{"gene":"SRP68","run_date":"2026-06-10T07:46:41","timeline":{"discoveries":[{"year":1990,"finding":"SRP68 is a basic protein of 622 amino acids with a glycine-rich region near its amino terminus shared with some RNA-binding proteins; no sequence similarity to any known protein was detected at the time.","method":"cDNA cloning and sequencing of canine SRP68","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — primary sequence determination by cDNA cloning, single study","pmids":["1702390"],"is_preprint":false},{"year":1992,"finding":"SRP68/72 heterodimer binds directly and specifically to SRP RNA (Kd ≤7 nM) by increasing fluorescein anisotropy; binding is independent of and non-cooperative with SRP9/14 binding, indicating the two heterodimers associate randomly and independently with distinct domains of SRP RNA.","method":"Fluorescence spectroscopy using fluorescein-labeled SRP RNA, equilibrium binding assays","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with quantitative binding measurements, multiple controls, single lab","pmids":["1377027"],"is_preprint":false},{"year":1993,"finding":"SRP68 alone specifically binds 7S RNA via its NH2-terminal half; SRP72 incorporation into the RNP requires both 7S RNA and SRP68 (SRP72 cannot bind RNA alone); COOH-terminal portions of SRP68 and SRP72 contact each other, so SRP68 acts as a link between 7S RNA and SRP72.","method":"In vitro reconstitution of SRP RNP from purified components, domain-mapping with truncation constructs","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with domain-level mapping, replicated by later studies","pmids":["8388879"],"is_preprint":false},{"year":1994,"finding":"In yeast, Srp68p (SRP68 ortholog) is required for stable expression of yeast SRP: disruption of SRP68 leads to loss of SRP RNA and other SRP proteins, slow growth, and deficient protein translocation across the ER membrane.","method":"Gene disruption (knockout), immunoaffinity purification of yeast SRP, cell growth and translocation assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic KO with defined biochemical and cellular phenotypes, multiple orthogonal readouts","pmids":["7925282"],"is_preprint":false},{"year":2000,"finding":"GFP-SRP68 localizes not only to the cytoplasm and ER (consistent with its affinity for the ER-bound SRP receptor) but also to the nucleolus in transfected rat fibroblasts, suggesting partial SRP assembly or an unidentified activity occurs at the nucleolus.","method":"GFP fusion live-cell imaging and immunofluorescence in transfected rat fibroblasts","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization by live imaging with multiple SRP components examined, single lab","pmids":["10618370"],"is_preprint":false},{"year":2006,"finding":"The RNA-binding domain of SRP68 spans residues 52–252; a ~94-residue C-terminal region mediates binding to SRP72; the SRP68–SRP72 interaction is salt-stable and engages ~150 N-terminal residues of SRP72 within its predicted TPR-like region.","method":"Recombinant protein expression and purification, proteolytic fragment binding assays (pulldown/filter binding)","journal":"Protein science","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — domain mapping with multiple truncation fragments, single lab","pmids":["16672232"],"is_preprint":false},{"year":2006,"finding":"SRP68/72 binding to 7SL RNA brings the lower parts of helices 6 and 8 closer together, protects the SRP54 binding site (helix 8 asymmetric loop) from chemical modification, and—together with SRP19—rearranges the RNA into an SRP54-binding-competent state.","method":"Chemical and enzymatic probing (ethylation interference, hydroxyl radical footprinting, DMS modification, RNase cleavage) of all S-domain assembly intermediates","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal RNA probing methods on defined assembly intermediates, single lab","pmids":["17254600"],"is_preprint":false},{"year":2007,"finding":"SRP68/72 contacts SRP RNA primarily through residues in helices 5 (positions 222–231) and helix 8 (positions 176–191 and 202–214); SRP72 alone contacts only the 5ef region of helix 5 (residues 120–128) and does not require helices 6 or 8.","method":"Systematic mutagenesis of 18 SRP RNA helix positions combined with competitive double-filter binding assay with purified SRP68/72 and a SRP72 fragment","journal":"RNA biology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — systematic mutagenesis with defined readout, single lab","pmids":["18347438"],"is_preprint":false},{"year":2008,"finding":"SRP19 and SRP68/72 both bind helices 6 and 8 of SRP RNA but on opposite faces and at opposite ends; SRP72 binds largely via non-electrostatic interactions and enhances SRP68 affinity; the two proteins bind with moderate anti-cooperativity, arising from stabilization of distinct RNA conformations.","method":"Quantitative binding assays (filter binding), SHAPE RNA probing, analysis of cooperativity between SRP19 and SRP68/72","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — multiple methods (binding + RNA probing) in a single study, single lab","pmids":["18564060"],"is_preprint":false},{"year":2012,"finding":"SRP68/72 heterodimer (but not intact SRP) binds histone H4 tail peptides in vitro; H4R3 methylation (by PRMT1 or PRMT5) inhibits this binding; SRP68 and SRP72 associate with chromatin in vivo and activate transcription when tethered to a reporter, revealing a non-canonical chromatin/transcriptional regulatory function.","method":"Peptide pulldown/proteomics, in vitro histone tail binding assay, ChIP, tethered transcription reporter assay, PRMT1/PRMT5 regulation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (pulldown, ChIP, reporter assay), single lab","pmids":["23048028"],"is_preprint":false},{"year":2014,"finding":"Crystal structures of the SRP68 RNA-binding domain (SRP68-RBD) alone and in complex with SRP RNA and SRP19 reveal that