{"gene":"ELSPBP1","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2012,"finding":"ELSPBP1 is secreted by epididymal epithelial cells into the epididymal fluid and is associated with epididymosomes (small membranous vesicles). Epididymosomes transfer ELSPBP1 specifically to spermatozoa that are already dead before incubation; live spermatozoa do not acquire ELSPBP1. This transfer is enhanced by the presence of zinc in the incubation medium. ELSPBP1 expression is highest in the caput and corpus epididymis at the mRNA level, and the protein is present in epididymal fluid throughout the epididymis.","method":"Real-time RT-PCR for tissue expression; immunohistochemistry for localization; Western blot on tissue homogenates and epididymal fluid fractions; immunocytometry on spermatozoa; in vitro incubation of caput spermatozoa with cauda epididymosomes under varying conditions (with/without zinc)","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (fractionation, immunocytometry, functional transfer assay with defined conditions) in a single study; demonstrates subcellular localization tied to functional consequence (selective transfer to dead sperm), but single lab","pmids":["22875906"],"is_preprint":false}],"current_model":"ELSPBP1 is an epididymal secretory protein packaged into epididymosomes by epididymal epithelial cells and selectively transferred to membrane-compromised (dead) spermatozoa during epididymal transit, with zinc enhancing this transfer, suggesting ELSPBP1 acts as a tag marking dead spermatozoa for recognition during epididymal transit."},"narrative":{"mechanistic_narrative":"ELSPBP1 is an epididymal secretory protein that functions in the post-testicular maturation environment of spermatozoa, where it is produced by epididymal epithelial cells and released into the epididymal fluid in association with epididymosomes [PMID:22875906]. The protein is expressed most highly at the mRNA level in the caput and corpus epididymis, while the secreted protein is present in epididymal fluid throughout the duct [PMID:22875906]. Mechanistically, epididymosomes deliver ELSPBP1 selectively to spermatozoa that are already dead before incubation, with no transfer to live spermatozoa, and this membrane-targeted transfer is enhanced by zinc [PMID:22875906]. This selective acquisition by membrane-compromised cells positions ELSPBP1 as a marker distinguishing dead from viable spermatozoa during epididymal transit. Beyond this single characterization [PMID:22875906], no further molecular mechanism, binding partner, or downstream consequence of ELSPBP1 has been characterized in the available corpus.","teleology":[{"year":2012,"claim":"Established where ELSPBP1 is produced and how it reaches spermatozoa, answering whether the protein acts as an epididymis-derived, vesicle-delivered factor rather than a sperm-intrinsic one.","evidence":"RT-PCR tissue profiling, immunohistochemistry, Western blot on epididymal fluid fractions, and immunocytometry on spermatozoa in rat/bovine epididymis","pmids":["22875906"],"confidence":"Medium","gaps":["single-lab study not independently replicated","molecular receptor or binding partner on the sperm membrane that mediates ELSPBP1 acquisition is unidentified","the biochemical activity of ELSPBP1 itself is uncharacterized"]},{"year":2012,"claim":"Demonstrated that ELSPBP1 transfer is selective for dead spermatozoa and zinc-dependent, establishing it as a candidate molecular tag for membrane-compromised cells.","evidence":"in vitro incubation of caput spermatozoa with cauda epididymosomes under defined conditions with and without zinc, scored by immunocytometry","pmids":["22875906"],"confidence":"Medium","gaps":["the mechanism by which membrane compromise enables ELSPBP1 binding is unknown","the role of zinc in promoting transfer is not mechanistically defined","the functional consequence of ELSPBP1 deposition on dead sperm (e.g., recognition, clearance) is not demonstrated"]},{"year":null,"claim":"The molecular activity of ELSPBP1 and whether its presence on dead spermatozoa triggers a downstream recognition or clearance process remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["no biochemical or enzymatic activity defined for the protein","no identified sperm-surface or epididymosome partner","no structural model or domain-level mechanism"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[0]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96BH3","full_name":"Epididymal sperm-binding protein 1","aliases":["Epididymal secretory protein 12","hE12"],"length_aa":223,"mass_kda":26.1,"function":"Binds to spermatozoa upon ejaculation and may play a role in sperm capacitation. Has phosphorylcholine-binding activity (By similarity)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q96BH3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ELSPBP1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ELSPBP1","total_profiled":1310},"omim":[{"mim_id":"607443","title":"EPIDIDYMAL SPERM BINDING PROTEIN 1; ELSPBP1","url":"https://www.omim.org/entry/607443"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"epididymis","ntpm":2669.4}],"url":"https://www.proteinatlas.org/search/ELSPBP1"},"hgnc":{"alias_symbol":["HE12","E12","EDDM12"],"prev_symbol":[]},"alphafold":{"accession":"Q96BH3","domains":[{"cath_id":"2.10.10.10","chopping":"32-64","consensus_level":"high","plddt":94.0061,"start":32,"end":64},{"cath_id":"2.10.10.10","chopping":"181-223","consensus_level":"medium","plddt":89.0307,"start":181,"end":223}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96BH3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96BH3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96BH3-F1-predicted_aligned_error_v6.png","plddt_mean":84.