOGNITION PARTICLE, 9-KD; SRP9","url":"https://www.omim.org/entry/600707"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SRP9"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P49458","domains":[{"cath_id":"3.30.720.10","chopping":"6-73","consensus_level":"high","plddt":97.1949,"start":6,"end":73}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P49458","model_url":"https://alphafold.ebi.ac.uk/files/AF-P49458-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P49458-F1-predicted_aligned_error_v6.png","plddt_mean":90.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SRP9","jax_strain_url":"https://www.jax.org/strain/search?query=SRP9"},"sequence":{"accession":"P49458","fasta_url":"https://rest.uniprot.org/uniprotkb/P49458.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P49458/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P49458"}},"corpus_meta":[{"pmid":"18549262","id":"PMC_18549262","title":"Proteomic expression analysis of surgical human colorectal cancer tissues: up-regulation of PSB7, PRDX1, and SRP9 and hypoxic adaptation in cancer.","date":"2008","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/18549262","citation_count":89,"is_preprint":false},{"pmid":"7542942","id":"PMC_7542942","title":"The SRP9/14 subunit of the signal recognition particle (SRP) is present in more than 20-fold excess over SRP in primate cells and exists primarily free but also in complex with small cytoplasmic Alu RNAs.","date":"1995","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/7542942","citation_count":54,"is_preprint":false},{"pmid":"8617357","id":"PMC_8617357","title":"Crystallization and preliminary X-ray analysis of the 9 kDa protein of the mouse signal recognition particle and the selenomethionyl-SRP9.","date":"1996","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/8617357","citation_count":52,"is_preprint":false},{"pmid":"8932367","id":"PMC_8932367","title":"Monomeric scAlu and nascent dimeric Alu RNAs induced by adenovirus are assembled into SRP9/14-containing RNPs in HeLa cells.","date":"1996","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/8932367","citation_count":49,"is_preprint":false},{"pmid":"7730321","id":"PMC_7730321","title":"Human signal recognition particle (SRP) Alu-associated protein also binds Alu interspersed repeat sequence RNAs. Characterization of human SRP9.","date":"1995","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7730321","citation_count":49,"is_preprint":false},{"pmid":"9233785","id":"PMC_9233785","title":"The crystal structure of the signal recognition particle Alu RNA binding heterodimer, SRP9/14.","date":"1997","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/9233785","citation_count":46,"is_preprint":false},{"pmid":"9016560","id":"PMC_9016560","title":"The SRP9/14 subunit of the human signal recognition particle binds to a variety of Alu-like RNAs and with higher affinity than its mouse homolog.","date":"1997","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/9016560","citation_count":46,"is_preprint":false},{"pmid":"9032241","id":"PMC_9032241","title":"The decline in human Alu retroposition was accompanied by an asymmetric decrease in SRP9/14 binding to dimeric Alu RNA and increased expression of small cytoplasmic Alu RNA.","date":"1997","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9032241","citation_count":40,"is_preprint":false},{"pmid":"20348448","id":"PMC_20348448","title":"Residues in SRP9/14 essential for elongation arrest activity of the signal recognition particle define a positively charged functional domain on one side of the protein.","date":"2010","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/20348448","citation_count":39,"is_preprint":false},{"pmid":"9605471","id":"PMC_9605471","title":"Heterodimer SRP9/14 is an integral part of the neural BC200 RNP in primate brain.","date":"1998","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/9605471","citation_count":37,"is_preprint":false},{"pmid":"25697503","id":"PMC_25697503","title":"Alu RNA regulates the cellular pool of active ribosomes by targeted delivery of SRP9/14 to 40S subunits.","date":"2015","source":"Nucleic acids 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research","url":"https://pubmed.ncbi.nlm.nih.gov/9092618","citation_count":25,"is_preprint":false},{"pmid":"7518078","id":"PMC_7518078","title":"The heterodimeric subunit SRP9/14 of the signal recognition particle functions as permuted single polypeptide chain.","date":"1994","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/7518078","citation_count":23,"is_preprint":false},{"pmid":"25590037","id":"PMC_25590037","title":"Identification of Srp9 as a febrile seizure susceptibility gene.","date":"2014","source":"Annals of clinical and translational neurology","url":"https://pubmed.ncbi.nlm.nih.gov/25590037","citation_count":15,"is_preprint":false},{"pmid":"39563162","id":"PMC_39563162","title":"The role of SRP9/SRP14 in regulating Alu RNA.","date":"2024","source":"RNA biology","url":"https://pubmed.ncbi.nlm.nih.gov/39563162","citation_count":6,"is_preprint":false},{"pmid":"37156570","id":"PMC_37156570","title":"Nuclear