{"gene":"SRP14","run_date":"2026-06-10T07:46:41","timeline":{"discoveries":[{"year":1990,"finding":"SRP9 and SRP14 form a heterodimer that is required for stable binding to SRP RNA; neither protein alone binds specifically to SRP RNA. The heterodimer is also required to restore elongation arrest activity to SRP depleted of SRP9/14.","method":"In vitro reconstitution with recombinant proteins, RNA-protein binding assay, elongation arrest assay in cell-free translation system","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with functional readout (elongation arrest), replicated across multiple experiments in the same study","pmids":["2153922"],"is_preprint":false},{"year":1994,"finding":"Single-chain fusion proteins encoding SRP14 and SRP9 sequences in either permutation bind SRP RNA as monomers folded into a heterodimer-like structure and restore elongation arrest and translocation activity to SRP(-9/14), demonstrating that the N- and C-termini of both proteins are dispensable for folding, RNA binding, and biological function.","method":"In vitro reconstitution, RNA-binding assay, cell-free elongation arrest and translocation assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with functional validation, single lab with multiple orthogonal assays","pmids":["7518078"],"is_preprint":false},{"year":1995,"finding":"SRP9/14 heterodimer is present at more than 20-fold excess over SRP in primate cells, with the majority cytoplasmic and not bound to small RNAs; a significant fraction of small cytoplasmic Alu RNA is complexed with SRP9/14 in an 8.5S particle in vivo.","method":"Immunoprecipitation, subcellular fractionation, sucrose gradient sedimentation, quantitative immunoblotting","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and fractionation with quantitative analysis, single lab but multiple orthogonal methods","pmids":["7542942"],"is_preprint":false},{"year":1995,"finding":"In early anthropoids, the SRP14 gene acquired a GCA trinucleotide repeat in its 3'-coding region producing SRP14 isoforms with extended alanine-rich C-terminal tails; this C-terminal extension is associated with increased SRP14 polypeptide levels and Alu RNA-binding activity.","method":"Gene cloning, sequencing, in vitro binding assays, comparative genomics","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — binding assays and genetic analysis, single lab, multiple species comparisons","pmids":["7534378"],"is_preprint":false},{"year":1996,"finding":"Monomeric scAlu RNA and nascent dimeric Alu RNAs are assembled into SRP9/14-containing RNPs in vivo after adenovirus infection, while SRP levels remain unchanged, demonstrating that induced Alu transcripts are specifically recruited to SRP9/14.","method":"Immunoprecipitation with anti-SRP9 antisera, Northern blotting","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — immunoprecipitation with co-purified RNA analysis, single lab, consistent results across conditions","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 share an alpha-beta-beta-beta-alpha fold (Alu binding module), form a pseudo 2-fold symmetric saddle-like heterodimer with a curved six-stranded amphipathic beta-sheet, and present a positively charged concave surface for RNA binding.","method":"X-ray crystallography at 2.5 Å resolution","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure with detailed atomic model","pmids":["9233785"],"is_preprint":false},{"year":1997,"finding":"C-terminal truncation of SRP14 (SRP14-20C) forms a stable complex with SRP9 and SRP RNA but completely abolishes elongation arrest activity; the truncated particle retains signal recognition, targeting, and ribosome binding, indicating that the C-terminus of SRP14 is specifically required for interactions with the ribosome that effect elongation arrest. The truncation also induces tertiary structure changes in the Alu RNA, revealing a critical role of the RNA conformation in elongation arrest.","method":"In vitro reconstitution, cell-free translation/translocation assay, chemical probing of RNA structure, elongation arrest assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution with mutagenesis and multiple functional assays, single lab with multiple orthogonal methods","pmids":["9115358"],"is_preprint":false},{"year":1997,"finding":"Mutational analysis identified that in SRP9, acidic residues in the N-terminal alpha-helix and adjacent loop are critical for RNA binding, while in SRP14, a flexible internal loop region is critical for RNA binding; dimerization requirements differ substantially between SRP9 and SRP14. SRP RNA can rescue certain dimerization-defective SRP14 variants into stable complexes.","method":"In vitro dimerization and RNA-binding assays, site-directed mutagenesis","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic mutagenesis with quantitative binding assays, multiple mutants tested","pmids":["9214658"],"is_preprint":false},{"year":1997,"finding":"An 86-nucleotide minimal Alu RNA folding domain (SA86) was defined that specifically binds SRPphi14-9 (single-chain SRP14-SRP9 fusion); this minimal domain consists of two stem-loops connected by a conserved bulge and part of the central adaptor stem, and it functions as an autonomous folding unit for SRP9/14 recognition.","method":"Ribozyme-mediated in vitro RNA production, quantitative equilibrium competition binding assay","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — quantitative in vitro binding assays with systematic RNA variant analysis, multiple controls","pmids":["9409618"],"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; the relative dissociation constants are inversely proportional to evolutionary distance between the Alu RNA species and 7SL RNA. The additional C-terminal domain of anthropoid SRP14 does not explain this higher affinity.","method":"Quantitative binding assays (equilibrium competition), comparison of recombinant human and mouse SRP9/14","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative binding assays with multiple RNA species and two protein variants, single lab","pmids":["9016560"],"is_preprint":false},{"year":1998,"finding":"The SRP9 protein (and by inference the SRP9/14 heterodimer) is an integral part of the neural BC200 RNP in primate brain in vivo, as demonstrated by immunoprecipitation of BC200 RNA with anti-SRP9 antibodies.","method":"Immunoprecipitation from brain tissue with anti-SRP9 antibodies","journal":"Neuroscience letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single immunoprecipitation experiment from brain tissue, corroborated by in vitro binding data","pmids":["9605471"],"is_preprint":false},{"year":1999,"finding":"In S. cerevisiae, the Alu domain homolog consists of Srp14p bound as a homodimer (not a heterodimer with SRP9) to the 5' sequences of scR1 RNA; the minimal binding site is 99 nt. The conserved UGUAAU motif and certain basic amino acid residues conserved between mammalian SRP14 and yeast Srp14p are essential for RNA binding in both organisms.","method":"Immunoprecipitation, RNA footprinting, site-directed mutagenesis, in vitro binding assays","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis combined with footprinting and binding assays, multiple orthogonal methods","pmids":["10573124"],"is_preprint":false},{"year":2000,"finding":"Two crystal structures of the SRP9/14 heterodimer bound to the Alu RNA 5' domain, and to a construct containing both 5' and 3' domains, revealed that SRP9/14 binds strongly to the conserved core of the 5' domain which forms a U-turn, and that the 3' domain docks more weakly. A model of the complete Alu domain consistent with biochemical data was proposed.","method":"X-ray crystallography (two structures), biochemical validation","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — two crystal structures in a single study, supported by extensive biochemical data","pmids":["11089964"],"is_preprint":false},{"year":2000,"finding":"Yeast SRP has elongation arrest activity; C-terminal truncation of Srp14p (deltaC29) eliminates elongation arrest, substantially reduces translocation efficiency, and causes constitutive defects in coupling protein translation and translocation and temperature-sensitive growth in vivo. This demonstrates that elongation arrest is a physiologically important and conserved function of eukaryotic SRP.","method":"Yeast SRP purification, in vitro elongation arrest assay, in vivo growth and translocation assays, genetic analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro and in vivo assays with defined mutant, multiple orthogonal readouts, yeast model","pmids":["10921896"],"is_preprint":false},{"year":2001,"finding":"The SRP Alu domain assembles hierarchically: SRP9 and SRP14 first heterodimerize, then bind the Alu RNA 5' domain, creating the binding site for the 3' domain; Alu RNA then undergoes a large conformational change where the flexibly