SRP68-RBD is a tetratricopeptide-like module that binds a RNA three-way junction, bends the RNA, and inserts an α-helical arginine-rich motif (ARM) into the RNA major groove, thereby opening the conserved 5f RNA loop (which contacts ribosomal RNA in ribosome-bound SRP).","method":"X-ray crystallography of SRP68-RBD alone and in ternary complex with SRP RNA and SRP19","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structures with functional validation of RNA remodeling, landmark study","pmids":["24700861"],"is_preprint":false},{"year":2016,"finding":"Crystal structures of the SRP68 protein-binding domain (PBD) in complex with SRP72-PBD and of SRP72-RBD bound to the full S domain show: SRP72-PBD is a TPR repeat that binds an extended linear motif of SRP68 with high affinity; SRP72-RBD is a flexible peptide that crawls along 5e/5f RNA loops; a conserved tryptophan inserts into the 5e loop forming a novel K⁺-stabilized RNA kink-turn; SRP72-RBD remodels the 5f loop involved in ribosome binding. Cryo-EM docking reveals multiple SRP68/72–ribosome contact sites.","method":"X-ray crystallography of SRP68-PBD/SRP72-PBD complex and SRP72-RBD/S-domain complex; cryo-EM docking","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures complemented by cryo-EM, multiple complexes resolved in a single rigorous study","pmids":["27899666"],"is_preprint":false},{"year":2017,"finding":"Crystal structures of human apo-SRP72 and the SRP68/72 complex (1.7 Å) show SRP72 contains four atypical TPR repeats and a flexible C-terminal cap; apo-SRP72 dimerizes in solution but the homodimer dissociates to accommodate SRP68; a 23-residue hydrophobic extended peptide of SRP68 is sufficient for tight binding to SRP72. Cancer-associated mutations that disrupt SRP68–SRP72 interaction also abolish their co-localization with ER in mammalian cells.","method":"X-ray crystallography (apo-SRP72 and SRP68/72 complex), biophysical analyses (SEC, ITC), mutagenesis, co-localization in mammalian cells","journal":"Journal of molecular cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure at 1.7 Å with mutagenesis and cellular co-localization, multiple orthogonal methods","pmids":["28369529"],"is_preprint":false},{"year":2017,"finding":"CELF1 directly binds the SRP68 mRNA and destabilizes it; overexpression of SRP68 alone (causing SRP subunit imbalance) impairs cell migration/wound healing, indicating that balanced SRP68 levels are required for normal secretion and extracellular matrix function in myoblasts.","method":"RIP-crosslinking, in vitro CELF1 binding assay, mRNA half-life measurement in CELF1 KD cells, SRP68 overexpression with wound-healing assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (RIP, half-life, OE phenotype), single lab","pmids":["28129347"],"is_preprint":false},{"year":2019,"finding":"Reconstituted human SRP68/72 heterodimer shows ultrasensitive (avidity-based) binding to the ribosome via multiple contact sites dominated by the C-terminus of SRP72; SRP RNA alone does not bind the ribosome; full SRP binds ribosomes with nanomolar affinity through a two-step mechanism involving SRP54.","method":"Large-scale recombinant reconstitution of all human SRP components; microscale thermophoresis binding assays for individual components and assembly intermediates","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — complete reconstitution of human SRP with quantitative biophysical characterization, multiple components tested","pmids":["30649417"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM of full-length SRP68/72 reveals an extended dimerization domain beyond the previously characterized domains; SRP68 and SRP72 depend on each other for stability. The newly identified dimerization domain is both a protein- and RNA-binding domain. Comparative structural analysis suggests this domain undergoes dramatic translocation upon SRP docking onto the SRP receptor and positions near the Alu domain, indicating it may release elongation arrest by binding and detaching SRP9/14 from the ribosomal surface.","method":"Cryo-EM structure of full-length SRP68/72; comparative structural analysis with existing models","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — cryo-EM structure of full-length complex, mechanistic model is proposed from structural comparison rather than directly tested experimentally","pmids":["38366771"],"is_preprint":false}],"current_model":"SRP68 is the RNA-binding scaffold subunit of the SRP68/72 heterodimer: its N-terminal tetratricopeptide-like RNA-binding domain (RBD) contacts the three-way junction of helices 5/6/8 in SRP RNA, bending the RNA and inserting an arginine-rich motif into the major groove to open the 5f loop required for ribosome contact and elongation arrest; its C-terminal peptide binds the TPR domain of SRP72 with high affinity, and SRP68 is required for SRP72 incorporation into the particle; together, SRP68/72 remodel the 7SL RNA into an SRP54-binding-competent conformation and make multiple avidity-driven contacts with the ribosome, with the extended dimerization domain proposed to disengage the Alu domain/SRP9-14 from the ribosome upon ER docking; additionally, the SRP68/72 heterodimer has a non-canonical nuclear function in which it binds histone H4 tails and regulates transcription in a manner inhibited by H4R3 arginine methylation."