SRP9/SRP14 heterodimer transcriptionally regulates 7SL and BC200 RNA expression.","date":"2023","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/37156570","citation_count":5,"is_preprint":false},{"pmid":"40345827","id":"PMC_40345827","title":"Alu RNA pseudoknot alterations influence SRP9/SRP14 association.","date":"2025","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/40345827","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.09.674968","title":"Lysosomal RNA profiling reveals targeting of specific types of RNAs for degradation","date":"2025-09-09","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.09.674968","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.16.628748","title":"Identification of a minimal  <i>Alu</i>  domain required for retrotransposition","date":"2024-12-16","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.16.628748","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11611,"output_tokens":4510,"usd":0.051242,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12501,"output_tokens":4523,"usd":0.08779,"stage2_stop_reason":"end_turn"},"total_usd":0.139032,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"SRP9 and SRP14 form a heterodimer that binds SRP RNA and is required for elongation arrest activity; fusion single-chain polypeptides containing both sequences retain RNA binding and elongation arrest activity, demonstrating that the normal N- and C-termini are dispensable for folding, RNA-binding, and biological activities.\",\n      \"method\": \"In vitro reconstitution with fusion proteins, SRP RNA binding assay, elongation arrest and translocation cell-free assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution and functional assays in a single rigorous study with multiple orthogonal readouts\",\n      \"pmids\": [\"7518078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Human SRP9, together with SRP14, forms the Alu RNA-binding protein (RBP) activity; the SRP9/14 heterodimer binds the Alu region of 7SL RNA, scAlu RNA, and scB1 RNA with Kd values of ~203 pM, ~318 pM, and ~1.8 nM respectively; the primate-specific C-terminal tail of SRP14 does not appreciably affect scAlu RNA binding.\",\n      \"method\": \"Purification of SRP9/14 from HeLa cells, quantitative equilibrium binding assays (Kd determination)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — quantitative in vitro binding assay with purified protein, replicated across multiple RNA substrates\",\n      \"pmids\": [\"7730321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"SRP9/14 is present in >20-fold excess over SRP in primate cells; the excess is predominantly cytoplasmic and largely free of small RNAs, but a significant fraction of small cytoplasmic Alu RNA is complexed with SRP9/14 in an 8.5S particle in vivo.\",\n      \"method\": \"Antibody characterization, subcellular fractionation, immunoprecipitation, sedimentation analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal immunoprecipitation and fractionation, single lab, two orthogonal methods\",\n      \"pmids\": [\"7542942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"SRP9 was crystallized and X-ray diffraction data collected to 2.3 Å resolution, establishing the feasibility of structural analysis of the mouse SRP9 protein.\",\n      \"method\": \"Protein crystallography (hanging drop vapor diffusion, X-ray diffraction)\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystallization and preliminary diffraction only, no functional validation in this paper\",\n      \"pmids\": [\"8617357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"SRP9 immunoprecipitates both scAlu RNA and dimeric Alu RNAs in vivo; adenovirus infection increases dimeric Alu RNP levels without affecting SRP9, SRP14, SRP54, or 7SL RNA levels, showing that induced Alu transcripts are assembled into SRP9/14-containing RNPs.\",\n      \"method\": \"Immunoprecipitation with anti-SRP9 antiserum from HeLa cells, Northern blotting\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — immunoprecipitation in vivo with multiple RNA species analyzed, single lab\",\n      \"pmids\": [\"8932367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Crystal structure of the mouse SRP9/14 heterodimer resolved at 2.5 Å reveals that SRP9 and SRP14 are structurally homologous, each containing an alpha-beta-beta-beta-alpha fold (designated the Alu binding module); the heterodimer has pseudo 2-fold symmetry, is saddle-shaped with a curved six-stranded amphipathic beta-sheet, and presents a positively charged concave surface proposed to interact with RNA.\",\n      \"method\": \"X-ray crystallography at 2.5 Å resolution\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure, foundational structural paper for the heterodimer\",\n      \"pmids\": [\"9233785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Human SRP9/14 binds with higher affinity than mouse SRP9/14 to all Alu-like RNAs tested (including BC200 RNA), and this difference is not explained by the additional C-terminal domain of anthropoid SRP14; relative dissociation constants are inversely proportional to evolutionary distance between the Alu RNA species and 7SL RNA.