linked 3' domain folds back 180° onto the 5' domain complex to form the final compact Alu RNP.","method":"Biochemical assembly assays (gel shift, filter binding), small-angle X-ray scattering, analytical ultracentrifugation","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple biophysical and biochemical methods establishing ordered assembly pathway","pmids":["11350037"],"is_preprint":false},{"year":2004,"finding":"Protein cross-linking in functional complexes demonstrates that SRP14 is in close physical proximity to several ribosomal proteins; cross-linking occurs even without a signal sequence, but upon signal sequence recognition, SRP14 cross-links to proteins from both the large and small ribosomal subunits, indicating that the Alu domain occupies a defined position at the ribosomal subunit interface during elongation arrest.","method":"Protein-protein cross-linking in functional SRP-ribosome complexes, immunoprecipitation","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct cross-linking in defined functional complexes with signal sequence-dependent changes, multiple ribosomal contacts mapped","pmids":["14705936"],"is_preprint":false},{"year":2008,"finding":"SRP14 depletion in mammalian cells causes inefficient targeting of preproteins due to rate-limiting SRP receptor (SR) concentrations; complementation with elongation-arrest-deficient SRP14 mutants results in defects in secretion, depletion of endogenous membrane proteins, and reduced cell growth. These defects are rescued by reducing protein synthesis rate or increasing SR expression, demonstrating that the elongation arrest function of SRP14 keeps nascent chains translocation-competent during SR-limited targeting.","method":"siRNA depletion in mammalian cells, complementation with mutant SRP14 variants, secretion assays, cell growth assays, SR overexpression rescue","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KD/KO with defined rescue experiments, multiple orthogonal readouts across multiple conditions, independently validated mechanisms","pmids":["18455985"],"is_preprint":false},{"year":2008,"finding":"APOBEC3G and APOBEC3F are recruited into HIV virions when SRP14 (or SRP19) is depleted by RNA interference, indicating that 7SL RNA (which requires SRP14 for its assembly into SRP) competes with APOBEC3 proteins for virion packaging but is not an essential mediator of APOBEC3F/3G packaging.","method":"siRNA knockdown of SRP14, HIV virion infectivity assay, RT-PCR for 7SL RNA","journal":"Retrovirology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — siRNA knockdown with virology readouts, single lab, two SRP components tested","pmids":["18597676"],"is_preprint":false},{"year":2010,"finding":"Mutational analysis identified two patches of basic amino acid residues essential for SRP elongation arrest activity: a basic pentapeptide KRDKK in SRP14 and three lysines in the solvent-accessible alpha2 helix of SRP9; the internal loop of SRP14 is dispensable. All essential residues cluster on one face of the heterodimer, suggesting they form a positively charged platform for interactions with ribosomal RNA phosphate backbone.","method":"Site-directed mutagenesis, cell-free translation/translocation assay, mammalian cell complementation assay","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic mutagenesis with functional validation in both cell-free and cellular systems, multiple orthogonal methods","pmids":["20348448"],"is_preprint":false},{"year":2009,"finding":"Crystal structure of S. pombe SRP14 (SpSRP14) reveals it crystallizes as a homodimer; comparison with human SRP9/14-Alu RNA complex suggests that many protein-RNA contacts centered on the conserved U-turn motif are likely conserved in fission yeast.","method":"X-ray crystallography (RIP and SAD phasing), structural comparison","journal":"Acta crystallographica. Section D, Biological crystallography","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — crystal structure of ortholog, functional inference by structural comparison only, single study","pmids":["19390147"],"is_preprint":false},{"year":2013,"finding":"Overexpression of human SRP14 (along with other secretory pathway components) in CHO cells restored proper processing and secretion of a difficult-to-express immunoglobulin that was subject to translational arrest, improper light chain cleavage, and insoluble aggregation, demonstrating that SRP14 is rate-limiting for protein translocation efficiency.","method":"Overexpression in CHO cells, secretion assays, protein fractionation, Western blotting","journal":"Metabolic engineering","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — gain-of-function in mammalian cells with defined secretion readout, single lab","pmids":["23380542"],"is_preprint":false},{"year":2021,"finding":"SRP14 binds directly to TIM-TAM, a conserved RNA sequence-structure in HIV tat mRNA that functions as a Tat IRES modulator; knockdown of SRP14 negatively affects tat mRNA processing and translation as well as Tat-mediated transactivation, increasing latent infection. Overexpression of SRP14 in resting CD4+ T cells from ART patients reversed HIV-1 latency and induced virus production.","method":"Affinity purification-mass spectrometry, RNA footprinting, siRNA knockdown, luciferase reporter assay, dual-color HIV reporter virus infection, overexpression in primary T cells","journal":"Frontiers in genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods including footprinting and functional assays, single lab","pmids":["34194479"],"is_preprint":false},{"year":2021,"finding":"SRP14 interacts with HPIP (under hypoxic conditions) and stimulates MMP9 synthesis, contributing to cell migration/invasion and EMT in breast cancer cells.","method":"Co-immunoprecipitation, siRNA knockdown, MMP9 expression assays, migration/invasion assays","journal":"Cancer letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP and phenotypic assays, single lab, interaction mechanism not deeply characterized","pmids":["34767928"],"is_preprint":false},{"year":2022,"finding":"SRP14 promotes PRRSV genome synthesis by interacting with viral nonstructural protein Nsp2; knockdown of SRP14 inhibits PRRSV replication, and this pathway is regulated upstream by IRF8 (which suppresses miR-10a) and miR-10a (which targets SRP14 mRNA for translational repression).","method":"Co-immunoprecipitation (SRP14-Nsp2 interaction), siRNA knockdown, viral replication assays, luciferase reporter assay for miR-10a targeting","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP of SRP14-Nsp2 interaction combined with functional knockdown assays, consistent with prior study (PMID:28086075)","pmids":["35293774"],"is_preprint":false},{"year":2023,"finding":"SRP9/SRP14 localizes to the nucleus and transcriptionally regulates 7SL RNA and BC200 RNA expression; knockdown of SRP9/SRP14 reduces 7SL and BC200 steady-state levels by reducing their transcription rate rather than altering RNA decay. Nuclear localization of SRP9/SRP14 was confirmed by immunofluorescence and subcellular fractionation.","method":"siRNA knockdown, RNA transcription rate measurements, RNA stability assays, immunofluorescence, subcellular fractionation","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — nuclear localization confirmed by two methods with functional transcriptional consequence, single lab","pmids":["37156570"],"is_preprint":false},{"year":2024,"finding":"During ER stress, PERK-mediated eIF2α phosphorylation causes a reduction in SRP14 protein levels (independent of ATF4/ATF3 transcription factors); this SRP14 reduction correlates with decreased translocation of cathepsin D. Enforced expression of elongation-arrest-capable SRP14 prevents reduced translocation in stressed cells, whereas an elongation-arrest-deficient mutant does not. Overexpression of SRP14 augments UPR and aggravates ER-stress-induced cell death, indicating that the PERK-SRP14 axis mediates translocational attenuation as a protective UPR mechanism.","method":"Multi-omics analysis, siRNA knockdown, overexpression of wild-type and mutant SRP14, cathepsin D translocation assay, cell viability assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — defined loss- and gain-of-function with elongation-arrest mutant controls and specific translocation readout, multiple orthogonal methods","pmids":["38943644"],"is_preprint":false},{"year":2024,"finding":"The P124A mutation in the alanine-rich C-terminal domain of SRP14 causes faster migration on SDS-PAGE but does not affect SRP RNA stability, cell morphology, or cell growth, demonstrating it is a functionally neutral natural variant.","method":"Mutagenesis, SDS-PAGE, ectopic expression in multiple cell lines, functional assays (cell growth, morphology, SRP RNA stability)","journal":"Acta biochimica et biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — mutagenesis with multiple functional