},"narrative":{"mechanistic_narrative":"SRP68 is the RNA-binding scaffold subunit of the signal recognition particle (SRP) S domain, functioning together with SRP72 to remodel SRP (7SL) RNA into a conformation competent for co-translational protein targeting to the ER [PMID:8388879, PMID:17254600]. The SRP68/72 heterodimer binds SRP RNA directly and specifically with high affinity, associating with a distinct RNA domain independently of the SRP9/14 (Alu) module [PMID:1377027]. SRP68 makes the primary RNA contact through its N-terminal RNA-binding domain (residues ~52–252), while a C-terminal peptide links the particle to SRP72; SRP72 cannot bind RNA on its own and requires both 7S RNA and SRP68 for incorporation, so SRP68 acts as the obligatory bridge between RNA and SRP72 [PMID:8388879, PMID:16672232]. Crystallographic work established that the SRP68 RNA-binding domain is a tetratricopeptide-like module that binds an RNA three-way junction, bends the RNA, and inserts an arginine-rich α-helical motif into the major groove to open the conserved 5f loop that contacts ribosomal RNA in ribosome-bound SRP [PMID:24700861], while SRP68/72 binding draws helices 6 and 8 together and protects the SRP54-binding site, rearranging the RNA into an SRP54-competent state [PMID:17254600]. The reconstituted heterodimer binds the ribosome with ultrasensitive avidity through multiple contact sites, an interaction SRP RNA alone cannot make [PMID:30649417], and a full-length structure reveals an extended dimerization domain that, upon SRP docking onto the SRP receptor, repositions near the Alu domain and is implicated in releasing elongation arrest [PMID:38366771]. Genetically, SRP68 is required for stable SRP assembly and efficient ER translocation: its loss in yeast destabilizes the entire particle and impairs protein translocation [PMID:7925282]. Beyond its canonical role, the SRP68/72 heterodimer has a non-canonical nuclear activity, binding histone H4 tails, associating with chromatin, and activating transcription in a manner inhibited by H4R3 methylation [PMID:23048028].","teleology":[{"year":1990,"claim":"Established the primary structure of SRP68 as a basic, glycine-rich protein, providing the molecular starting point but leaving its function undefined since it matched no known protein.","evidence":"cDNA cloning and sequencing of canine SRP68","pmids":["1702390"],"confidence":"Medium","gaps":["No functional or RNA-binding activity demonstrated","No domain architecture defined beyond a glycine-rich region"]},{"year":1992,"claim":"Showed that SRP68/72 binds SRP RNA directly, specifically, and at a distinct site from SRP9/14, defining it as an independent RNA-binding module of the particle.","evidence":"Fluorescence anisotropy equilibrium binding assays with fluorescein-labeled SRP RNA","pmids":["1377027"],"confidence":"High","gaps":["Did not resolve which subunit contacts RNA","No RNA structural consequence of binding established"]},{"year":1993,"claim":"Resolved that SRP68 is the RNA-contacting subunit and the obligatory bridge that recruits SRP72, which cannot bind RNA alone, establishing the assembly hierarchy of the S domain.","evidence":"In vitro reconstitution from purified components with truncation domain mapping","pmids":["8388879"],"confidence":"High","gaps":["Residue-level RNA contacts unmapped","Structural basis of the SRP68–SRP72 interface unknown"]},{"year":1994,"claim":"Demonstrated in vivo that SRP68 is required for stable SRP assembly and efficient ER protein translocation, linking the biochemical scaffold role to cellular secretion function.","evidence":"Yeast gene disruption with SRP purification, growth, and translocation assays","pmids":["7925282"],"confidence":"High","gaps":["Did not separate assembly defects from translocation defects mechanistically","No structural detail of the assembled particle"]},{"year":2000,"claim":"Revealed an unexpected nucleolar pool of SRP68 in addition to cytoplasmic/ER localization, hinting at partial assembly or non-canonical activity outside the secretory pathway.","evidence":"GFP fusion live-cell imaging and immunofluorescence in rat fibroblasts","pmids":["10618370"],"confidence":"Medium","gaps":["Functional role of the nucleolar pool not defined","Overexpressed GFP fusion may not reflect endogenous distribution"]},{"year":2008,"claim":"Mapped the SRP RNA helices and residues contacted by SRP68/72 and showed the heterodimer remodels the RNA to protect and create the SRP54-binding site, defining the functional consequence of binding.","evidence":"Chemical/enzymatic RNA probing, SHAPE, systematic helix mutagenesis, and competitive filter binding across assembly intermediates","pmids":["17254600","18347438","18564060"],"confidence":"Medium","gaps":["No atomic-resolution structure of the contacts at this stage","Cooperativity mechanism with SRP19 inferred indirectly"]},{"year":2014,"claim":"Provided the atomic mechanism of RNA remodeling: SRP68-RBD is a TPR-like module that bends the RNA three-way junction and inserts an arginine-rich motif into the major groove to open the ribosome-contacting 5f loop.","evidence":"X-ray crystallography of SRP68-RBD alone and in ternary complex with SRP RNA and SRP19","pmids":["24700861"],"confidence":"High","gaps":["SRP68–SRP72 interface not resolved in this structure","Did not capture the full-length particle on the ribosome"]},{"year":2017,"claim":"Defined the SRP68–SRP72 interface structurally, showing a short SRP68 peptide displaces an SRP72 homodimer to bind its TPR repeats with high affinity, and linked interface-disrupting cancer-associated mutations to loss of ER co-localization.","evidence":"X-ray crystallography of apo-SRP72 and SRP68/72 complex at 1.7 Å with ITC, SEC, mutagenesis, and cellular co-localization","pmids":["27899666","28369529","16672232"],"confidence":"High","gaps":["Disease causation by the mutations not established beyond co-localization","Full-length heterodimer architecture still incomplete"]},{"year":2019,"claim":"Demonstrated with a fully reconstituted human SRP that the heterodimer drives ultrasensitive avidity-based ribosome binding, explaining how SRP engages the ribosome where RNA alone cannot.","evidence":"Recombinant reconstitution of all human SRP components with microscale thermophoresis binding assays","pmids":["30649417"],"confidence":"High","gaps":["Individual ribosome contact sites not mapped at residue level","Dynamics during targeting not directly observed"]},{"year":2024,"claim":"Identified