\",\n      \"method\": \"In vitro RNA-binding assays comparing human and mouse SRP9/14 with multiple Alu-like RNAs\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro quantitative binding assay, single lab, multiple RNA substrates and species compared\",\n      \"pmids\": [\"9016560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"A minimal 86-nucleotide Alu RNA folding domain (SA86) specifically binds SRP9/14 (as a fusion SRPphi14-9); smaller RNAs fail to compete, and circularly permuted variants require a ≥4-nt linker to compete, indicating that Alu RNA identity is determined by a characteristic tertiary structure.\",\n      \"method\": \"In vitro equilibrium competition binding assay with ribozyme-generated RNA variants\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — quantitative in vitro binding assay with systematic mutagenesis/deletion series, single lab\",\n      \"pmids\": [\"9409618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"G24 of SRP RNA is critical for high-affinity binding to SRP9/14; G24C mutation reduces SRP9/14 binding ≥50-fold, G24A ~2-fold, G24U ~5-fold; despite impaired binding, reconstituted SRPs with mutant RNAs retain translation arrest activity, indicating G24 promotes arrest indirectly by mediating SRP9/14 binding affinity rather than direct interaction with the translational machinery.\",\n      \"method\": \"Site-directed mutagenesis of SRP RNA, in vitro SRP9/14 binding assays, cell-free translation arrest reconstitution\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis combined with quantitative binding and functional reconstitution assays\",\n      \"pmids\": [\"9092618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Mutations accompanying Alu RNA evolution in the right monomer destabilized a conserved structural motif and decreased its affinity for SRP9/14; the Alu left monomer maintained structural integrity and high SRP9/14 affinity; loss of right monomer SRP9/14 affinity correlates with increased scAlu RNA production from Alu elements in vivo and with decreased Alu amplification rates.\",\n      \"method\": \"In vitro binding assays with evolutionary Alu RNA variants, structural analysis, in vivo correlations\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro binding assays plus in vivo correlative evidence, single lab\",\n      \"pmids\": [\"9032241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"SRP9 protein is a component of the neural BC200 RNP in primate brain in vivo; anti-SRP9 antibody immunoprecipitates BC200 RNA, indicating SRP9/14 binds the Alu-like 5' domain of BC200 RNA in neurons.\",\n      \"method\": \"Immunoprecipitation with anti-SRP9 antibody from primate brain, RNA analysis\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo immunoprecipitation from brain tissue, single lab, consistent with in vitro binding data from other groups\",\n      \"pmids\": [\"9605471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Two patches of positively charged residues in SRP9/14 are essential for elongation arrest activity: a basic pentapeptide KRDKK in SRP14 (replaceable by four lysines) and three lysines in the solvent-accessible alpha2 helix of SRP9; all essential residues localize to one face of SRP9/14, forming a positively charged platform likely mediating electrostatic interactions with ribosomal RNA; the internal loop of SRP14 is dispensable.\",\n      \"method\": \"Site-directed mutagenesis, cell-free translation/translocation assays, mammalian cell-based assays\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic active-site mutagenesis validated by both cell-free and cell-based functional assays, single lab\",\n      \"pmids\": [\"20348448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SRP9/14 (but not SRP) localizes to stress granules (SGs) following arsenite or hippuristanol treatment; this localization depends on its ability to bind directly to 40S ribosomal subunits; depletion of SRP9/14 decreases SG size and number of SG-positive cells; binding of SRP9/14 to 40S and to Alu RNA is mutually exclusive, and increasing cytoplasmic Alu RNA promotes SG disassembly by competitively disengaging SRP9/14 from 40S.\",\n      \"method\": \"Immunofluorescence localization, siRNA depletion, 40S binding assays, Alu RNA overexpression and binding-defective mutant expression in human cells\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (localization, depletion, direct binding assay, mutant rescue) in a single study\",\n      \"pmids\": [\"25200073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Alu RNPs inhibit both cap-dependent and IRES-mediated translation initiation; inhibition involves direct binding of SRP9/14 to 40S ribosomal subunits and requires Alu RNA as an assembly factor but not its continuous association with 40S; SRP9/14 bound to 40S prevents 48S complex formation by blocking mRNA recruitment to 40S subunits; in cells, Alu RNA overexpression decreases translation of reporter mRNAs in an SRP9/14 binding-dependent manner.