readouts, single lab, negative functional result well controlled","pmids":["38273782"],"is_preprint":false},{"year":2025,"finding":"The Alu domain of SRP RNAs (mediated by SRP9 and SRP14 protein interactions) is sufficient to target SRP RNAs to lysosomes for degradation in an autophagy-dependent manner.","method":"Lysosomal RNA profiling, autophagy mutant analysis, domain-swap experiments","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single study, mechanistic detail of SRP14-specific contribution not fully separated from SRP9","pmids":["40964324"],"is_preprint":true},{"year":2025,"finding":"Mutation of a critical guanosine in the U-turn motif of the BC200 Alu pseudoknot domain significantly reduces BC200 expression. A short human Alu RNA (EB120) lacking the canonical U-turn nucleotide triad also lacks association with SRP9/SRP14 in a cellular context, demonstrating that the pseudoknot U-turn structure is required for SRP9/SRP14 binding to Alu RNAs.","method":"Site-directed mutagenesis, immunoprecipitation, cell line and tissue expression analysis, small-angle X-ray scattering, computational structure prediction","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis combined with structural analysis and cellular immunoprecipitation, single lab","pmids":["40345827"],"is_preprint":false}],"current_model":"SRP14 functions as the key component of the SRP Alu domain, forming an obligate heterodimer with SRP9 (or homodimer in some yeasts) that binds the Alu RNA of 7SL to constitute the elongation arrest domain of SRP; this interaction requires a positively charged surface formed by conserved basic residues on both proteins, the Alu domain occupies the ribosomal subunit interface upon signal sequence recognition to delay nascent chain elongation and ensure translocation competence at rate-limiting SRP receptor concentrations, the PERK-SRP14 axis additionally mediates translocational attenuation during ER stress, SRP9/SRP14 exists in large excess over SRP in primate cells and binds Alu and BC200 RNAs in vivo, and the heterodimer also localizes to the nucleus where it transcriptionally regulates 7SL and BC200 RNA expression."},"narrative":{"mechanistic_narrative":"SRP14 is the defining protein component of the signal recognition particle (SRP) Alu domain, the module that couples nascent-chain elongation to membrane targeting. It functions as an obligate heterodimer with SRP9: neither protein alone binds SRP RNA specifically, and the heterodimer is required both for stable RNA association and for restoring elongation arrest activity to SRP depleted of SRP9/14 [PMID:2153922]. Crystallography shows SRP9 and SRP14 adopt a shared alpha-beta-beta-beta-alpha fold that assembles into a pseudo-2-fold symmetric saddle presenting a positively charged concave surface that docks onto the conserved U-turn core of the Alu RNA 5' domain, after which the 3' domain folds back to form the compact Alu RNP [PMID:9233785, PMID:11089964, PMID:11350037, PMID:40345827]. Functionally, the C-terminal tail of SRP14 mediates ribosomal contacts required for elongation arrest — its truncation abolishes arrest while leaving signal recognition, targeting, and ribosome binding intact [PMID:9115358] — and a basic platform formed by the KRDKK pentapeptide of SRP14 together with lysines of SRP9 contacts the ribosome at the subunit interface to delay elongation [PMID:14705936, PMID:20348448]. This elongation arrest is physiologically important: it keeps nascent chains translocation-competent when SRP receptor is rate-limiting, so arrest-deficient SRP14 produces secretion defects and reduced growth that are rescued by lowering translation rate or raising receptor levels [PMID:18455985]. The arrest function is conserved to yeast, where Srp14p acts as a homodimer on scR1 RNA and its C-terminal truncation impairs translocation and growth in vivo [PMID:10573124, PMID:10921896]. Beyond its core SRP role, SRP9/SRP14 exists in large cytoplasmic excess over SRP and binds Alu and neural BC200 RNAs in vivo [PMID:7542942, PMID:9605471], localizes to the nucleus where it transcriptionally promotes 7SL and BC200 RNA expression [PMID:37156570], and participates in the PERK-driven unfolded protein response, where PERK-mediated loss of SRP14 attenuates translocation as a protective ER-stress mechanism dependent on its elongation-arrest activity [PMID:38943644].","teleology":[{"year":1990,"claim":"Established that SRP14 does not act alone but requires SRP9 to form a functional RNA-binding unit, defining the molecular basis of the Alu domain.","evidence":"In vitro reconstitution with recombinant proteins and elongation arrest assays in cell-free translation","pmids":["2153922"],"confidence":"High","gaps":["Did not resolve the structural basis of heterodimerization","Did not map which residues contact RNA"]},{"year":1994,"claim":"Showed the heterodimer fold, not the native chain termini, is what matters, since single-chain fusions in either permutation reconstitute RNA binding and function.","evidence":"Single-chain SRP9-SRP14 fusion proteins tested in RNA-binding and cell-free arrest/translocation assays","pmids":["7518078"],"confidence":"High","gaps":["Did not define the minimal RNA element recognized","Did not localize ribosome-contacting regions"]},{"year":1995,"claim":"Revealed that SRP9/14 is far more abundant than SRP and binds Alu RNAs as a distinct 8.5S particle in vivo, implying functions beyond the canonical SRP.","evidence":"Immunoprecipitation, subcellular fractionation and quantitative immunoblotting in primate cells","pmids":["7542942"],"confidence":"High","gaps":["Function of the excess cytoplasmic pool not determined","Significance of Alu RNA complexes left open"]},{"year":1995,"claim":"Linked an anthropoid GCA-repeat expansion to extended alanine-rich SRP14 isoforms with elevated protein levels and Alu RNA-binding activity, an evolutionary specialization.","evidence":"Gene cloning, sequencing, in vitro binding assays and comparative genomics","pmids":["7534378"],"confidence":"Medium","gaps":["Functional consequence of the C-terminal extension for SRP not directly tested","Mechanism linking extension to higher protein levels unknown"]},{"year":1997,"claim":"Provided the atomic structure of the heterodimer, showing a saddle-shaped pseudo-symmetric dimer with a basic concave RNA-binding surface.","evidence":"2.5 A X-ray crystal structure of mouse SRP9/14","pmids":["9233785"],"confidence":"High","gaps":["Structure was protein-only, without bound RNA","Ribosome contacts not visualized"]},{"year":1997,"claim":"Separated SRP14's roles by mutation: the C-terminus is dispensable for assembly and targeting but specifically required for ribosome contacts that produce elongation arrest, and it influences Alu RNA conformation.","evidence":"C-terminal truncation (SRP14-20C) reconstitution, RNA chemical probing, cell-free arrest/translocation assays","pmids":["9115358"],"confidence":"High","gaps":["Exact ribosomal partners of the C-terminus not identified","Structural detail of the RNA conformational change unresolved"]},{"year":1997,"claim":"Mapped residue-level determinants of RNA binding and dimerization, distinguishing the contributions of SRP9 and SRP14 to the complex.","evidence":"Site-directed mutagenesis with in vitro dimerization and RNA-binding assays","pmids":["9214658"],"confidence":"High","gaps":["Did not connect these residues to elongation arrest output","Did not test mutants in cellular context"]},{"year":1997,"claim":"Defined an 86-nt minimal autonomous Alu RNA folding unit (SA86) sufficient for SRP9/14 recognition, delimiting the binding determinant.","evidence":"Ribozyme-generated RNA variants and quantitative equilibrium competition binding assays","pmids":["9409618"],"confidence":"High","gaps":["Structure of the bound minimal RNA not resolved at this stage","Functional readout of arrest not tested with minimal RNA"]},{"year":1997,"claim":"Showed binding affinity for diverse Alu-like RNAs (including BC200) scales inversely with evolutionary distance from 7SL, indicating broad but ranked recognition.","evidence":"Quantitative competition binding with recombinant human and mouse SRP9/14 across RNA species","pmids":["9016560"],"confidence":"Medium","gaps":["Higher human affinity not explained by the C-terminal extension","In vivo consequence of differential affinity not established"]},{"year":1998,"claim":"Demonstrated SRP9/14 is a bona fide component of the neural BC200 RNP in primate brain, extending its biology to a non-SRP context in vivo.","evidence":"Immunoprecipitation of BC200 RNA with anti-SRP9 antibodies from brain tissue","pmids":["9605471"],"confidence":"Medium","gaps":["Functional role within the BC200 RNP not determined","Single immunoprecipitation without reciprocal validation"]},{"year":1999,"claim":"Established conservation and divergence of the Alu domain in yeast, where