{"gene":"SRPRA","run_date":"2026-06-10T07:46:41","timeline":{"discoveries":[{"year":1997,"finding":"SRPRα (SR alpha) and SRP54 are in the empty (nucleotide-free) site conformation prior to contact between the SRP-ribosome complex and the membrane-bound SR. Cooperative binding of GTP to both SRP54 and SRPRα stabilizes the SRP-SR complex and initiates signal sequence transfer from SRP54 to Sec61α. SRPRα performs a predominant role in complex stabilization, and GTP hydrolysis by both SRPRα and SRP54 is required for dissociation of the SRP-SR complex.","method":"In vitro GTPase assay, ribosome-nascent chain targeting reconstitution, biochemical characterization of nucleotide-binding states","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of the SRP targeting cycle with defined biochemical steps and mutagenesis-compatible mechanistic dissection; published in high-impact journal with multiple orthogonal assays","pmids":["9182758"],"is_preprint":false},{"year":2022,"finding":"The NG domain of human SRPRα is responsible for binding to SRP54, interacting with RNA, and binding and hydrolysing GTP. A complete SRPRα-NG construct including the first N-terminal helix (previously omitted) was successfully expressed and purified, enabling structural and NMR studies; the role of the N-terminal helix in protein–protein interactions remains to be determined.","method":"Recombinant protein expression and purification; isotopic labelling for NMR; domain boundary mapping","journal":"Protein expression and purification","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — domain function assignments are biochemically supported by purification and prior literature context, but direct functional validation of the N-terminal helix in this paper is not reported; single lab, single method","pmids":["35640773"],"is_preprint":false},{"year":2023,"finding":"Human genetic defects in SRPRA cause severe congenital neutropenia; using in vitro iPSC differentiation and in vivo zebrafish models, SRP-dependent protein processing, intracellular trafficking, and proteome homeostasis were shown to be critically required for neutrophil granulocyte differentiation. A heterologous cell-based inducible expression system validated effects of SRP dysfunction on specific proteins identified in patient proteome screens.","method":"Patient genetics, in vitro iPSC-to-neutrophil differentiation, zebrafish in vivo knockout, quantitative proteomics, heterologous cell-based protein expression validation","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (patient genetics, iPSC differentiation, zebrafish in vivo model, proteomics, cell-based validation) across human and model-organism systems","pmids":["36223592"],"is_preprint":false},{"year":2016,"finding":"SRPRA (Srpr, SRP receptor α subunit) promotes keratinocyte proliferation by affecting cell cycle progression; knockdown of Srpr reduces proliferation, and miR-330-5p directly inhibits Srpr expression to regulate this process.","method":"Knockdown of SRPRA in mouse epidermal keratinocytes, cell cycle analysis, luciferase reporter assay confirming miR-330-5p binding to Srpr 3′UTR","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — loss-of-function with defined cellular phenotype and direct miRNA-target validation, but single lab with no mechanistic pathway placement beyond cell cycle","pmids":["27768721"],"is_preprint":false},{"year":1992,"finding":"The human SRPRA gene was chromosomally mapped by PCR-based somatic cell hybrid analysis to chromosome 11, in a region flanked by the 11q23 and 11q24 breakpoints associated with constitutional and neuroepithelioma (11;22) translocations.","method":"PCR-based inter-species somatic cell hybrid panel mapping","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct experimental localization of the gene locus, single lab, single method","pmids":["1312991"],"is_preprint":false}],"current_model":"SRPRα (SRPRA) is the GTPase subunit of the SRP receptor that, together with SRP54, operates an obligatorily coupled GTPase cycle: both proteins begin in the nucleotide-empty state, cooperatively bind GTP upon SRP–SR docking at the ER membrane to stabilize the complex and hand off the signal sequence to Sec61α (with SRPRα playing the dominant stabilization role), then both hydrolyze GTP to drive SRP–SR dissociation; its NG domain mediates GTP binding/hydrolysis, SRP54 interaction, and RNA binding; in vivo, loss of SRPRA disrupts cotranslational protein targeting, intracellular trafficking, and proteome homeostasis, causing a block in neutrophil granulocyte differentiation in humans and zebrafish, and its expression level is regulated by miR-330-5p to control keratinocyte proliferation."