a previously uncharacterized extended dimerization domain of SRP68/72 and proposed it translocates upon SRP receptor docking to detach SRP9/14 and release elongation arrest, extending the mechanistic model to the targeting cycle.","evidence":"Cryo-EM of full-length SRP68/72 with comparative structural analysis","pmids":["38366771"],"confidence":"Medium","gaps":["Elongation-arrest release model inferred from structural comparison, not directly tested","Conformational translocation not captured in a functional intermediate"]},{"year":2012,"claim":"Uncovered a non-canonical nuclear function in which SRP68/72 binds histone H4 tails and activates transcription, regulated by H4R3 arginine methylation, separating a chromatin role from the cytoplasmic SRP role.","evidence":"Peptide pulldown, in vitro histone tail binding, ChIP, tethered transcription reporter, and PRMT1/PRMT5 regulation assays","pmids":["23048028"],"confidence":"Medium","gaps":["Target genes regulated in vivo not defined","How free heterodimer is partitioned between SRP and chromatin roles unknown"]},{"year":2017,"claim":"Showed SRP68 mRNA is destabilized by CELF1 and that subunit imbalance impairs cell migration, indicating SRP68 dosage is post-transcriptionally tuned for normal secretory/ECM function.","evidence":"RIP-crosslinking, in vitro CELF1 binding, mRNA half-life in CELF1 knockdown, and SRP68 overexpression wound-healing assay in myoblasts","pmids":["28129347"],"confidence":"Medium","gaps":["Mechanistic link between imbalance and migration defect not resolved","Physiological CELF1–SRP68 regulation in other tissues untested"]},{"year":null,"claim":"How the extended dimerization domain mechanically couples SRP receptor docking to Alu-domain release and elongation-arrest relief, and how the heterodimer is partitioned between its SRP and chromatin functions, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No functional assay directly tests the proposed elongation-arrest release mechanism","Regulation distributing SRP68/72 between cytoplasmic and nuclear roles is uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[1,2,6,7,10]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[9]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[2,3]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[9]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[4,12]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[4]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[3,14]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[9]}],"complexes":["Signal recognition particle (SRP)","SRP68/72 heterodimer"],"partners":["SRP72","SRP RNA (7SL)","SRP19","CELF1","HISTONE H4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UHB9","full_name":"Signal recognition particle subunit SRP68","aliases":["Signal recognition particle 68 kDa protein"],"length_aa":627,"mass_kda":70.7,"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) (PubMed:34020957). The SRP complex interacts with the signal sequence in nascent secretory and membrane proteins and directs them to the membrane of the ER (PubMed:34020957). The SRP complex targets the ribosome-nascent chain complex to the SRP receptor (SR), which is anchored in the ER, where SR compaction and GTPase rearrangement drive cotranslational protein translocation into the ER (PubMed:34020957). Binds the signal recognition particle RNA (7SL RNA), SRP72 binds to this complex subsequently (PubMed:16672232, PubMed:27899666). The SRP complex possibly participates in the elongation arrest function (By similarity)","subcellular_location":"Cytoplasm; Nucleus, nucleolus; Endoplasmic reticulum","url":"https://www.uniprot.org/uniprotkb/Q9UHB9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SRP68","classification":"Common Essential","n_dependent_lines":1120,"n_total_lines":1208,"dependency_fraction":0.9271523178807947},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000167881","cell_line_id":"CID001063","localizations":[{"compartment":"cytoplasmic","grade":3}],"interactors":[{"gene":"RPS11","stoichiometry":10.0},{"gene":"RPS16","stoichiometry":10.0},{"gene":"SRP19","stoichiometry":10.0},{"gene":"SRP72","stoichiometry":10.0},{"gene":"RPS15","stoichiometry":10.0},{"gene":"RPL13A;RPL13A","stoichiometry":10.0},{"gene":"RPL35","stoichiometry":10.0},{"gene":"SRP9","stoichiometry":10.0},{"gene":"RPL28","stoichiometry":10.0},{"gene":"RPL21","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001063","total_profiled":1310},"omim":[{"mim_id":"620534","title":"NEUTROPENIA, SEVERE CONGENITAL, 10, AUTOSOMAL RECESSIVE; SCN10","url":"https://www.omim.org/entry/620534"},{"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"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SRP68"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q9UHB9","domains":[{"cath_id":"1.10.3450.40","chopping":"60-103_115-202","consensus_level":"medium","plddt":94.1943,"start":60,"end":202},{"cath_id":"1.20.1440","chopping":"295-362_372-408_420-447","consensus_level":"medium","plddt":88.1032,"start":295,"end":447},{"cath_id":"1.20.58","chopping":"461-535","consensus_level":"high","plddt":88.2485,"start":461,"end":535}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UHB9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UHB9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UHB9-F1-predicted_aligned_error_v6.png","plddt_mean":78.