Srp14p binds scR1 RNA as a homodimer using conserved RNA motifs and basic residues.","evidence":"Immunoprecipitation, RNA footprinting and mutagenesis in S. cerevisiae","pmids":["10573124"],"confidence":"High","gaps":["Why yeast uses a homodimer versus heterodimer not explained","Did not test elongation arrest in this study"]},{"year":2000,"claim":"Visualized SRP9/14 bound to Alu RNA, showing tight binding to the U-turn core of the 5' domain and weaker docking of the 3' domain, yielding a model of the assembled Alu domain.","evidence":"Two X-ray crystal structures of SRP9/14-Alu RNA complexes with biochemical validation","pmids":["11089964"],"confidence":"High","gaps":["Conformation in the context of the ribosome not captured","Dynamics of 3' domain docking inferred, not directly observed"]},{"year":2000,"claim":"Showed elongation arrest is a physiologically essential, conserved SRP function by tying Srp14p C-terminal truncation to translocation defects and growth phenotypes in vivo.","evidence":"Yeast SRP purification, in vitro arrest assays, in vivo growth and translocation assays with deltaC29 mutant","pmids":["10921896"],"confidence":"High","gaps":["Molecular detail of ribosome interaction in yeast not mapped","Did not establish the mammalian in vivo requirement"]},{"year":2001,"claim":"Defined the ordered assembly pathway: heterodimerization precedes 5' domain binding, which creates the site for a 180-degree fold-back of the 3' domain into the compact Alu RNP.","evidence":"Gel shift, filter binding, small-angle X-ray scattering and analytical ultracentrifugation","pmids":["11350037"],"confidence":"High","gaps":["Trigger for the large conformational change not defined","Kinetics of assembly in cells unknown"]},{"year":2004,"claim":"Placed the Alu domain physically at the ribosomal subunit interface, with SRP14 contacting both subunits upon signal sequence recognition, explaining how arrest is effected.","evidence":"Protein-protein cross-linking in functional SRP-ribosome complexes with immunoprecipitation","pmids":["14705936"],"confidence":"High","gaps":["Identity of all contacted ribosomal proteins not fully resolved","Static rather than dynamic view of the interaction"]},{"year":2010,"claim":"Identified the basic platform—SRP14 KRDKK plus SRP9 lysines clustered on one heterodimer face—as the elongation-arrest interface with ribosomal RNA.","evidence":"Site-directed mutagenesis with cell-free and mammalian cell complementation arrest assays","pmids":["20348448"],"confidence":"High","gaps":["Direct structural contact with rRNA phosphate backbone inferred, not visualized","Whether these residues also contact ribosomal proteins unresolved"]},{"year":2008,"claim":"Demonstrated the physiological purpose of elongation arrest in mammals: it keeps nascent chains translocation-competent when SRP receptor is limiting, with arrest-deficient SRP14 causing secretion and growth defects rescuable by tuning translation or receptor levels.","evidence":"siRNA depletion and mutant complementation in mammalian cells with secretion, growth, and SR-overexpression rescue","pmids":["18455985"],"confidence":"High","gaps":["Quantitative thresholds of SR limitation not defined","Did not address SRP14 roles outside targeting"]},{"year":2008,"claim":"Linked SRP14 (via 7SL RNA) to competition with APOBEC3 proteins for HIV virion packaging, an unexpected virology connection.","evidence":"siRNA knockdown of SRP14, HIV virion infectivity assays and 7SL RT-PCR","pmids":["18597676"],"confidence":"Medium","gaps":["7SL shown not essential for APOBEC3 packaging","Direct SRP14 involvement versus 7SL effect not separated"]},{"year":2009,"claim":"Provided a structural ortholog (S. pombe SRP14 homodimer) supporting conservation of U-turn-centered RNA contacts across fungi.","evidence":"X-ray crystallography of SpSRP14 with structural comparison to human complex","pmids":["19390147"],"confidence":"Medium","gaps":["Functional inference by structural comparison only","No bound RNA in the structure"]},{"year":2013,"claim":"Showed SRP14 is rate-limiting for translocation in industrial cells, since its overexpression rescued processing and secretion of an arrest-prone antibody.","evidence":"Overexpression in CHO cells with secretion and fractionation assays","pmids":["23380542"],"confidence":"Medium","gaps":["Mechanistic specificity to SRP14 versus co-overexpressed factors not isolated","Single cell-engineering context"]},{"year":2021,"claim":"Identified a non-canonical SRP14 role in HIV biology through direct binding to the tat mRNA TIM-TAM element, controlling tat translation and latency.","evidence":"AP-MS, RNA footprinting, knockdown, reporter assays and overexpression in primary CD4+ T cells","pmids":["34194479"],"confidence":"Medium","gaps":["Relationship to canonical SRP function unclear","Single lab without independent confirmation"]},{"year":2022,"claim":"Extended SRP14 to another viral system, showing interaction with PRRSV Nsp2 to promote genome synthesis under miR-10a/IRF8 regulation.","evidence":"Co-immunoprecipitation, knockdown, replication assays and miR-10a reporter assays","pmids":["35293774"],"confidence":"Medium","gaps":["Direct versus indirect SRP14-Nsp2 interaction not fully characterized","Mechanism of genome synthesis support unresolved"]},{"year":2023,"claim":"Revealed a nuclear, transcription-regulatory function: SRP9/SRP14 promotes 7SL and BC200 transcription, indicating feedback control over its own RNA partners.","evidence":"Knockdown with transcription-rate and stability measurements, immunofluorescence and subcellular fractionation","pmids":["37156570"],"confidence":"Medium","gaps":["Mechanism of transcriptional stimulation unknown","Nuclear import pathway not defined"]},{"year":2024,"claim":"Placed SRP14 in the unfolded protein response, where PERK-driven loss of SRP14 attenuates translocation as a protective mechanism dependent on its arrest activity.","evidence":"Multi-omics, knockdown and wild-type/arrest-mutant overexpression with cathepsin D translocation and viability assays","pmids":["38943644"],"confidence":"High","gaps":["Mechanism of PERK-driven SRP14 reduction not fully defined","Breadth of substrates affected during stress unknown"]},{"year":2024,"claim":"Classified the C-terminal P124A change as a functionally neutral natural variant, refining interpretation of SRP14 sequence variation.","evidence":"Mutagenesis with ectopic expression and growth, morphology and RNA-stability assays across cell lines","pmids":["38273782"],"confidence":"Medium","gaps":["Did not test elongation arrest directly","Other C-terminal variants not surveyed"]},{"year":2025,"claim":"Pinpointed the pseudoknot U-turn structure as the structural requirement for SRP9/SRP14 binding to Alu RNAs, including BC200.","evidence":"Mutagenesis, immunoprecipitation, expression analysis, SAXS and computational structure 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The heterodimer is also required to restore elongation arrest activity to SRP depleted of SRP9/14.\",\n      \"method\": \"In vitro reconstitution with recombinant proteins, RNA-protein binding assay, elongation arrest assay in cell-free translation system\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with functional readout (elongation arrest), replicated across multiple experiments in the same study\",\n      \"pmids\": [\"2153922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Single-chain fusion proteins encoding SRP14 and SRP9 sequences in either permutation bind SRP RNA as monomers folded into a heterodimer-like structure and restore elongation arrest and translocation activity to SRP(-9/14), demonstrating that the N- and C-termini of both proteins are dispensable for folding, RNA binding, and biological function.\",\n      \"method\": \"In vitro reconstitution, RNA-binding assay, cell-free elongation arrest and translocation assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with functional validation, single lab with multiple orthogonal assays\",\n      \"pmids\": [\"7518078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"SRP9/14 heterodimer is present at more than 20-fold excess over SRP in primate cells, with the majority cytoplasmic and not bound to small RNAs; a significant fraction of small cytoplasmic Alu RNA is complexed with SRP9/14 in an 8.5S particle in vivo.\",\n      \"method\": \"Immunoprecipitation, subcellular fractionation, sucrose gradient sedimentation, quantitative immunoblotting\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and fractionation with quantitative analysis, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"7542942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"In early anthropoids, the SRP14 gene acquired a GCA trinucleotide repeat in its 3'-coding region producing SRP14 isoforms with extended alanine-rich C-terminal tails; this C-terminal extension is associated with increased SRP14 polypeptide levels and Alu RNA-binding activity.