},"narrative":{"mechanistic_narrative":"SRPRA (SRPRα) is the GTPase subunit of the signal recognition particle (SRP) receptor that governs cotranslational targeting of nascent secretory and membrane proteins to the endoplasmic reticulum [PMID:9182758]. SRPRα and SRP54 begin nucleotide-free and cooperatively bind GTP upon SRP–SR docking to stabilize the targeting complex—with SRPRα playing the dominant stabilization role—enabling handoff of the signal sequence to Sec61α, after which GTP hydrolysis by both subunits drives complex dissociation [PMID:9182758]. These activities reside in the NG domain, which mediates SRP54 interaction, RNA binding, and GTP binding/hydrolysis [PMID:35640773]. In vivo, loss of SRPRA disrupts SRP-dependent protein processing, intracellular trafficking, and proteome homeostasis, and biallelic SRPRA defects cause severe congenital neutropenia by blocking neutrophil granulocyte differentiation in human iPSC and zebrafish models [PMID:36223592]. SRPRA expression promotes keratinocyte proliferation through cell-cycle progression and is directly repressed by miR-330-5p [PMID:27768721].","teleology":[{"year":1997,"claim":"Established how the SRP receptor enforces fidelity in protein targeting by defining the coupled SRPRα–SRP54 GTPase cycle from empty state through GTP-stabilized docking to hydrolysis-driven release.","evidence":"In vitro GTPase assays and reconstituted ribosome-nascent chain targeting with defined nucleotide-binding states","pmids":["9182758"],"confidence":"High","gaps":["Structural basis of cooperative GTP binding not resolved here","Kinetics of signal-sequence handoff to Sec61α not quantified","Contribution of individual domains to each step not dissected"]},{"year":2016,"claim":"Connected SRPRA dosage to a tissue-level proliferative phenotype, showing it drives keratinocyte cell-cycle progression and is a direct miR-330-5p target.","evidence":"SRPRA knockdown with cell cycle analysis and luciferase reporter validation of miR-330-5p binding in mouse keratinocytes","pmids":["27768721"],"confidence":"Medium","gaps":["No mechanistic link between SRP targeting function and cell-cycle control","Single lab with no pathway placement beyond cell cycle","Whether the proliferation effect reflects general secretory load is unknown"]},{"year":2022,"claim":"Assigned SRP54 interaction, RNA binding, and GTP binding/hydrolysis to the human SRPRα NG domain and enabled full-length NG structural study by including the previously omitted N-terminal helix.","evidence":"Recombinant expression/purification with isotopic labeling for NMR and domain boundary mapping","pmids":["35640773"],"confidence":"Medium","gaps":["Functional role of the N-terminal helix in protein–protein interactions not determined","Single lab, single method","No structure reported in this work"]},{"year":2023,"claim":"Demonstrated that SRPRA-dependent cotranslational targeting is critically required for neutrophil differentiation, defining a Mendelian disease link to severe congenital neutropenia.","evidence":"Patient genetics, iPSC-to-neutrophil differentiation, zebrafish knockout, quantitative proteomics, and heterologous protein-expression validation","pmids":["36223592"],"confidence":"High","gaps":["Why neutrophil lineage is selectively vulnerable not mechanistically explained","Specific client proteins driving the differentiation block only partially defined","Genotype-phenotype relationship across mutations not established"]},{"year":null,"claim":"How the general SRP targeting defect produces cell-type-specific outcomes (neutrophil block versus keratinocyte proliferation) and the structural basis of the N-terminal helix function remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No unifying model linking SRP function to lineage-specific phenotypes","N-terminal helix interaction partners unknown","No high-resolution structure of full-length human SRPRα in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,2]}],"complexes":["SRP receptor"],"partners":["SRP54","SEC61A1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P08240","full_name":"Signal recognition particle receptor subunit alpha","aliases":["Docking protein alpha","DP-alpha"],"length_aa":638,"mass_kda":69.8,"function":"Component of the signal recognition particle (SRP) complex receptor (SR) (PubMed:16439358). Ensures, in conjunction with the SRP complex, the correct targeting of the nascent secretory proteins to the endoplasmic reticulum membrane system (PubMed:16675701, PubMed:34020957). Forms a guanosine 5'-triphosphate (GTP)-dependent complex with the SRP subunit SRP54 (PubMed:34020957). SRP receptor compaction and GTPase rearrangement drive SRP-mediated cotranslational protein translocation into the ER (PubMed:34020957)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/P08240/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SRPRA","classification":"Common Essential","n_dependent_lines":967,"n_total_lines":1208,"dependency_fraction":0.8004966887417219},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000182934","cell_line_id":"CID001598","localizations":[{"compartment":"er","grade":3}],"interactors":[{"gene":"SRPRB","stoichiometry":10.0},{"gene":"SRPR","stoichiometry":10.0},{"gene":"ASPH","stoichiometry":0.2},{"gene":"MOSPD2","stoichiometry":0.2},{"gene":"TMX1","stoichiometry":0.2},{"gene":"POR","stoichiometry":0.2},{"gene":"CYB5A","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001598","total_profiled":1310},"omim":[{"mim_id":"616883","title":"SRP