\",\n      \"method\": \"Cell-free translation assays, 40S binding assays, 48S complex formation assays, reporter translation assays in cells with Alu RNA mutants\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mechanistic dissection with multiple orthogonal assays (cell-free reconstitution, direct binding, cellular reporters, mutant RNAs), single lab\",\n      \"pmids\": [\"25697503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In vivo knockdown of brain Srp9 reduces febrile seizure susceptibility in mice and reduces hippocampal AMPA and NMDA currents; downregulation of neuronal Srp9 reduces surface expression of AMPA receptor subunit GluA1, indicating SRP9 conveys its effects through ER-dependent synthesis and trafficking of membrane proteins including glutamate receptors.\",\n      \"method\": \"In vivo Srp9 knockdown, electrophysiology (AMPA/NMDA currents), surface expression assays for GluA1\",\n      \"journal\": \"Annals of clinical and translational neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KD with electrophysiological and cell-surface readouts, single lab\",\n      \"pmids\": [\"25590037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SRP9/14 has a distinct nuclear localization (shown by immunofluorescent imaging and subcellular fractionation); nuclear SRP9/14 transcriptionally regulates 7SL RNA and BC200 RNA expression, as demonstrated by changes in steady-state levels and transcriptional activity under SRP9/14 knockdown conditions.\",\n      \"method\": \"Immunofluorescence, subcellular fractionation, siRNA knockdown, transcription rate measurements in MCF-7 cells\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by fractionation plus functional transcriptional readouts under knockdown, single lab\",\n      \"pmids\": [\"37156570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The Alu domain of SRP RNA is sufficient to target SRP RNAs to lysosomes for degradation, and this targeting depends on the SRP9 and SRP14 proteins.\",\n      \"method\": \"Lysosomal RNA profiling, genetic perturbation of SRP9/SRP14 in cells\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — preprint, single lab, abstract-level description without full methodological detail\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A 46-nucleotide domain at the 5' end of Alu RNA is necessary for retrotransposition; this domain associates with SRP9/14 in HeLa cell extracts and promotes a single round of retrotransposition, consistent with a model in which SRP9/14 binding mediates ribosomal association required for LINE-1 ORF2p hijacking.\",\n      \"method\": \"HeLa cell retrotransposition assays, deletion mutagenesis of Alu RNA, immunoprecipitation of SRP9/14 from cell extracts\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — preprint, single lab, limited mechanistic detail in abstract\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The 5' pseudoknot U-turn motif in Alu RNA (critical guanosine) is required for SRP9/14 association; a short human Alu RNA (EB120) that lacks the canonical U-turn nucleotide triad also lacks association with SRP9/14 in cellular context, demonstrating that the pseudoknot fold is required for SRP9/14 binding.\",\n      \"method\": \"Co-immunoprecipitation in 18 human cell lines/tissues, site-directed mutagenesis of BC200, SAXS structure prediction of Alu domain variants\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP across multiple cell lines combined with mutagenesis and structural analysis, single lab\",\n      \"pmids\": [\"40345827\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SRP9, as the obligate heterodimeric partner of SRP14 (SRP9/14), binds the Alu domain of 7SL SRP RNA via a positively charged concave surface (alpha-beta-beta-beta-alpha fold) and mediates translational elongation arrest by docking onto the 40S ribosomal subunit; in addition, SRP9/14 binds free cytoplasmic Alu-like RNAs (forming Alu RNPs that inhibit translation initiation and regulate stress granule formation), localizes to the nucleus to transcriptionally regulate 7SL and BC200 RNA expression, facilitates Alu RNA retrotransposition through a 46-nt 5' domain interaction, and regulates surface trafficking of AMPA receptors via its canonical ER-targeting function.