\",\n      \"method\": \"Gene cloning, sequencing, in vitro binding assays, comparative genomics\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — binding assays and genetic analysis, single lab, multiple species comparisons\",\n      \"pmids\": [\"7534378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Monomeric scAlu RNA and nascent dimeric Alu RNAs are assembled into SRP9/14-containing RNPs in vivo after adenovirus infection, while SRP levels remain unchanged, demonstrating that induced Alu transcripts are specifically recruited to SRP9/14.\",\n      \"method\": \"Immunoprecipitation with anti-SRP9 antisera, Northern blotting\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — immunoprecipitation with co-purified RNA analysis, single lab, consistent results across conditions\",\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 share an alpha-beta-beta-beta-alpha fold (Alu binding module), form a pseudo 2-fold symmetric saddle-like heterodimer with a curved six-stranded amphipathic beta-sheet, and present a positively charged concave surface for RNA binding.\",\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 with detailed atomic model\",\n      \"pmids\": [\"9233785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"C-terminal truncation of SRP14 (SRP14-20C) forms a stable complex with SRP9 and SRP RNA but completely abolishes elongation arrest activity; the truncated particle retains signal recognition, targeting, and ribosome binding, indicating that the C-terminus of SRP14 is specifically required for interactions with the ribosome that effect elongation arrest. The truncation also induces tertiary structure changes in the Alu RNA, revealing a critical role of the RNA conformation in elongation arrest.\",\n      \"method\": \"In vitro reconstitution, cell-free translation/translocation assay, chemical probing of RNA structure, elongation arrest assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution with mutagenesis and multiple functional assays, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"9115358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Mutational analysis identified that in SRP9, acidic residues in the N-terminal alpha-helix and adjacent loop are critical for RNA binding, while in SRP14, a flexible internal loop region is critical for RNA binding; dimerization requirements differ substantially between SRP9 and SRP14. SRP RNA can rescue certain dimerization-defective SRP14 variants into stable complexes.\",\n      \"method\": \"In vitro dimerization and RNA-binding assays, site-directed mutagenesis\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic mutagenesis with quantitative binding assays, multiple mutants tested\",\n      \"pmids\": [\"9214658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"An 86-nucleotide minimal Alu RNA folding domain (SA86) was defined that specifically binds SRPphi14-9 (single-chain SRP14-SRP9 fusion); this minimal domain consists of two stem-loops connected by a conserved bulge and part of the central adaptor stem, and it functions as an autonomous folding unit for SRP9/14 recognition.\",\n      \"method\": \"Ribozyme-mediated in vitro RNA production, quantitative equilibrium competition binding assay\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — quantitative in vitro binding assays with systematic RNA variant analysis, multiple controls\",\n      \"pmids\": [\"9409618\"],\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; the relative dissociation constants are inversely proportional to evolutionary distance between the Alu RNA species and 7SL RNA. The additional C-terminal domain of anthropoid SRP14 does not explain this higher affinity.\",\n      \"method\": \"Quantitative binding assays (equilibrium competition), comparison of recombinant human and mouse SRP9/14\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative binding assays with multiple RNA species and two protein variants, single lab\",\n      \"pmids\": [\"9016560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The SRP9 protein (and by inference the SRP9/14 heterodimer) is an integral part of the neural BC200 RNP in primate brain in vivo, as demonstrated by immunoprecipitation of BC200 RNA with anti-SRP9 antibodies.\",\n      \"method\": \"Immunoprecipitation from brain tissue with anti-SRP9 antibodies\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single immunoprecipitation experiment from brain tissue, corroborated by in vitro binding data\",\n      \"pmids\": [\"9605471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"In S. cerevisiae, the Alu domain homolog consists of Srp14p bound as a homodimer (not a heterodimer with SRP9) to the 5' sequences of scR1 RNA; the minimal binding site is 99 nt. The conserved UGUAAU motif and certain basic amino acid residues conserved between mammalian SRP14 and yeast Srp14p are essential for RNA binding in both organisms.\",\n      \"method\": \"Immunoprecipitation, RNA footprinting, site-directed mutagenesis, in vitro binding assays\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis combined with footprinting and binding assays, multiple orthogonal methods\",\n      \"pmids\": [\"10573124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Two crystal structures of the SRP9/14 heterodimer bound to the Alu RNA 5' domain, and to a construct containing both 5' and 3' domains, revealed that SRP9/14 binds strongly to the conserved core of the 5' domain which forms a U-turn, and that the 3' domain docks more weakly. A model of the complete Alu domain consistent with biochemical data was proposed.\",\n      \"method\": \"X-ray crystallography (two structures), biochemical validation\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — two crystal structures in a single study, supported by extensive biochemical data\",\n      \"pmids\": [\"11089964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Yeast SRP has elongation arrest activity; C-terminal truncation of Srp14p (deltaC29) eliminates elongation arrest, substantially reduces translocation efficiency, and causes constitutive defects in coupling protein translation and translocation and temperature-sensitive growth in vivo. This demonstrates that elongation arrest is a physiologically important and conserved function of eukaryotic SRP.\",\n      \"method\": \"Yeast SRP purification, in vitro elongation arrest assay, in vivo growth and translocation assays, genetic analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro and in vivo assays with defined mutant, multiple orthogonal readouts, yeast model\",\n      \"pmids\": [\"10921896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The SRP Alu domain assembles hierarchically: SRP9 and SRP14 first heterodimerize, then bind the Alu RNA 5' domain, creating the binding site for the 3' domain; Alu RNA then undergoes a large conformational change where the flexibly linked 3' domain folds back 180° onto the 5' domain complex to form the final compact Alu RNP.\",\n      \"method\": \"Biochemical assembly assays (gel shift, filter binding), small-angle X-ray scattering, analytical ultracentrifugation\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple biophysical and biochemical methods establishing ordered assembly pathway\",\n      \"pmids\": [\"11350037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Protein cross-linking in functional complexes demonstrates that SRP14 is in close physical proximity to several ribosomal proteins; cross-linking occurs even without a signal sequence, but upon signal sequence recognition, SRP14 cross-links to proteins from both the large and small ribosomal subunits, indicating that the Alu domain occupies a defined position at the ribosomal subunit interface during elongation arrest.\",\n      \"method\": \"Protein-protein cross-linking in functional SRP-ribosome complexes, immunoprecipitation\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cross-linking in defined functional complexes with signal sequence-dependent changes, multiple ribosomal contacts mapped\",\n      \"pmids\": [\"14705936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SRP14 depletion in mammalian cells causes inefficient targeting of preproteins due to rate-limiting SRP receptor (SR) concentrations; complementation with elongation-arrest-deficient SRP14 mutants results in defects in secretion, depletion of endogenous membrane proteins, and reduced cell growth. These defects are rescued by reducing protein synthesis rate or increasing SR expression, demonstrating that the elongation arrest function of SRP14 keeps nascent chains translocation-competent during SR-limited targeting.