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SRP68","jax_strain_url":"https://www.jax.org/strain/search?query=SRP68"},"sequence":{"accession":"Q9UHB9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UHB9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UHB9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UHB9"}},"corpus_meta":[{"pmid":"10618370","id":"PMC_10618370","title":"Signal 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cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/28369529","citation_count":17,"is_preprint":false},{"pmid":"8594607","id":"PMC_8594607","title":"The Signal Recognition Particle Database (SRPDB).","date":"1996","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/8594607","citation_count":17,"is_preprint":false},{"pmid":"17715370","id":"PMC_17715370","title":"Down-regulation of the trypanosomatid signal recognition particle affects the biogenesis of polytopic membrane proteins but not of signal peptide-containing proteins.","date":"2007","source":"Eukaryotic cell","url":"https://pubmed.ncbi.nlm.nih.gov/17715370","citation_count":16,"is_preprint":false},{"pmid":"9016514","id":"PMC_9016514","title":"The Signal Recognition Particle Database (SRPDB).","date":"1997","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/9016514","citation_count":12,"is_preprint":false},{"pmid":"28129347","id":"PMC_28129347","title":"The CELF1 RNA-Binding Protein Regulates Decay of Signal Recognition Particle mRNAs and Limits Secretion in Mouse Myoblasts.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28129347","citation_count":11,"is_preprint":false},{"pmid":"18347438","id":"PMC_18347438","title":"Identification of the RNA binding regions of SRP68/72 and SRP72 by systematic mutagenesis of human SRP RNA.","date":"2007","source":"RNA biology","url":"https://pubmed.ncbi.nlm.nih.gov/18347438","citation_count":9,"is_preprint":false},{"pmid":"7524020","id":"PMC_7524020","title":"The signal recognition particle database (SRPDB).","date":"1994","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/7524020","citation_count":6,"is_preprint":false},{"pmid":"18564060","id":"PMC_18564060","title":"Anti-cooperative assembly of the SRP19 and SRP68/72 components of the signal recognition particle.","date":"2008","source":"The Biochemical 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research","url":"https://pubmed.ncbi.nlm.nih.gov/38366771","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17526,"output_tokens":3940,"usd":0.055839,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11694,"output_tokens":4166,"usd":0.08131,"stage2_stop_reason":"end_turn"},"total_usd":0.137149,"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\": 1990,\n      \"finding\": \"SRP68 is a basic protein of 622 amino acids with a glycine-rich region near its amino terminus shared with some RNA-binding proteins; no sequence similarity to any known protein was detected at the time.\",\n      \"method\": \"cDNA cloning and sequencing of canine SRP68\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — primary sequence determination by cDNA cloning, single study\",\n      \"pmids\": [\"1702390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"SRP68/72 heterodimer binds directly and specifically to SRP RNA (Kd ≤7 nM) by increasing fluorescein anisotropy; binding is independent of and non-cooperative with SRP9/14 binding, indicating the two heterodimers associate randomly and independently with distinct domains of SRP RNA.\",\n      \"method\": \"Fluorescence spectroscopy using fluorescein-labeled SRP RNA, equilibrium binding assays\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with quantitative binding measurements, multiple controls, single lab\",\n      \"pmids\": [\"1377027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"SRP68 alone specifically binds 7S RNA via its NH2-terminal half; SRP72 incorporation into the RNP requires both 7S RNA and SRP68 (SRP72 cannot bind RNA alone); COOH-terminal portions of SRP68 and SRP72 contact each other, so SRP68 acts as a link between 7S RNA and SRP72.\",\n      \"method\": \"In vitro reconstitution of SRP RNP from purified components, domain-mapping with truncation constructs\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with domain-level mapping, replicated by later studies\",\n      \"pmids\": [\"8388879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"In yeast, Srp68p (SRP68 ortholog) is required for stable expression of yeast SRP: disruption of SRP68 leads to loss of SRP RNA and other SRP proteins, slow growth, and deficient protein translocation across the ER membrane.\",\n      \"method\": \"Gene disruption (knockout), immunoaffinity purification of yeast SRP, cell growth and translocation assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic KO with defined biochemical and cellular phenotypes, multiple orthogonal readouts\",\n      \"pmids\": [\"7925282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"GFP-SRP68 localizes not only to the cytoplasm and ER (consistent with its affinity for the ER-bound SRP receptor) but also to the nucleolus in transfected rat fibroblasts, suggesting partial SRP assembly or an unidentified activity occurs at the nucleolus.\",\n      \"method\": \"GFP fusion live-cell imaging and immunofluorescence in transfected rat fibroblasts\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization by live imaging with multiple SRP components examined, single lab\",\n      \"pmids\": [\"10618370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The RNA-binding domain of SRP68 spans residues 52–252; a ~94-residue C-terminal region mediates binding to SRP72; the SRP68–SRP72 interaction is salt-stable and engages ~150 N-terminal residues of SRP72 within its predicted TPR-like region.\",\n      \"method\": \"Recombinant protein expression and purification, proteolytic fragment binding assays (pulldown/filter binding)\",\n      \"journal\": \"Protein science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — domain mapping with multiple truncation fragments, single lab\",\n      \"pmids\": [\"16672232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SRP68/72 binding to 7SL RNA brings the lower parts of helices 6 and 8 closer together, protects the SRP54 binding site (helix 8 asymmetric loop) from chemical modification, and—together with SRP19—rearranges the RNA into an SRP54-binding-competent state.