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SRP9 is an RNA-binding protein that functions as the obligate heterodimeric partner of SRP14, forming the Alu RNA-binding module that mediates translational elongation arrest as part of the signal recognition particle [#0, #1]. Crystallography of the mouse SRP9/14 heterodimer shows that SRP9 and SRP14 are structurally homologous, each adopting an alpha-beta-beta-beta-alpha fold and together forming a saddle-shaped dimer with a curved amphipathic beta-sheet that presents a positively charged concave surface for RNA binding [#5]; a basic platform contributed by lysines in the solvent-accessible alpha2 helix of SRP9 (together with a basic SRP14 pentapeptide) constitutes the surface essential for elongation arrest, consistent with electrostatic contacts to ribosomal RNA [#11]. The heterodimer binds the Alu domain of 7SL RNA and other Alu-like RNAs with high affinity, recognizing a characteristic tertiary fold rather than primary sequence, including a 5' pseudoknot U-turn motif required for binding [#1, #7, #18]. Beyond the canonical particle, SRP9/14 exists in large cytoplasmic excess and assembles with free Alu-like and dimeric Alu RNAs into 8.5S RNPs in vivo [#2, #4]. These Alu RNPs inhibit cap-dependent and IRES-mediated translation initiation: SRP9/14 binds directly to 40S ribosomal subunits and blocks mRNA recruitment to prevent 48S complex formation, using Alu RNA as an assembly factor [#13]. Because binding of SRP9/14 to 40S and to Alu RNA is mutually exclusive, SRP9/14 also localizes to stress granules in a 40S-binding-dependent manner and is required for stress granule formation, with cytoplasmic Alu RNA competitively driving granule disassembly [#12]. SRP9/14 additionally displays a distinct nuclear localization where it transcriptionally regulates 7SL and BC200 RNA expression [#15], and is a component of the neural BC200 RNP in primate brain [#10]. In vivo, brain Srp9 supports surface trafficking of AMPA receptors and influences febrile seizure susceptibility through its ER-dependent role in membrane-protein synthesis [#14].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established that SRP9 acts only as a heterodimer with SRP14 to bind SRP RNA and confer elongation arrest, defining the functional unit and showing its termini are dispensable for activity.\",\n      \"evidence\": \"In vitro reconstitution with single-chain fusion proteins, RNA-binding and cell-free elongation arrest/translocation assays\",\n      \"pmids\": [\"7518078\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural basis of RNA recognition\", \"Did not define the residues contacting the ribosome\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Quantified SRP9/14 affinity for 7SL and Alu-like RNAs and showed a large cytoplasmic pool largely free of SRP RNA but partly assembled with small Alu RNAs, broadening SRP9 beyond the canonical particle.\",\n      \"evidence\": \"Purification of SRP9/14 from HeLa cells, equilibrium Kd measurements, subcellular fractionation and immunoprecipitation\",\n      \"pmids\": [\"7730321\", \"7542942\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Function of the free cytoplasmic pool not established\", \"Biological consequence of Alu RNP assembly unknown at this stage\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Showed in vivo that SRP9/14 assembles induced Alu transcripts into RNPs without altering core SRP component levels, indicating a dedicated Alu RNP pathway distinct from SRP assembly.\",\n      \"evidence\": \"Anti-SRP9 immunoprecipitation and Northern blotting in HeLa cells with adenovirus induction\",\n      \"pmids\": [\"8932367\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of Alu RNPs not yet demonstrated\", \"Single-lab correlative evidence\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Determined the heterodimer crystal structure, revealing the shared alpha-beta-beta-beta-alpha Alu-binding fold and a positively charged concave RNA-binding surface, providing the structural framework for all subsequent mechanism.\",\n      \"evidence\": \"X-ray crystallography of the mouse SRP9/14 heterodimer at 2.5 Å\",\n      \"pmids\": [\"9233785\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RNA-bound structure not solved\", \"Ribosome-contacting residues not yet mapped\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Defined RNA recognition determinants, showing SRP9/14 reads a characteristic Alu tertiary fold (minimal 86-nt domain) and that a single SRP RNA nucleotide (G24) governs binding affinity, which indirectly enables elongation arrest.\",\n      \"evidence\": \"In vitro competition binding with ribozyme-generated RNA variants; site-directed RNA mutagenesis with binding and arrest reconstitution\",\n      \"pmids\": [\"9409618\", \"9092618\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve protein-side contact residues\", \"Did not establish in vivo selectivity among Alu variants\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Linked SRP9/14 binding affinity to Alu RNA evolution and amplification, connecting biochemical recognition to genome biology and retroelement activity.\",\n      \"evidence\": \"In vitro binding with evolutionary Alu variants and species comparison, plus in vivo correlations with scAlu production and Alu amplification\",\n      \"pmids\": [\"9016560\", \"9032241\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal mechanism linking affinity to retrotransposition not demonstrated\", \"Correlative in vivo data only\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Extended SRP9 to a tissue-specific RNP by identifying it as a component of the neural BC200 RNP in primate brain, implying neuronal functions for the Alu-binding activity.