\",\n      \"method\": \"siRNA depletion in mammalian cells, complementation with mutant SRP14 variants, secretion assays, cell growth assays, SR overexpression rescue\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KD/KO with defined rescue experiments, multiple orthogonal readouts across multiple conditions, independently validated mechanisms\",\n      \"pmids\": [\"18455985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"APOBEC3G and APOBEC3F are recruited into HIV virions when SRP14 (or SRP19) is depleted by RNA interference, indicating that 7SL RNA (which requires SRP14 for its assembly into SRP) competes with APOBEC3 proteins for virion packaging but is not an essential mediator of APOBEC3F/3G packaging.\",\n      \"method\": \"siRNA knockdown of SRP14, HIV virion infectivity assay, RT-PCR for 7SL RNA\",\n      \"journal\": \"Retrovirology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — siRNA knockdown with virology readouts, single lab, two SRP components tested\",\n      \"pmids\": [\"18597676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Mutational analysis identified two patches of basic amino acid residues essential for SRP elongation arrest activity: a basic pentapeptide KRDKK in SRP14 and three lysines in the solvent-accessible alpha2 helix of SRP9; the internal loop of SRP14 is dispensable. All essential residues cluster on one face of the heterodimer, suggesting they form a positively charged platform for interactions with ribosomal RNA phosphate backbone.\",\n      \"method\": \"Site-directed mutagenesis, cell-free translation/translocation assay, mammalian cell complementation assay\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic mutagenesis with functional validation in both cell-free and cellular systems, multiple orthogonal methods\",\n      \"pmids\": [\"20348448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Crystal structure of S. pombe SRP14 (SpSRP14) reveals it crystallizes as a homodimer; comparison with human SRP9/14-Alu RNA complex suggests that many protein-RNA contacts centered on the conserved U-turn motif are likely conserved in fission yeast.\",\n      \"method\": \"X-ray crystallography (RIP and SAD phasing), structural comparison\",\n      \"journal\": \"Acta crystallographica. Section D, Biological crystallography\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystal structure of ortholog, functional inference by structural comparison only, single study\",\n      \"pmids\": [\"19390147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Overexpression of human SRP14 (along with other secretory pathway components) in CHO cells restored proper processing and secretion of a difficult-to-express immunoglobulin that was subject to translational arrest, improper light chain cleavage, and insoluble aggregation, demonstrating that SRP14 is rate-limiting for protein translocation efficiency.\",\n      \"method\": \"Overexpression in CHO cells, secretion assays, protein fractionation, Western blotting\",\n      \"journal\": \"Metabolic engineering\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — gain-of-function in mammalian cells with defined secretion readout, single lab\",\n      \"pmids\": [\"23380542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SRP14 binds directly to TIM-TAM, a conserved RNA sequence-structure in HIV tat mRNA that functions as a Tat IRES modulator; knockdown of SRP14 negatively affects tat mRNA processing and translation as well as Tat-mediated transactivation, increasing latent infection. Overexpression of SRP14 in resting CD4+ T cells from ART patients reversed HIV-1 latency and induced virus production.\",\n      \"method\": \"Affinity purification-mass spectrometry, RNA footprinting, siRNA knockdown, luciferase reporter assay, dual-color HIV reporter virus infection, overexpression in primary T cells\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods including footprinting and functional assays, single lab\",\n      \"pmids\": [\"34194479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SRP14 interacts with HPIP (under hypoxic conditions) and stimulates MMP9 synthesis, contributing to cell migration/invasion and EMT in breast cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, MMP9 expression assays, migration/invasion assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP and phenotypic assays, single lab, interaction mechanism not deeply characterized\",\n      \"pmids\": [\"34767928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SRP14 promotes PRRSV genome synthesis by interacting with viral nonstructural protein Nsp2; knockdown of SRP14 inhibits PRRSV replication, and this pathway is regulated upstream by IRF8 (which suppresses miR-10a) and miR-10a (which targets SRP14 mRNA for translational repression).\",\n      \"method\": \"Co-immunoprecipitation (SRP14-Nsp2 interaction), siRNA knockdown, viral replication assays, luciferase reporter assay for miR-10a targeting\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP of SRP14-Nsp2 interaction combined with functional knockdown assays, consistent with prior study (PMID:28086075)\",\n      \"pmids\": [\"35293774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SRP9/SRP14 localizes to the nucleus and transcriptionally regulates 7SL RNA and BC200 RNA expression; knockdown of SRP9/SRP14 reduces 7SL and BC200 steady-state levels by reducing their transcription rate rather than altering RNA decay. Nuclear localization of SRP9/SRP14 was confirmed by immunofluorescence and subcellular fractionation.\",\n      \"method\": \"siRNA knockdown, RNA transcription rate measurements, RNA stability assays, immunofluorescence, subcellular fractionation\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — nuclear localization confirmed by two methods with functional transcriptional consequence, single lab\",\n      \"pmids\": [\"37156570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"During ER stress, PERK-mediated eIF2α phosphorylation causes a reduction in SRP14 protein levels (independent of ATF4/ATF3 transcription factors); this SRP14 reduction correlates with decreased translocation of cathepsin D. Enforced expression of elongation-arrest-capable SRP14 prevents reduced translocation in stressed cells, whereas an elongation-arrest-deficient mutant does not. Overexpression of SRP14 augments UPR and aggravates ER-stress-induced cell death, indicating that the PERK-SRP14 axis mediates translocational attenuation as a protective UPR mechanism.\",\n      \"method\": \"Multi-omics analysis, siRNA knockdown, overexpression of wild-type and mutant SRP14, cathepsin D translocation assay, cell viability assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined loss- and gain-of-function with elongation-arrest mutant controls and specific translocation readout, multiple orthogonal methods\",\n      \"pmids\": [\"38943644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The P124A mutation in the alanine-rich C-terminal domain of SRP14 causes faster migration on SDS-PAGE but does not affect SRP RNA stability, cell morphology, or cell growth, demonstrating it is a functionally neutral natural variant.\",\n      \"method\": \"Mutagenesis, SDS-PAGE, ectopic expression in multiple cell lines, functional assays (cell growth, morphology, SRP RNA stability)\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — mutagenesis with multiple functional readouts, single lab, negative functional result well controlled\",\n      \"pmids\": [\"38273782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The Alu domain of SRP RNAs (mediated by SRP9 and SRP14 protein interactions) is sufficient to target SRP RNAs to lysosomes for degradation in an autophagy-dependent manner.\",\n      \"method\": \"Lysosomal RNA profiling, autophagy mutant analysis, domain-swap experiments\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single study, mechanistic detail of SRP14-specific contribution not fully separated from SRP9\",\n      \"pmids\": [\"40964324\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Mutation of a critical guanosine in the U-turn motif of the BC200 Alu pseudoknot domain significantly reduces BC200 expression. A short human Alu RNA (EB120) lacking the canonical U-turn nucleotide triad also lacks association with SRP9/SRP14 in a cellular context, demonstrating that the pseudoknot U-turn structure is required for SRP9/SRP14 binding to Alu RNAs.