\",\n      \"method\": \"Chemical and enzymatic probing (ethylation interference, hydroxyl radical footprinting, DMS modification, RNase cleavage) of all S-domain assembly intermediates\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal RNA probing methods on defined assembly intermediates, single lab\",\n      \"pmids\": [\"17254600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SRP68/72 contacts SRP RNA primarily through residues in helices 5 (positions 222–231) and helix 8 (positions 176–191 and 202–214); SRP72 alone contacts only the 5ef region of helix 5 (residues 120–128) and does not require helices 6 or 8.\",\n      \"method\": \"Systematic mutagenesis of 18 SRP RNA helix positions combined with competitive double-filter binding assay with purified SRP68/72 and a SRP72 fragment\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — systematic mutagenesis with defined readout, single lab\",\n      \"pmids\": [\"18347438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SRP19 and SRP68/72 both bind helices 6 and 8 of SRP RNA but on opposite faces and at opposite ends; SRP72 binds largely via non-electrostatic interactions and enhances SRP68 affinity; the two proteins bind with moderate anti-cooperativity, arising from stabilization of distinct RNA conformations.\",\n      \"method\": \"Quantitative binding assays (filter binding), SHAPE RNA probing, analysis of cooperativity between SRP19 and SRP68/72\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multiple methods (binding + RNA probing) in a single study, single lab\",\n      \"pmids\": [\"18564060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SRP68/72 heterodimer (but not intact SRP) binds histone H4 tail peptides in vitro; H4R3 methylation (by PRMT1 or PRMT5) inhibits this binding; SRP68 and SRP72 associate with chromatin in vivo and activate transcription when tethered to a reporter, revealing a non-canonical chromatin/transcriptional regulatory function.\",\n      \"method\": \"Peptide pulldown/proteomics, in vitro histone tail binding assay, ChIP, tethered transcription reporter assay, PRMT1/PRMT5 regulation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (pulldown, ChIP, reporter assay), single lab\",\n      \"pmids\": [\"23048028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Crystal structures of the SRP68 RNA-binding domain (SRP68-RBD) alone and in complex with SRP RNA and SRP19 reveal that SRP68-RBD is a tetratricopeptide-like module that binds a RNA three-way junction, bends the RNA, and inserts an α-helical arginine-rich motif (ARM) into the RNA major groove, thereby opening the conserved 5f RNA loop (which contacts ribosomal RNA in ribosome-bound SRP).\",\n      \"method\": \"X-ray crystallography of SRP68-RBD alone and in ternary complex with SRP RNA and SRP19\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structures with functional validation of RNA remodeling, landmark study\",\n      \"pmids\": [\"24700861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Crystal structures of the SRP68 protein-binding domain (PBD) in complex with SRP72-PBD and of SRP72-RBD bound to the full S domain show: SRP72-PBD is a TPR repeat that binds an extended linear motif of SRP68 with high affinity; SRP72-RBD is a flexible peptide that crawls along 5e/5f RNA loops; a conserved tryptophan inserts into the 5e loop forming a novel K⁺-stabilized RNA kink-turn; SRP72-RBD remodels the 5f loop involved in ribosome binding. Cryo-EM docking reveals multiple SRP68/72–ribosome contact sites.\",\n      \"method\": \"X-ray crystallography of SRP68-PBD/SRP72-PBD complex and SRP72-RBD/S-domain complex; cryo-EM docking\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures complemented by cryo-EM, multiple complexes resolved in a single rigorous study\",\n      \"pmids\": [\"27899666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Crystal structures of human apo-SRP72 and the SRP68/72 complex (1.7 Å) show SRP72 contains four atypical TPR repeats and a flexible C-terminal cap; apo-SRP72 dimerizes in solution but the homodimer dissociates to accommodate SRP68; a 23-residue hydrophobic extended peptide of SRP68 is sufficient for tight binding to SRP72. Cancer-associated mutations that disrupt SRP68–SRP72 interaction also abolish their co-localization with ER in mammalian cells.\",\n      \"method\": \"X-ray crystallography (apo-SRP72 and SRP68/72 complex), biophysical analyses (SEC, ITC), mutagenesis, co-localization in mammalian cells\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure at 1.7 Å with mutagenesis and cellular co-localization, multiple orthogonal methods\",\n      \"pmids\": [\"28369529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CELF1 directly binds the SRP68 mRNA and destabilizes it; overexpression of SRP68 alone (causing SRP subunit imbalance) impairs cell migration/wound healing, indicating that balanced SRP68 levels are required for normal secretion and extracellular matrix function in myoblasts.\",\n      \"method\": \"RIP-crosslinking, in vitro CELF1 binding assay, mRNA half-life measurement in CELF1 KD cells, SRP68 overexpression with wound-healing assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (RIP, half-life, OE phenotype), single lab\",\n      \"pmids\": [\"28129347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Reconstituted human SRP68/72 heterodimer shows ultrasensitive (avidity-based) binding to the ribosome via multiple contact sites dominated by the C-terminus of SRP72; SRP RNA alone does not bind the ribosome; full SRP binds ribosomes with nanomolar affinity through a two-step mechanism involving SRP54.