RECEPTOR SUBUNIT, BETA; SRPRB","url":"https://www.omim.org/entry/616883"},{"mim_id":"182180","title":"SRP RECEPTOR SUBUNIT, ALPHA; SRPRA","url":"https://www.omim.org/entry/182180"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SRPRA"},"hgnc":{"alias_symbol":["SRP-alpha","Sralpha","SR-alpha"],"prev_symbol":["SRPR"]},"alphafold":{"accession":"P08240","domains":[{"cath_id":"3.30.450.60","chopping":"3-130","consensus_level":"high","plddt":81.7129,"start":3,"end":130},{"cath_id":"-","chopping":"332-396","consensus_level":"high","plddt":88.8058,"start":332,"end":396},{"cath_id":"3.40.50.300","chopping":"404-635","consensus_level":"high","plddt":91.8453,"start":404,"end":635}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P08240","model_url":"https://alphafold.ebi.ac.uk/files/AF-P08240-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P08240-F1-predicted_aligned_error_v6.png","plddt_mean":73.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SRPRA","jax_strain_url":"https://www.jax.org/strain/search?query=SRPRA"},"sequence":{"accession":"P08240","fasta_url":"https://rest.uniprot.org/uniprotkb/P08240.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P08240/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P08240"}},"corpus_meta":[{"pmid":"2827008","id":"PMC_2827008","title":"SR alpha promoter: an efficient and versatile mammalian cDNA expression system composed of the simian virus 40 early promoter and the R-U5 segment of human T-cell leukemia virus type 1 long terminal repeat.","date":"1988","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/2827008","citation_count":1501,"is_preprint":false},{"pmid":"9182758","id":"PMC_9182758","title":"Empty site forms of the SRP54 and SR alpha GTPases mediate targeting of ribosome-nascent chain complexes to the endoplasmic reticulum.","date":"1997","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/9182758","citation_count":109,"is_preprint":false},{"pmid":"36223592","id":"PMC_36223592","title":"Human genetic defects in SRP19 and SRPRA cause severe congenital neutropenia with distinctive proteome changes.","date":"2023","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/36223592","citation_count":21,"is_preprint":false},{"pmid":"21441510","id":"PMC_21441510","title":"An antirepressor, SrpR, is involved in transcriptional regulation of the SrpABC solvent tolerance efflux pump of Pseudomonas putida S12.","date":"2011","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/21441510","citation_count":17,"is_preprint":false},{"pmid":"15467743","id":"PMC_15467743","title":"Mxi1-SRalpha: a novel Mxi1 isoform with enhanced transcriptional repression potential.","date":"2004","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/15467743","citation_count":15,"is_preprint":false},{"pmid":"27768721","id":"PMC_27768721","title":"Regulation of Srpr Expression by miR-330-5p Controls Proliferation of Mouse Epidermal Keratinocyte.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27768721","citation_count":12,"is_preprint":false},{"pmid":"17697116","id":"PMC_17697116","title":"Differential effects of Mxi1-SRalpha and Mxi1-SRbeta in Myc antagonism.","date":"2007","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/17697116","citation_count":8,"is_preprint":false},{"pmid":"1334614","id":"PMC_1334614","title":"Expression pattern of SR alpha promoter in human embryonal carcinoma and transgenic tissues in mice.","date":"1992","source":"Acta pathologica japonica","url":"https://pubmed.ncbi.nlm.nih.gov/1334614","citation_count":7,"is_preprint":false},{"pmid":"32945019","id":"PMC_32945019","title":"Unique regulator SrpR mediates crosstalk between efflux pumps TtgABC and SrpABC in Pseudomonas putida B6-2 (DSM 28064).","date":"2020","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/32945019","citation_count":6,"is_preprint":false},{"pmid":"8935656","id":"PMC_8935656","title":"A putative signal recognition particle receptor alpha subunit (SR alpha) homologue is expressed in the hyperthermophilic crenarchaeon Sulfolobus acidocaldarius.","date":"1996","source":"FEMS microbiology letters","url":"https://pubmed.ncbi.nlm.nih.gov/8935656","citation_count":6,"is_preprint":false},{"pmid":"10444742","id":"PMC_10444742","title":"Signal recognition particle receptor (SRPR) is downregulated in a rat model of cyclosporin A-induced gingival overgrowth.","date":"1999","source":"Journal of periodontal research","url":"https://pubmed.ncbi.nlm.nih.gov/10444742","citation_count":4,"is_preprint":false},{"pmid":"1312991","id":"PMC_1312991","title":"PCR-assisted localization of the human SRPR gene.","date":"1992","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/1312991","citation_count":3,"is_preprint":false},{"pmid":"35640773","id":"PMC_35640773","title":"Expression and purification of the NG domain from human SRα, a