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ELSPBP1","jax_strain_url":"https://www.jax.org/strain/search?query=ELSPBP1"},"sequence":{"accession":"Q96BH3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96BH3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96BH3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96BH3"}},"corpus_meta":[{"pmid":"1649701","id":"PMC_1649701","title":"Functional activity of myogenic HLH proteins requires hetero-oligomerization with E12/E47-like proteins in vivo.","date":"1991","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/1649701","citation_count":794,"is_preprint":false},{"pmid":"1846322","id":"PMC_1846322","title":"An inhibitory domain of E12 transcription factor prevents DNA binding in E12 homodimers but not in E12 heterodimers.","date":"1991","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/1846322","citation_count":385,"is_preprint":false},{"pmid":"11309385","id":"PMC_11309385","title":"A new role for E12/E47 in the repression of E-cadherin expression and epithelial-mesenchymal transitions.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11309385","citation_count":378,"is_preprint":false},{"pmid":"3487685","id":"PMC_3487685","title":"Vitamin E supplementation suppresses prostaglandin E1(2) synthesis and enhances the immune response of aged mice.","date":"1986","source":"Mechanisms of ageing and development","url":"https://pubmed.ncbi.nlm.nih.gov/3487685","citation_count":214,"is_preprint":false},{"pmid":"9705952","id":"PMC_9705952","title":"Induction of early B cell factor (EBF) and multiple B lineage genes by the basic helix-loop-helix transcription factor E12.","date":"1998","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/9705952","citation_count":190,"is_preprint":false},{"pmid":"21258409","id":"PMC_21258409","title":"miR-495 is upregulated by E12/E47 in breast cancer stem cells, and promotes oncogenesis and hypoxia resistance via downregulation of E-cadherin and REDD1.","date":"2011","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/21258409","citation_count":181,"is_preprint":false},{"pmid":"2799390","id":"PMC_2799390","title":"The gene for enhancer binding proteins E12/E47 lies at the t(1;19) breakpoint in acute leukemias.","date":"1989","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/2799390","citation_count":172,"is_preprint":false},{"pmid":"1990271","id":"PMC_1990271","title":"B-cell- and myocyte-specific E2-box-binding factors contain E12/E47-like subunits.","date":"1991","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/1990271","citation_count":164,"is_preprint":false},{"pmid":"7532918","id":"PMC_7532918","title":"The utility of basal cell-specific anti-cytokeratin antibody (34 beta E12) in the diagnosis of prostate cancer. 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neuroepithelium","date":"2024-09-25","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.25.614873","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.11.15.619407","title":"Enhanced Intestinal Epithelial Co-Culture Model with Orbital Mechanical Stimulation: A Proof-of-Concept Application in Food Nanotoxicology","date":"2024-11-17","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.15.619407","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.31.606092","title":"SMURF1/2 are novel regulators of WNK1 stability","date":"2024-08-01","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.31.606092","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46077,"output_tokens":895,"usd":0.075828,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6750,"output_tokens":1360,"usd":0.033875,"stage2_stop_reason":"end_turn"},"total_usd":0.109703,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the corpus, I need to identify papers about the canonical ELSPBP1 protein (also known as HE12, E12, EDDM12 in the HGNC alias context).\n\n**Critical disambiguation:** The HGNC aliases listed (HE12, E12, EDDM12) for this gene query refer to **ELSPBP1** — the epididymal sperm binding protein 1. However, the vast majority of papers in this corpus use \"E12\" to refer to the **E2A gene product** (TCF3/E12/E47), a basic helix-loop-helix transcription factor. These are **different proteins** — the E2A-derived E12 is a bHLH transcription factor, while ELSPBP1 is an epididymal protein.\n\nThe HGNC alias \"HE12\" for ELSPBP1 refers to the human epididymis protein E12, not the E2A bHLH protein. Paper [43] mentions \"ZFE12 homologue of the human E12 protein\" in the context of bHLH/daughterless — this is the E2A E12, not ELSPBP1.