{"gene":"SEMG1","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":2018,"finding":"miR-525-3p directly targets the 3'-UTR of SEMG1 mRNA and suppresses its expression, providing a post-transcriptional regulatory mechanism for SEMG1 levels in spermatozoa.","method":"Luciferase reporter assay confirming miR-525-3p binding to SEMG1 3'-UTR; Western blot and real-time PCR for expression quantification","journal":"Andrology","confidence":"Medium","confidence_rationale":"Tier 2 — luciferase reporter assay with expression validation, single lab, moderate methods","pmids":["30575326"],"is_preprint":false},{"year":2008,"finding":"The core promoter of SEMG1 spans the region between two putative GATA-1 binding domains, and this region is necessary and sufficient for basal promoter activity in myeloma cells; the promoter is responsive to IL-4 and IL-6.","method":"Promoter deletion/reporter assays in myeloma cells","journal":"Leukemia research","confidence":"Medium","confidence_rationale":"Tier 2 — functional promoter dissection with deletion constructs, single lab","pmids":["18602691"],"is_preprint":false},{"year":2020,"finding":"SEMG1 physically associates with the glycolytic enzymes pyruvate kinase M2 (PKM2) and lactate dehydrogenase A (LDHA), and increases the protein levels and enzymatic activity of both, leading to enhanced glycolysis, mitochondrial membrane potential, respiration, and ROS production in cancer cells.","method":"Pull-down assay followed by LC-MS/MS mass spectrometry; enzymatic activity assays; mitochondrial membrane potential assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — pull-down/MS identification plus functional enzymatic and metabolic assays in a single study","pmids":["33311447"],"is_preprint":false},{"year":2020,"finding":"Silencing SEMG1 in GC-1 spg spermatogonia cells by siRNA promotes apoptosis, associated with increased caspase-3 and decreased BCL2 protein levels, without affecting cell cycle distribution.","method":"siRNA knockdown; flow cytometry for apoptosis; Western blot for caspase-3 and BCL2","journal":"Zhonghua nan ke xue = National journal of andrology","confidence":"Low","confidence_rationale":"Tier 3 — single lab, loss-of-function with phenotypic readout but limited mechanistic depth","pmids":["33377697"],"is_preprint":false},{"year":2024,"finding":"SEMG1 overexpression in OSCC cells augments reactive oxygen species production, increases mitochondrial membrane potential, promotes S-phase entry, and correlates with expression of metabolic enzymes ENO1 and PKM2.","method":"Stable SEMG1 overexpression and shRNA knockdown in CAL27 cells; fluorescent dihydroethidium ROS assay; mitochondrial membrane potential assay; flow cytometry cell cycle analysis; immunohistochemistry and Western blot","journal":"Oral diseases","confidence":"Low","confidence_rationale":"Tier 3 — single lab, correlative metabolic enzyme link without direct enzymatic or binding assay","pmids":["39155514"],"is_preprint":false},{"year":2025,"finding":"Recombinant SEMG1 inhibits sperm hyperactivation and progressive motility by suppressing CatSper calcium channel currents at physiologically relevant concentrations; two functional domains (Q32-V118 and R98-S220) within SEMG1 mediate this inhibition and differ in their EPPIN-binding capacities.","method":"Electrophysiological recordings of CatSper currents; truncated recombinant fragment assays; sperm motility/hyperactivation assays; EPPIN-binding assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1-2 — in vitro electrophysiology plus domain-mapping with truncation mutants; preprint, single lab","pmids":["bio_10.1101_2025.09.05.674523"],"is_preprint":true}],"current_model":"SEMG1 is a seminal plasma protein that suppresses sperm hyperactivation by inhibiting the CatSper calcium channel via two distinct functional domains, with EPPIN binding contributing to this regulation; its expression is post-transcriptionally repressed by miR-525-3p, transcriptionally activated through a GATA-1-flanked core promoter responsive to IL-4/IL-6, and in cancer contexts it physically interacts with PKM2 and LDHA to upregulate glycolytic and mitochondrial energy metabolism."