\",\n      \"method\": \"Site-directed mutagenesis, immunoprecipitation, cell line and tissue expression analysis, small-angle X-ray scattering, computational structure prediction\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis combined with structural analysis and cellular immunoprecipitation, single lab\",\n      \"pmids\": [\"40345827\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SRP14 functions as the key component of the SRP Alu domain, forming an obligate heterodimer with SRP9 (or homodimer in some yeasts) that binds the Alu RNA of 7SL to constitute the elongation arrest domain of SRP; this interaction requires a positively charged surface formed by conserved basic residues on both proteins, the Alu domain occupies the ribosomal subunit interface upon signal sequence recognition to delay nascent chain elongation and ensure translocation competence at rate-limiting SRP receptor concentrations, the PERK-SRP14 axis additionally mediates translocational attenuation during ER stress, SRP9/SRP14 exists in large excess over SRP in primate cells and binds Alu and BC200 RNAs in vivo, and the heterodimer also localizes to the nucleus where it transcriptionally regulates 7SL and BC200 RNA expression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SRP14 is the defining protein component of the signal recognition particle (SRP) Alu domain, the module that couples nascent-chain elongation to membrane targeting. It functions as an obligate heterodimer with SRP9: neither protein alone binds SRP RNA specifically, and the heterodimer is required both for stable RNA association and for restoring elongation arrest activity to SRP depleted of SRP9/14 [#0]. Crystallography shows SRP9 and SRP14 adopt a shared alpha-beta-beta-beta-alpha fold that assembles into a pseudo-2-fold symmetric saddle presenting a positively charged concave surface that docks onto the conserved U-turn core of the Alu RNA 5' domain, after which the 3' domain folds back to form the compact Alu RNP [#5, #12, #14, #28]. Functionally, the C-terminal tail of SRP14 mediates ribosomal contacts required for elongation arrest — its truncation abolishes arrest while leaving signal recognition, targeting, and ribosome binding intact [#6] — and a basic platform formed by the KRDKK pentapeptide of SRP14 together with lysines of SRP9 contacts the ribosome at the subunit interface to delay elongation [#15, #18]. This elongation arrest is physiologically important: it keeps nascent chains translocation-competent when SRP receptor is rate-limiting, so arrest-deficient SRP14 produces secretion defects and reduced growth that are rescued by lowering translation rate or raising receptor levels [#16]. The arrest function is conserved to yeast, where Srp14p acts as a homodimer on scR1 RNA and its C-terminal truncation impairs translocation and growth in vivo [#11, #13]. Beyond its core SRP role, SRP9/SRP14 exists in large cytoplasmic excess over SRP and binds Alu and neural BC200 RNAs in vivo [#2, #10], localizes to the nucleus where it transcriptionally promotes 7SL and BC200 RNA expression [#24], and participates in the PERK-driven unfolded protein response, where PERK-mediated loss of SRP14 attenuates translocation as a protective ER-stress mechanism dependent on its elongation-arrest activity [#25].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Established that SRP14 does not act alone but requires SRP9 to form a functional RNA-binding unit, defining the molecular basis of the Alu domain.\",\n      \"evidence\": \"In vitro reconstitution with recombinant proteins and elongation arrest assays in cell-free translation\",\n      \"pmids\": [\"2153922\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural basis of heterodimerization\", \"Did not map which residues contact RNA\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Showed the heterodimer fold, not the native chain termini, is what matters, since single-chain fusions in either permutation reconstitute RNA binding and function.\",\n      \"evidence\": \"Single-chain SRP9-SRP14 fusion proteins tested in RNA-binding and cell-free arrest/translocation assays\",\n      \"pmids\": [\"7518078\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the minimal RNA element recognized\", \"Did not localize ribosome-contacting regions\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Revealed that SRP9/14 is far more abundant than SRP and binds Alu RNAs as a distinct 8.5S particle in vivo, implying functions beyond the canonical SRP.\",\n      \"evidence\": \"Immunoprecipitation, subcellular fractionation and quantitative immunoblotting in primate cells\",\n      \"pmids\": [\"7542942\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Function of the excess cytoplasmic pool not determined\", \"Significance of Alu RNA complexes left open\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Linked an anthropoid GCA-repeat expansion to extended alanine-rich SRP14 isoforms with elevated protein levels and Alu RNA-binding activity, an evolutionary specialization.\",\n      \"evidence\": \"Gene cloning, sequencing, in vitro binding assays and comparative genomics\",\n      \"pmids\": [\"7534378\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the C-terminal extension for SRP not directly tested\", \"Mechanism linking extension to higher protein levels unknown\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Provided the atomic structure of the heterodimer, showing a saddle-shaped pseudo-symmetric dimer with a basic concave RNA-binding surface.\",\n      \"evidence\": \"2.5 A X-ray crystal structure of mouse SRP9/14\",\n      \"pmids\": [\"9233785\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure was protein-only, without bound RNA\", \"Ribosome contacts not visualized\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Separated SRP14's roles by mutation: the C-terminus is dispensable for assembly and targeting but specifically required for ribosome contacts that produce elongation arrest, and it influences Alu RNA conformation.\",\n      \"evidence\": \"C-terminal truncation (SRP14-20C) reconstitution, RNA chemical probing, cell-free arrest/translocation assays\",\n      \"pmids\": [\"9115358\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Exact ribosomal partners of the C-terminus not identified\", \"Structural detail of the RNA conformational change unresolved\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Mapped residue-level determinants of RNA binding and dimerization, distinguishing the contributions of SRP9 and SRP14 to the complex.\",\n      \"evidence\": \"Site-directed mutagenesis with in vitro dimerization and RNA-binding assays\",\n      \"pmids\": [\"9214658\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not connect these residues to elongation arrest output\", \"Did not test mutants in cellular context\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Defined an 86-nt minimal autonomous Alu RNA folding unit (SA86) sufficient for SRP9/14 recognition, delimiting the binding determinant.\",\n      \"evidence\": \"Ribozyme-generated RNA variants and quantitative equilibrium competition binding assays\",\n      \"pmids\": [\"9409618\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the bound minimal RNA not resolved at this stage\", \"Functional readout of arrest not tested with minimal RNA\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Showed binding affinity for diverse Alu-like RNAs (including BC200) scales inversely with evolutionary distance from 7SL, indicating broad but ranked recognition.\",\n      \"evidence\": \"Quantitative competition binding with recombinant human and mouse SRP9/14 across RNA species\",\n      \"pmids\": [\"9016560\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Higher human affinity not explained by the C-terminal extension\", \"In vivo consequence of differential affinity not established\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstrated SRP9/14 is a bona fide component of the neural BC200 RNP in primate brain, extending its biology to a non-SRP context in vivo.\",\n      \"evidence\": \"Immunoprecipitation of BC200 RNA with anti-SRP9 antibodies from brain tissue\",\n      \"pmids\": [\"9605471\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role within the BC200 RNP not determined\", \"Single immunoprecipitation without reciprocal validation\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Established conservation and divergence of the Alu domain in yeast, where Srp14p binds scR1 RNA as a homodimer using conserved RNA motifs and basic residues.\",\n      \"evidence\": \"Immunoprecipitation, RNA footprinting and mutagenesis in S. cerevisiae\",\n      \"pmids\": [\"10573124\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why yeast uses a homodimer versus heterodimer not explained\", \"Did not test elongation arrest in this study\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Visualized SRP9/14 bound to Alu RNA, showing tight binding to the U-turn core of the 5' domain and weaker docking of the 3' domain, yielding a model of the assembled Alu domain.\",\n      \"evidence\": \"Two X-ray crystal structures of SRP9/14-Alu RNA complexes with biochemical validation\",\n      \"pmids\": [\"11089964\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformation in the context of the ribosome not captured\", \"Dynamics of 3' domain docking inferred, not directly observed\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Showed elongation arrest is a physiologically essential, conserved SRP function by tying Srp14p C-terminal truncation to translocation defects and growth phenotypes in vivo.