key component of the Signal Recognition Particle (SRP) receptor.","date":"2022","source":"Protein expression and purification","url":"https://pubmed.ncbi.nlm.nih.gov/35640773","citation_count":1,"is_preprint":false},{"pmid":"8934208","id":"PMC_8934208","title":"[Analysis of JC pseudotype virus generated by expression of VP231-SR alpha in COS7 cells].","date":"1996","source":"[Hokkaido igaku zasshi] The Hokkaido journal of medical science","url":"https://pubmed.ncbi.nlm.nih.gov/8934208","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7174,"output_tokens":1437,"usd":0.021538,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8233,"output_tokens":1911,"usd":0.04447,"stage2_stop_reason":"end_turn"},"total_usd":0.066008,"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\": 1997,\n      \"finding\": \"SRPRα (SR alpha) and SRP54 are in the empty (nucleotide-free) site conformation prior to contact between the SRP-ribosome complex and the membrane-bound SR. Cooperative binding of GTP to both SRP54 and SRPRα stabilizes the SRP-SR complex and initiates signal sequence transfer from SRP54 to Sec61α. SRPRα performs a predominant role in complex stabilization, and GTP hydrolysis by both SRPRα and SRP54 is required for dissociation of the SRP-SR complex.\",\n      \"method\": \"In vitro GTPase assay, ribosome-nascent chain targeting reconstitution, biochemical characterization of nucleotide-binding states\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of the SRP targeting cycle with defined biochemical steps and mutagenesis-compatible mechanistic dissection; published in high-impact journal with multiple orthogonal assays\",\n      \"pmids\": [\"9182758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The NG domain of human SRPRα is responsible for binding to SRP54, interacting with RNA, and binding and hydrolysing GTP. A complete SRPRα-NG construct including the first N-terminal helix (previously omitted) was successfully expressed and purified, enabling structural and NMR studies; the role of the N-terminal helix in protein–protein interactions remains to be determined.\",\n      \"method\": \"Recombinant protein expression and purification; isotopic labelling for NMR; domain boundary mapping\",\n      \"journal\": \"Protein expression and purification\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — domain function assignments are biochemically supported by purification and prior literature context, but direct functional validation of the N-terminal helix in this paper is not reported; single lab, single method\",\n      \"pmids\": [\"35640773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Human genetic defects in SRPRA cause severe congenital neutropenia; using in vitro iPSC differentiation and in vivo zebrafish models, SRP-dependent protein processing, intracellular trafficking, and proteome homeostasis were shown to be critically required for neutrophil granulocyte differentiation. A heterologous cell-based inducible expression system validated effects of SRP dysfunction on specific proteins identified in patient proteome screens.\",\n      \"method\": \"Patient genetics, in vitro iPSC-to-neutrophil differentiation, zebrafish in vivo knockout, quantitative proteomics, heterologous cell-based protein expression validation\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (patient genetics, iPSC differentiation, zebrafish in vivo model, proteomics, cell-based validation) across human and model-organism systems\",\n      \"pmids\": [\"36223592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SRPRA (Srpr, SRP receptor α subunit) promotes keratinocyte proliferation by affecting cell cycle progression; knockdown of Srpr reduces proliferation, and miR-330-5p directly inhibits Srpr expression to regulate this process.\",\n      \"method\": \"Knockdown of SRPRA in mouse epidermal keratinocytes, cell cycle analysis, luciferase reporter assay confirming miR-330-5p binding to Srpr 3′UTR\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — loss-of-function with defined cellular phenotype and direct miRNA-target validation, but single lab with no mechanistic pathway placement beyond cell cycle\",\n      \"pmids\": [\"27768721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"The human SRPRA gene was chromosomally mapped by PCR-based somatic cell hybrid analysis to chromosome 11, in a region flanked by the 11q23 and 11q24 breakpoints associated with constitutional and neuroepithelioma (11;22) translocations.