},"narrative":{"teleology":[{"year":2008,"claim":"Defining how SEMG1 transcription is controlled revealed a core promoter between two GATA-1 sites that is necessary and sufficient for basal activity and is induced by IL-4/IL-6, establishing SEMG1 as a cytokine-responsive gene.","evidence":"Promoter deletion/reporter assays in myeloma cells","pmids":["18602691"],"confidence":"Medium","gaps":["Whether GATA-1 itself binds and drives the promoter was not confirmed by ChIP or EMSA","Relevance of IL-4/IL-6 responsiveness outside myeloma cells is untested","Upstream signaling pathways linking cytokine receptors to SEMG1 promoter are unknown"]},{"year":2018,"claim":"Identifying miR-525-3p as a direct post-transcriptional repressor of SEMG1 established a regulatory layer that could modulate SEMG1 protein levels in spermatozoa independently of transcription.","evidence":"Luciferase reporter assay confirming miR-525-3p binding to SEMG1 3'-UTR; Western blot and qPCR","pmids":["30575326"],"confidence":"Medium","gaps":["Physiological consequences of miR-525-3p–mediated SEMG1 repression on sperm function are not demonstrated","Whether other miRNAs also regulate SEMG1 is unexplored","Single-lab finding without independent replication"]},{"year":2020,"claim":"Demonstrating that SEMG1 physically binds PKM2 and LDHA and enhances their enzymatic activities revealed an unexpected metabolic function for this seminal protein in cancer cells, linking it to glycolysis and mitochondrial energetics.","evidence":"Pull-down/LC-MS/MS identification of PKM2 and LDHA; enzymatic activity assays; mitochondrial membrane potential measurements in cancer cells","pmids":["33311447"],"confidence":"Medium","gaps":["Structural basis of SEMG1–PKM2/LDHA interaction is unknown","Whether this metabolic role operates in normal seminal or spermatogenic physiology is untested","Reciprocal co-immunoprecipitation was not reported"]},{"year":2025,"claim":"Electrophysiological demonstration that SEMG1 directly suppresses CatSper channel currents, together with domain mapping showing two functionally distinct inhibitory regions with differential EPPIN binding, established a molecular mechanism for SEMG1's role in regulating sperm capacitation.","evidence":"Patch-clamp electrophysiology of CatSper currents; recombinant truncation mutant assays; sperm motility/hyperactivation assays; EPPIN-binding assays (preprint)","pmids":["bio_10.1101_2025.09.05.674523"],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","Whether SEMG1 binds CatSper directly or acts through an intermediary is not resolved","In vivo relevance in fertilization has not been tested with knockout models"]},{"year":null,"claim":"The relationship between SEMG1's sperm-regulatory function (CatSper inhibition) and its cancer-associated metabolic function (PKM2/LDHA activation) remains mechanistically unconnected, and whether these reflect context-dependent activities of distinct domains is unknown.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of SEMG1 exists to unify its multi-domain activities","No animal knockout or knockin model has been reported","Whether SEMG1's anti-apoptotic effect in spermatogonia is mediated through metabolic or CatSper-related pathways is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,5]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[5]}],"complexes":[],"partners":["PKM2","LDHA","EPPIN","CATSPER1"],"other_free_text":[]},"mechanistic_narrative":"SEMG1 is a seminal plasma protein that inhibits sperm hyperactivation by suppressing CatSper calcium channel currents through two distinct functional domains (Q32-V118 and R98-S220), which differ in their capacity to bind the sperm surface protein EPPIN [PMID:bio_10.1101_2025.09.05.674523]. Its transcription is driven by a core promoter flanked by GATA-1 binding domains and is responsive to IL-4 and IL-6 [PMID:18602691], while post-transcriptionally miR-525-3p represses SEMG1 by targeting its 3'-UTR [PMID:30575326]. In cancer cells, SEMG1 physically associates with the glycolytic enzymes PKM2 and LDHA, increasing their protein levels and enzymatic activities to enhance glycolysis, mitochondrial membrane potential, and ROS production [PMID:33311447]."