\n\n**Only paper [17]** directly describes the canonical ELSPBP1 protein (epididymal sperm binding protein 1) with experimental mechanistic findings.\n\nAll other papers describe either: the E2A bHLH transcription factor product E12/E47, cytokeratin antibody 34βE12, cell line HT29-MTX-E12, hemoglobin variants at position E12, or unrelated organisms/pathogens. These are symbol/alias collisions, not the ELSPBP1 protein.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"ELSPBP1 is secreted by epididymal epithelial cells into the epididymal fluid and is associated with epididymosomes (small membranous vesicles). Epididymosomes transfer ELSPBP1 specifically to spermatozoa that are already dead before incubation; live spermatozoa do not acquire ELSPBP1. This transfer is enhanced by the presence of zinc in the incubation medium. ELSPBP1 expression is highest in the caput and corpus epididymis at the mRNA level, and the protein is present in epididymal fluid throughout the epididymis.\",\n      \"method\": \"Real-time RT-PCR for tissue expression; immunohistochemistry for localization; Western blot on tissue homogenates and epididymal fluid fractions; immunocytometry on spermatozoa; in vitro incubation of caput spermatozoa with cauda epididymosomes under varying conditions (with/without zinc)\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (fractionation, immunocytometry, functional transfer assay with defined conditions) in a single study; demonstrates subcellular localization tied to functional consequence (selective transfer to dead sperm), but single lab\",\n      \"pmids\": [\"22875906\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ELSPBP1 is an epididymal secretory protein packaged into epididymosomes by epididymal epithelial cells and selectively transferred to membrane-compromised (dead) spermatozoa during epididymal transit, with zinc enhancing this transfer, suggesting ELSPBP1 acts as a tag marking dead spermatozoa for recognition during epididymal transit.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ELSPBP1 is an epididymal secretory protein that functions in the post-testicular maturation environment of spermatozoa, where it is produced by epididymal epithelial cells and released into the epididymal fluid in association with epididymosomes [#0]. The protein is expressed most highly at the mRNA level in the caput and corpus epididymis, while the secreted protein is present in epididymal fluid throughout the duct [#0]. Mechanistically, epididymosomes deliver ELSPBP1 selectively to spermatozoa that are already dead before incubation, with no transfer to live spermatozoa, and this membrane-targeted transfer is enhanced by zinc [#0]. This selective acquisition by membrane-compromised cells positions ELSPBP1 as a marker distinguishing dead from viable spermatozoa during epididymal transit. Beyond this single characterization [#0], no further molecular mechanism, binding partner, or downstream consequence of ELSPBP1 has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established where ELSPBP1 is produced and how it reaches spermatozoa, answering whether the protein acts as an epididymis-derived, vesicle-delivered factor rather than a sperm-intrinsic one.\",\n      \"evidence\": \"RT-PCR tissue profiling, immunohistochemistry, Western blot on epididymal fluid fractions, and immunocytometry on spermatozoa in rat/bovine epididymis\",\n      \"pmids\": [\"22875906\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"multiple orthogonal methods in a single lab\",\n      \"gaps\": [\n        \"single-lab study not independently replicated\",\n        \"molecular receptor or binding partner on the sperm membrane that mediates ELSPBP1 acquisition is unidentified\",\n        \"the biochemical activity of ELSPBP1 itself is uncharacterized\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated that ELSPBP1 transfer is selective for dead spermatozoa and zinc-dependent, establishing it as a candidate molecular tag for membrane-compromised cells.\",\n      \"evidence\": \"in vitro incubation of caput spermatozoa with cauda epididymosomes under defined conditions with and without zinc, scored by immunocytometry\",\n      \"pmids\": [\"22875906\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"functional transfer assay with defined conditions tied to localization\",\n      \"gaps\": [\n        \"the mechanism by which membrane compromise enables ELSPBP1 binding is unknown\",\n        \"the role of zinc in promoting transfer is not mechanistically defined\",\n        \"the functional consequence of ELSPBP1 deposition on dead sperm (e.g., recognition, clearance) is not demonstrated\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular activity of ELSPBP1 and whether its presence on dead spermatozoa triggers a downstream recognition or clearance process remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"no biochemical or enzymatic activity defined for the protein\",\n        \"no identified sperm-surface or epididymosome partner\",\n        \"no structural model or domain-level mechanism\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":3,"faith_pct":100.0}}