\",\n      \"evidence\": \"Anti-SRP9 immunoprecipitation of BC200 RNA from primate brain\",\n      \"pmids\": [\"9605471\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role in neurons not defined here\", \"Single-lab in vivo IP\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Mapped the elongation-arrest active surface to a positively charged platform including SRP9 alpha2-helix lysines, identifying which residues mediate ribosomal RNA contacts.\",\n      \"evidence\": \"Site-directed mutagenesis with cell-free and cell-based translation/translocation assays\",\n      \"pmids\": [\"20348448\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ribosome-contact structure not solved\", \"Did not address non-SRP functions of the same surface\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed a non-canonical role in stress granule biology, showing SRP9/14 localizes to stress granules via direct 40S binding and that Alu RNA competitively displaces it, coupling Alu RNP and ribosome-binding states.\",\n      \"evidence\": \"Immunofluorescence, siRNA depletion, 40S binding assays, and Alu RNA overexpression/binding-defective mutants in human cells\",\n      \"pmids\": [\"25200073\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological trigger of nuclear vs cytoplasmic partitioning unclear\", \"Downstream consequences of granule modulation not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated an in vivo neuronal function whereby brain Srp9 supports AMPA receptor surface expression and modulates seizure susceptibility through ER-dependent membrane-protein trafficking.\",\n      \"evidence\": \"In vivo Srp9 knockdown with electrophysiology and GluA1 surface-expression assays in mice\",\n      \"pmids\": [\"25590037\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not distinguish canonical SRP function from Alu RNP roles in neurons\", \"Mechanism of receptor selectivity unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Mechanistically defined how Alu RNPs repress translation initiation, showing 40S-bound SRP9/14 blocks mRNA recruitment and 48S formation with Alu RNA acting as an assembly factor.\",\n      \"evidence\": \"Cell-free translation, 40S binding, 48S complex formation, and cellular reporter assays with Alu RNA mutants\",\n      \"pmids\": [\"25697503\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological conditions that elevate Alu RNPs not fully defined\", \"Selectivity across endogenous mRNAs not mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a nuclear pool of SRP9/14 that transcriptionally regulates 7SL and BC200 RNA, indicating feedback control over its own RNA partners.\",\n      \"evidence\": \"Immunofluorescence, subcellular fractionation, siRNA knockdown, and transcription-rate measurements in MCF-7 cells\",\n      \"pmids\": [\"37156570\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of transcriptional regulation unknown\", \"Mode of nuclear import not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked the SRP9/14-bound Alu domain to RNA turnover, indicating the Alu domain is sufficient to target SRP RNAs to lysosomes in a SRP9/SRP14-dependent manner.\",\n      \"evidence\": \"Lysosomal RNA profiling and genetic perturbation of SRP9/SRP14 (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Preprint, single lab, abstract-level detail\", \"Mechanism of lysosomal targeting not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Refined the RNA recognition determinant by showing the 5' pseudoknot U-turn motif (a critical guanosine) is required for SRP9/14 association in cells.\",\n      \"evidence\": \"Co-immunoprecipitation across human cell lines/tissues, BC200 mutagenesis, and SAXS structural analysis\",\n      \"pmids\": [\"40345827\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Atomic-resolution RNA-protein contacts at the U-turn not solved\", \"Functional consequence of binding loss across endogenous Alu variants not quantified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SRP9/14 partitions between SRP, free Alu RNPs, 40S-bound, nuclear, and lysosome-targeting states under physiological signals, and how these states are coordinated, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model integrating cytoplasmic, ribosomal, and nuclear pools\", \"Regulation of state-switching unknown\", \"Disease relevance beyond seizure model uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 5, 7, 18]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0, 11, 13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [12, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 12]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 11, 13]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 7, 15]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"complexes\": [\n      \"SRP9/14 heterodimer\",\n      \"signal recognition particle (SRP)\",\n      \"Alu RNP (8.5S particle)\",\n      \"BC200 RNP\"\n    ],\n    \"partners\": [\n      \"SRP14\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}