},"prefetch_data":{"uniprot":{"accession":"P04279","full_name":"Semenogelin-1","aliases":["Cancer/testis antigen 103","Semenogelin I","SGI"],"length_aa":462,"mass_kda":52.1,"function":"Predominant protein in semen. It participates in the formation of a gel matrix entrapping the accessory gland secretions and ejaculated spermatozoa. Fragments of semenogelin and/or fragments of the related proteins may contribute to the activation of progressive sperm movements as the gel-forming proteins are fragmented by KLK3/PSA Alpha-inhibin-92 and alpha-inhibin-31, derived from the proteolytic degradation of semenogelin, inhibit the secretion of pituitary follicle-stimulating hormone","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P04279/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SEMG1","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/SEMG1","total_profiled":1310},"omim":[{"mim_id":"609872","title":"WAP 4-DISULFIDE CORE DOMAIN 12; WFDC12","url":"https://www.omim.org/entry/609872"},{"mim_id":"182140","title":"SEMENOGELIN I; SEMG1","url":"https://www.omim.org/entry/182140"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"seminal vesicle","ntpm":28650.3}],"url":"https://www.proteinatlas.org/search/SEMG1"},"hgnc":{"alias_symbol":["CT103"],"prev_symbol":["SEMG"]},"alphafold":{"accession":"P04279","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P04279","model_url":"https://alphafold.ebi.ac.uk/files/AF-P04279-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P04279-F1-predicted_aligned_error_v6.png","plddt_mean":32.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SEMG1","jax_strain_url":"https://www.jax.org/strain/search?query=SEMG1"},"sequence":{"accession":"P04279","fasta_url":"https://rest.uniprot.org/uniprotkb/P04279.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P04279/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P04279"}},"corpus_meta":[{"pmid":"11228421","id":"PMC_11228421","title":"Exercise induced muscle damage and recovery assessed by means of linear and non-linear sEMG analysis and ultrasonography.","date":"2001","source":"Journal of electromyography and kinesiology : official journal of the International Society of Electrophysiological Kinesiology","url":"https://pubmed.ncbi.nlm.nih.gov/11228421","citation_count":39,"is_preprint":false},{"pmid":"30575326","id":"PMC_30575326","title":"Expressions of miR-525-3p and its target gene SEMG1 in the spermatozoa of patients with asthenozoospermia.","date":"2018","source":"Andrology","url":"https://pubmed.ncbi.nlm.nih.gov/30575326","citation_count":28,"is_preprint":false},{"pmid":"26888905","id":"PMC_26888905","title":"Evaluation of the Check-Points Check MDR CT103 and CT103 XL Microarray Kits by Use of Preparatory Rapid Cell Lysis.","date":"2016","source":"Journal of clinical microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/26888905","citation_count":26,"is_preprint":false},{"pmid":"31058050","id":"PMC_31058050","title":"Expression Analysis of the CRISP2, CATSPER1, PATE1 and SEMG1 in the Sperm of Men with Idiopathic Asthenozoospermia.","date":"2019","source":"Journal of reproduction & infertility","url":"https://pubmed.ncbi.nlm.nih.gov/31058050","citation_count":18,"is_preprint":false},{"pmid":"33311447","id":"PMC_33311447","title":"SEMG1/2 augment energy metabolism of tumor cells.","date":"2020","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/33311447","citation_count":18,"is_preprint":false},{"pmid":"23289976","id":"PMC_23289976","title":"SEMG1 may be the candidate gene for idiopathic asthenozoospermia.","date":"2013","source":"Andrologia","url":"https://pubmed.ncbi.nlm.nih.gov/23289976","citation_count":13,"is_preprint":false},{"pmid":"18602691","id":"PMC_18602691","title":"Core promoter sequence of SEMG I spans between the two putative GATA-1 binding domains and is responsive to IL-4 and IL-6 in myeloma cells.","date":"2008","source":"Leukemia research","url":"https://pubmed.ncbi.nlm.nih.gov/18602691","citation_count":7,"is_preprint":false},{"pmid":"31535590","id":"PMC_31535590","title":"Association of semenogelin (SEMG) gene variants in idiopathic male infertility in Chinese-Han population.","date":"2019","source":"Journal of toxicology and environmental health. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/31535590","citation_count":6,"is_preprint":false},{"pmid":"33022663","id":"PMC_33022663","title":"A novel energy-motion model for continuous sEMG decoding: from muscle energy to motor pattern.","date":"2021","source":"Journal of neural engineering","url":"https://pubmed.ncbi.nlm.nih.gov/33022663","citation_count":5,"is_preprint":false},{"pmid":"39909897","id":"PMC_39909897","title":"Motor control performance-related modulation of beta-band EEG-sEMG coherence differs between general and local muscular exercise-induced fatigue.","date":"2025","source":"European journal of applied physiology","url":"https://pubmed.ncbi.nlm.nih.gov/39909897","citation_count":5,"is_preprint":false},{"pmid":"12827988","id":"PMC_12827988","title":"Neuropathology considerations: clinical and SEMG/biofeedback applications.","date":"2003","source":"Applied psychophysiology and biofeedback","url":"https://pubmed.ncbi.nlm.nih.gov/12827988","citation_count":1,"is_preprint":false},{"pmid":"41002842","id":"PMC_41002842","title":"High-Accuracy Lower-Limb Intent Recognition: A KPCA-ISSA-SVM Approach with sEMG-IMU Sensor Fusion.","date":"2025","source":"Biomimetics (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/41002842","citation_count":1,"is_preprint":false},{"pmid":"19241194","id":"PMC_19241194","title":"SEMG-1 expression in early stage chronic lymphocytic leukemia.","date":"2009","source":"Cytotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/19241194","citation_count":1,"is_preprint":false},{"pmid":"35845758","id":"PMC_35845758","title":"An sEMG-Based Human-Exoskeleton Interface Fusing Convolutional Neural Networks With Hand-Crafted Features.","date":"2022","source":"Frontiers in neurorobotics","url":"https://pubmed.ncbi.nlm.nih.gov/35845758","citation_count":1,"is_preprint":false},{"pmid":"33377697","id":"PMC_33377697","title":"[Effects of silencing the SEMG1 protein on the cycle and apoptosis of GC-1 spg cells].","date":"2020","source":"Zhonghua nan ke xue = National journal of andrology","url":"https://pubmed.ncbi.nlm.nih.gov/33377697","citation_count":0,"is_preprint":false},{"pmid":"39155514","id":"PMC_39155514","title":"The role of SEMG1 overexpression in OSCC tumorigenesis and its relation with metabolic molecules.","date":"2024","source":"Oral diseases","url":"https://pubmed.ncbi.nlm.nih.gov/39155514","citation_count":0,"is_preprint":false},{"pmid":"40013307","id":"PMC_40013307","title":"Facial expression recognition through muscle synergies and estimation of facial keypoint displacements through a skin-musculoskeletal model using facial sEMG signals.","date":"2025","source":"Frontiers in bioengineering and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/40013307","citation_count":0,"is_preprint":false},{"pmid":"41876445","id":"PMC_41876445","title":"Hydrogel-based electrodes for high-fidelity sEMG acquisition and robotic hand control.","date":"2026","source":"Microsystems & nanoengineering","url":"https://pubmed.ncbi.nlm.nih.gov/41876445","citation_count":0,"is_preprint":false},{"pmid":"40725747","id":"PMC_40725747","title":"Dynamic Changes in Mimic Muscle Tone During Early Orthodontic Treatment: An sEMG Study.","date":"2025","source":"Journal of clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40725747","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.05.674523","title":"Semenogelin-1 Inhibition of Mouse Sperm Hyperactivation Reveals Two Functional Domains Modulating CatSper Channel","date":"2025-09-10","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.05.674523","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.08.674890","title":"Impact of Noise on Deep Learning-Based Pseudo-Online Gesture Recognition with High-Density EMG","date":"2025-09-10","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.08.674890","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.10.08.25337421","title":"A Wearable Platform for Real-Time Control of a Prosthetic Hand by High-Density EMG","date":"2025-10-13","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.08.25337421","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.24.25336481","title":"An