\",\n      \"method\": \"PCR-based inter-species somatic cell hybrid panel mapping\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct experimental localization of the gene locus, single lab, single method\",\n      \"pmids\": [\"1312991\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SRPRα (SRPRA) is the GTPase subunit of the SRP receptor that, together with SRP54, operates an obligatorily coupled GTPase cycle: both proteins begin in the nucleotide-empty state, cooperatively bind GTP upon SRP–SR docking at the ER membrane to stabilize the complex and hand off the signal sequence to Sec61α (with SRPRα playing the dominant stabilization role), then both hydrolyze GTP to drive SRP–SR dissociation; its NG domain mediates GTP binding/hydrolysis, SRP54 interaction, and RNA binding; in vivo, loss of SRPRA disrupts cotranslational protein targeting, intracellular trafficking, and proteome homeostasis, causing a block in neutrophil granulocyte differentiation in humans and zebrafish, and its expression level is regulated by miR-330-5p to control keratinocyte proliferation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SRPRA (SRPRα) is the GTPase subunit of the signal recognition particle (SRP) receptor that governs cotranslational targeting of nascent secretory and membrane proteins to the endoplasmic reticulum [#0]. SRPRα and SRP54 begin nucleotide-free and cooperatively bind GTP upon SRP–SR docking to stabilize the targeting complex—with SRPRα playing the dominant stabilization role—enabling handoff of the signal sequence to Sec61α, after which GTP hydrolysis by both subunits drives complex dissociation [#0]. These activities reside in the NG domain, which mediates SRP54 interaction, RNA binding, and GTP binding/hydrolysis [#1]. In vivo, loss of SRPRA disrupts SRP-dependent protein processing, intracellular trafficking, and proteome homeostasis, and biallelic SRPRA defects cause severe congenital neutropenia by blocking neutrophil granulocyte differentiation in human iPSC and zebrafish models [#2]. SRPRA expression promotes keratinocyte proliferation through cell-cycle progression and is directly repressed by miR-330-5p [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established how the SRP receptor enforces fidelity in protein targeting by defining the coupled SRPRα–SRP54 GTPase cycle from empty state through GTP-stabilized docking to hydrolysis-driven release.\",\n      \"evidence\": \"In vitro GTPase assays and reconstituted ribosome-nascent chain targeting with defined nucleotide-binding states\",\n      \"pmids\": [\"9182758\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of cooperative GTP binding not resolved here\",\n        \"Kinetics of signal-sequence handoff to Sec61α not quantified\",\n        \"Contribution of individual domains to each step not dissected\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected SRPRA dosage to a tissue-level proliferative phenotype, showing it drives keratinocyte cell-cycle progression and is a direct miR-330-5p target.\",\n      \"evidence\": \"SRPRA knockdown with cell cycle analysis and luciferase reporter validation of miR-330-5p binding in mouse keratinocytes\",\n      \"pmids\": [\"27768721\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No mechanistic link between SRP targeting function and cell-cycle control\",\n        \"Single lab with no pathway placement beyond cell cycle\",\n        \"Whether the proliferation effect reflects general secretory load is unknown\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Assigned SRP54 interaction, RNA binding, and GTP binding/hydrolysis to the human SRPRα NG domain and enabled full-length NG structural study by including the previously omitted N-terminal helix.\",\n      \"evidence\": \"Recombinant expression/purification with isotopic labeling for NMR and domain boundary mapping\",\n      \"pmids\": [\"35640773\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional role of the N-terminal helix in protein–protein interactions not determined\",\n        \"Single lab, single method\",\n        \"No structure reported in this work\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated that SRPRA-dependent cotranslational targeting is critically required for neutrophil differentiation, defining a Mendelian disease link to severe congenital neutropenia.\",\n      \"evidence\": \"Patient genetics, iPSC-to-neutrophil differentiation, zebrafish knockout, quantitative proteomics, and heterologous protein-expression validation\",\n      \"pmids\": [\"36223592\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Why neutrophil lineage is selectively vulnerable not mechanistically explained\",\n        \"Specific client proteins driving the differentiation block only partially defined\",\n        \"Genotype-phenotype relationship across mutations not established\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the general SRP targeting defect produces cell-type-specific outcomes (neutrophil block versus keratinocyte proliferation) and the structural basis of the N-terminal helix function remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No unifying model linking SRP function to lineage-specific phenotypes\",\n        \"N-terminal helix interaction partners unknown\",\n        \"No high-resolution structure of full-length human SRPRα in the corpus\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [\"SRP receptor\"],\n    \"partners\": [\"SRP54\", \"SEC61A1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}