\",\n      \"method\": \"Large-scale recombinant reconstitution of all human SRP components; microscale thermophoresis binding assays for individual components and assembly intermediates\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — complete reconstitution of human SRP with quantitative biophysical characterization, multiple components tested\",\n      \"pmids\": [\"30649417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM of full-length SRP68/72 reveals an extended dimerization domain beyond the previously characterized domains; SRP68 and SRP72 depend on each other for stability. The newly identified dimerization domain is both a protein- and RNA-binding domain. Comparative structural analysis suggests this domain undergoes dramatic translocation upon SRP docking onto the SRP receptor and positions near the Alu domain, indicating it may release elongation arrest by binding and detaching SRP9/14 from the ribosomal surface.\",\n      \"method\": \"Cryo-EM structure of full-length SRP68/72; comparative structural analysis with existing models\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — cryo-EM structure of full-length complex, mechanistic model is proposed from structural comparison rather than directly tested experimentally\",\n      \"pmids\": [\"38366771\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SRP68 is the RNA-binding scaffold subunit of the SRP68/72 heterodimer: its N-terminal tetratricopeptide-like RNA-binding domain (RBD) contacts the three-way junction of helices 5/6/8 in SRP RNA, bending the RNA and inserting an arginine-rich motif into the major groove to open the 5f loop required for ribosome contact and elongation arrest; its C-terminal peptide binds the TPR domain of SRP72 with high affinity, and SRP68 is required for SRP72 incorporation into the particle; together, SRP68/72 remodel the 7SL RNA into an SRP54-binding-competent conformation and make multiple avidity-driven contacts with the ribosome, with the extended dimerization domain proposed to disengage the Alu domain/SRP9-14 from the ribosome upon ER docking; additionally, the SRP68/72 heterodimer has a non-canonical nuclear function in which it binds histone H4 tails and regulates transcription in a manner inhibited by H4R3 arginine methylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SRP68 is the RNA-binding scaffold subunit of the signal recognition particle (SRP) S domain, functioning together with SRP72 to remodel SRP (7SL) RNA into a conformation competent for co-translational protein targeting to the ER [#2, #6]. The SRP68/72 heterodimer binds SRP RNA directly and specifically with high affinity, associating with a distinct RNA domain independently of the SRP9/14 (Alu) module [#1]. SRP68 makes the primary RNA contact through its N-terminal RNA-binding domain (residues ~52\\u2013252), while a C-terminal peptide links the particle to SRP72; SRP72 cannot bind RNA on its own and requires both 7S RNA and SRP68 for incorporation, so SRP68 acts as the obligatory bridge between RNA and SRP72 [#2, #5]. Crystallographic work established that the SRP68 RNA-binding domain is a tetratricopeptide-like module that binds an RNA three-way junction, bends the RNA, and inserts an arginine-rich \\u03b1-helical motif into the major groove to open the conserved 5f loop that contacts ribosomal RNA in ribosome-bound SRP [#10], while SRP68/72 binding draws helices 6 and 8 together and protects the SRP54-binding site, rearranging the RNA into an SRP54-competent state [#6]. The reconstituted heterodimer binds the ribosome with ultrasensitive avidity through multiple contact sites, an interaction SRP RNA alone cannot make [#14], and a full-length structure reveals an extended dimerization domain that, upon SRP docking onto the SRP receptor, repositions near the Alu domain and is implicated in releasing elongation arrest [#15]. Genetically, SRP68 is required for stable SRP assembly and efficient ER translocation: its loss in yeast destabilizes the entire particle and impairs protein translocation [#3]. Beyond its canonical role, the SRP68/72 heterodimer has a non-canonical nuclear activity, binding histone H4 tails, associating with chromatin, and activating transcription in a manner inhibited by H4R3 methylation [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Established the primary structure of SRP68 as a basic, glycine-rich protein, providing the molecular starting point but leaving its function undefined since it matched no known protein.\",\n      \"evidence\": \"cDNA cloning and sequencing of canine SRP68\",\n      \"pmids\": [\"1702390\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional or RNA-binding activity demonstrated\", \"No domain architecture defined beyond a glycine-rich region\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Showed that SRP68/72 binds SRP RNA directly, specifically, and at a distinct site from SRP9/14, defining it as an independent RNA-binding module of the particle.\",\n      \"evidence\": \"Fluorescence anisotropy equilibrium binding assays with fluorescein-labeled SRP RNA\",\n      \"pmids\": [\"1377027\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which subunit contacts RNA\", \"No RNA structural consequence of binding established\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Resolved that SRP68 is the RNA-contacting subunit and the obligatory bridge that recruits SRP72, which cannot bind RNA alone, establishing the assembly hierarchy of the S domain.\",\n      \"evidence\": \"In vitro reconstitution from purified components with truncation domain mapping\",\n      \"pmids\": [\"8388879\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Residue-level RNA contacts unmapped\", \"Structural basis of the SRP68\\u2013SRP72 interface unknown\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Demonstrated in vivo that SRP68 is required for stable SRP assembly and efficient ER protein translocation, linking the biochemical scaffold role to cellular secretion function.