\",\n      \"evidence\": \"Yeast SRP purification, in vitro arrest assays, in vivo growth and translocation assays with deltaC29 mutant\",\n      \"pmids\": [\"10921896\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular detail of ribosome interaction in yeast not mapped\", \"Did not establish the mammalian in vivo requirement\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined the ordered assembly pathway: heterodimerization precedes 5' domain binding, which creates the site for a 180-degree fold-back of the 3' domain into the compact Alu RNP.\",\n      \"evidence\": \"Gel shift, filter binding, small-angle X-ray scattering and analytical ultracentrifugation\",\n      \"pmids\": [\"11350037\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger for the large conformational change not defined\", \"Kinetics of assembly in cells unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Placed the Alu domain physically at the ribosomal subunit interface, with SRP14 contacting both subunits upon signal sequence recognition, explaining how arrest is effected.\",\n      \"evidence\": \"Protein-protein cross-linking in functional SRP-ribosome complexes with immunoprecipitation\",\n      \"pmids\": [\"14705936\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of all contacted ribosomal proteins not fully resolved\", \"Static rather than dynamic view of the interaction\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified the basic platform—SRP14 KRDKK plus SRP9 lysines clustered on one heterodimer face—as the elongation-arrest interface with ribosomal RNA.\",\n      \"evidence\": \"Site-directed mutagenesis with cell-free and mammalian cell complementation arrest assays\",\n      \"pmids\": [\"20348448\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct structural contact with rRNA phosphate backbone inferred, not visualized\", \"Whether these residues also contact ribosomal proteins unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated the physiological purpose of elongation arrest in mammals: it keeps nascent chains translocation-competent when SRP receptor is limiting, with arrest-deficient SRP14 causing secretion and growth defects rescuable by tuning translation or receptor levels.\",\n      \"evidence\": \"siRNA depletion and mutant complementation in mammalian cells with secretion, growth, and SR-overexpression rescue\",\n      \"pmids\": [\"18455985\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative thresholds of SR limitation not defined\", \"Did not address SRP14 roles outside targeting\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Linked SRP14 (via 7SL RNA) to competition with APOBEC3 proteins for HIV virion packaging, an unexpected virology connection.\",\n      \"evidence\": \"siRNA knockdown of SRP14, HIV virion infectivity assays and 7SL RT-PCR\",\n      \"pmids\": [\"18597676\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"7SL shown not essential for APOBEC3 packaging\", \"Direct SRP14 involvement versus 7SL effect not separated\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Provided a structural ortholog (S. pombe SRP14 homodimer) supporting conservation of U-turn-centered RNA contacts across fungi.\",\n      \"evidence\": \"X-ray crystallography of SpSRP14 with structural comparison to human complex\",\n      \"pmids\": [\"19390147\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional inference by structural comparison only\", \"No bound RNA in the structure\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed SRP14 is rate-limiting for translocation in industrial cells, since its overexpression rescued processing and secretion of an arrest-prone antibody.\",\n      \"evidence\": \"Overexpression in CHO cells with secretion and fractionation assays\",\n      \"pmids\": [\"23380542\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic specificity to SRP14 versus co-overexpressed factors not isolated\", \"Single cell-engineering context\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified a non-canonical SRP14 role in HIV biology through direct binding to the tat mRNA TIM-TAM element, controlling tat translation and latency.\",\n      \"evidence\": \"AP-MS, RNA footprinting, knockdown, reporter assays and overexpression in primary CD4+ T cells\",\n      \"pmids\": [\"34194479\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relationship to canonical SRP function unclear\", \"Single lab without independent confirmation\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended SRP14 to another viral system, showing interaction with PRRSV Nsp2 to promote genome synthesis under miR-10a/IRF8 regulation.\",\n      \"evidence\": \"Co-immunoprecipitation, knockdown, replication assays and miR-10a reporter assays\",\n      \"pmids\": [\"35293774\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect SRP14-Nsp2 interaction not fully characterized\", \"Mechanism of genome synthesis support unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a nuclear, transcription-regulatory function: SRP9/SRP14 promotes 7SL and BC200 transcription, indicating feedback control over its own RNA partners.\",\n      \"evidence\": \"Knockdown with transcription-rate and stability measurements, immunofluorescence and subcellular fractionation\",\n      \"pmids\": [\"37156570\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of transcriptional stimulation unknown\", \"Nuclear import pathway not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed SRP14 in the unfolded protein response, where PERK-driven loss of SRP14 attenuates translocation as a protective mechanism dependent on its arrest activity.\",\n      \"evidence\": \"Multi-omics, knockdown and wild-type/arrest-mutant overexpression with cathepsin D translocation and viability assays\",\n      \"pmids\": [\"38943644\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of PERK-driven SRP14 reduction not fully defined\", \"Breadth of substrates affected during stress unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Classified the C-terminal P124A change as a functionally neutral natural variant, refining interpretation of SRP14 sequence variation.\",\n      \"evidence\": \"Mutagenesis with ectopic expression and growth, morphology and RNA-stability assays across cell lines\",\n      \"pmids\": [\"38273782\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not test elongation arrest directly\", \"Other C-terminal variants not surveyed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Pinpointed the pseudoknot U-turn structure as the structural requirement for SRP9/SRP14 binding to Alu RNAs, including BC200.\",\n      \"evidence\": \"Mutagenesis, immunoprecipitation, expression analysis, SAXS and computational structure prediction\",\n      \"pmids\": [\"40345827\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Affinity contributions of individual U-turn residues not quantified\", \"Functional consequence for SRP arrest not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Suggested the Alu domain targets SRP RNAs to lysosomes for autophagy-dependent degradation, implicating SRP14 in RNA turnover.\",\n      \"evidence\": \"Lysosomal RNA profiling, autophagy mutant analysis and domain-swap experiments (preprint)\",\n      \"pmids\": [\"40964324\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"SRP14-specific contribution not separated from SRP9\", \"Physiological role of this degradation pathway unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SRP14's canonical SRP/translocation function mechanistically relates to its nuclear transcriptional regulation, non-SRP RNP partnerships, and the diverse viral interactions remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model linking cytoplasmic SRP, nuclear, and viral functions\", \"Nuclear import and transcriptional mechanism undefined\", \"Direct structural basis of viral RNA/protein interactions uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 2, 8, 9, 11, 28]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [6, 15, 16, 18]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0, 6, 13, 16]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 15]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [24]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 6, 16]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [16, 25]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [24]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [25]}\n    ],\n    \"complexes\": [\n      \"signal recognition particle (SRP)\",\n      \"SRP9/SRP14 heterodimer (Alu domain)\",\n      \"BC200 RNP\"\n    ],\n    \"partners\": [\n      \"SRP9\",\n      \"HPIP\",\n      \"PRRSV Nsp2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}