\",\n      \"evidence\": \"Yeast gene disruption with SRP purification, growth, and translocation assays\",\n      \"pmids\": [\"7925282\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not separate assembly defects from translocation defects mechanistically\", \"No structural detail of the assembled particle\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Revealed an unexpected nucleolar pool of SRP68 in addition to cytoplasmic/ER localization, hinting at partial assembly or non-canonical activity outside the secretory pathway.\",\n      \"evidence\": \"GFP fusion live-cell imaging and immunofluorescence in rat fibroblasts\",\n      \"pmids\": [\"10618370\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of the nucleolar pool not defined\", \"Overexpressed GFP fusion may not reflect endogenous distribution\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Mapped the SRP RNA helices and residues contacted by SRP68/72 and showed the heterodimer remodels the RNA to protect and create the SRP54-binding site, defining the functional consequence of binding.\",\n      \"evidence\": \"Chemical/enzymatic RNA probing, SHAPE, systematic helix mutagenesis, and competitive filter binding across assembly intermediates\",\n      \"pmids\": [\"17254600\", \"18347438\", \"18564060\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No atomic-resolution structure of the contacts at this stage\", \"Cooperativity mechanism with SRP19 inferred indirectly\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Provided the atomic mechanism of RNA remodeling: SRP68-RBD is a TPR-like module that bends the RNA three-way junction and inserts an arginine-rich motif into the major groove to open the ribosome-contacting 5f loop.\",\n      \"evidence\": \"X-ray crystallography of SRP68-RBD alone and in ternary complex with SRP RNA and SRP19\",\n      \"pmids\": [\"24700861\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SRP68\\u2013SRP72 interface not resolved in this structure\", \"Did not capture the full-length particle on the ribosome\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the SRP68\\u2013SRP72 interface structurally, showing a short SRP68 peptide displaces an SRP72 homodimer to bind its TPR repeats with high affinity, and linked interface-disrupting cancer-associated mutations to loss of ER co-localization.\",\n      \"evidence\": \"X-ray crystallography of apo-SRP72 and SRP68/72 complex at 1.7 \\u00c5 with ITC, SEC, mutagenesis, and cellular co-localization\",\n      \"pmids\": [\"27899666\", \"28369529\", \"16672232\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Disease causation by the mutations not established beyond co-localization\", \"Full-length heterodimer architecture still incomplete\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated with a fully reconstituted human SRP that the heterodimer drives ultrasensitive avidity-based ribosome binding, explaining how SRP engages the ribosome where RNA alone cannot.\",\n      \"evidence\": \"Recombinant reconstitution of all human SRP components with microscale thermophoresis binding assays\",\n      \"pmids\": [\"30649417\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Individual ribosome contact sites not mapped at residue level\", \"Dynamics during targeting not directly observed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified a previously uncharacterized extended dimerization domain of SRP68/72 and proposed it translocates upon SRP receptor docking to detach SRP9/14 and release elongation arrest, extending the mechanistic model to the targeting cycle.\",\n      \"evidence\": \"Cryo-EM of full-length SRP68/72 with comparative structural analysis\",\n      \"pmids\": [\"38366771\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Elongation-arrest release model inferred from structural comparison, not directly tested\", \"Conformational translocation not captured in a functional intermediate\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Uncovered a non-canonical nuclear function in which SRP68/72 binds histone H4 tails and activates transcription, regulated by H4R3 arginine methylation, separating a chromatin role from the cytoplasmic SRP role.\",\n      \"evidence\": \"Peptide pulldown, in vitro histone tail binding, ChIP, tethered transcription reporter, and PRMT1/PRMT5 regulation assays\",\n      \"pmids\": [\"23048028\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Target genes regulated in vivo not defined\", \"How free heterodimer is partitioned between SRP and chromatin roles unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed SRP68 mRNA is destabilized by CELF1 and that subunit imbalance impairs cell migration, indicating SRP68 dosage is post-transcriptionally tuned for normal secretory/ECM function.\",\n      \"evidence\": \"RIP-crosslinking, in vitro CELF1 binding, mRNA half-life in CELF1 knockdown, and SRP68 overexpression wound-healing assay in myoblasts\",\n      \"pmids\": [\"28129347\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between imbalance and migration defect not resolved\", \"Physiological CELF1\\u2013SRP68 regulation in other tissues untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the extended dimerization domain mechanically couples SRP receptor docking to Alu-domain release and elongation-arrest relief, and how the heterodimer is partitioned between its SRP and chromatin functions, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional assay directly tests the proposed elongation-arrest release mechanism\", \"Regulation distributing SRP68/72 between cytoplasmic and nuclear roles is uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [1, 2, 6, 7, 10]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [4, 12]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [3, 14]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"complexes\": [\n      \"Signal recognition particle (SRP)\",\n      \"SRP68/72 heterodimer\"\n    ],\n    \"partners\": [\n      \"SRP72\",\n      \"SRP RNA (7SL)\",\n      \"SRP19\",\n      \"CELF1\",\n      \"histone H4\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}