Artificial Intelligence Approach to Augmentative and Assistive Communication for Patients with Amyotrophic Lateral Sclerosis","date":"2025-09-27","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.24.25336481","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.20.665786","title":"A PAM-CNN recognition approach to Muscle Fatigue of Special Operators by sEMG signals","date":"2025-07-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.20.665786","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.10.675422","title":"Effects of Spatial and Signal-Imposed Noises on Motor Unit Decomposition","date":"2025-09-16","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.10.675422","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13358,"output_tokens":1365,"usd":0.030274},"stage2":{"model":"claude-opus-4-6","input_tokens":4600,"output_tokens":1513,"usd":0.091237},"total_usd":0.121511,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"miR-525-3p directly targets the 3'-UTR of SEMG1 mRNA and suppresses its expression, providing a post-transcriptional regulatory mechanism for SEMG1 levels in spermatozoa.\",\n      \"method\": \"Luciferase reporter assay confirming miR-525-3p binding to SEMG1 3'-UTR; Western blot and real-time PCR for expression quantification\",\n      \"journal\": \"Andrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — luciferase reporter assay with expression validation, single lab, moderate methods\",\n      \"pmids\": [\"30575326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The core promoter of SEMG1 spans the region between two putative GATA-1 binding domains, and this region is necessary and sufficient for basal promoter activity in myeloma cells; the promoter is responsive to IL-4 and IL-6.\",\n      \"method\": \"Promoter deletion/reporter assays in myeloma cells\",\n      \"journal\": \"Leukemia research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional promoter dissection with deletion constructs, single lab\",\n      \"pmids\": [\"18602691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SEMG1 physically associates with the glycolytic enzymes pyruvate kinase M2 (PKM2) and lactate dehydrogenase A (LDHA), and increases the protein levels and enzymatic activity of both, leading to enhanced glycolysis, mitochondrial membrane potential, respiration, and ROS production in cancer cells.\",\n      \"method\": \"Pull-down assay followed by LC-MS/MS mass spectrometry; enzymatic activity assays; mitochondrial membrane potential assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pull-down/MS identification plus functional enzymatic and metabolic assays in a single study\",\n      \"pmids\": [\"33311447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Silencing SEMG1 in GC-1 spg spermatogonia cells by siRNA promotes apoptosis, associated with increased caspase-3 and decreased BCL2 protein levels, without affecting cell cycle distribution.\",\n      \"method\": \"siRNA knockdown; flow cytometry for apoptosis; Western blot for caspase-3 and BCL2\",\n      \"journal\": \"Zhonghua nan ke xue = National journal of andrology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, loss-of-function with phenotypic readout but limited mechanistic depth\",\n      \"pmids\": [\"33377697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SEMG1 overexpression in OSCC cells augments reactive oxygen species production, increases mitochondrial membrane potential, promotes S-phase entry, and correlates with expression of metabolic enzymes ENO1 and PKM2.\",\n      \"method\": \"Stable SEMG1 overexpression and shRNA knockdown in CAL27 cells; fluorescent dihydroethidium ROS assay; mitochondrial membrane potential assay; flow cytometry cell cycle analysis; immunohistochemistry and Western blot\",\n      \"journal\": \"Oral diseases\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, correlative metabolic enzyme link without direct enzymatic or binding assay\",\n      \"pmids\": [\"39155514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Recombinant SEMG1 inhibits sperm hyperactivation and progressive motility by suppressing CatSper calcium channel currents at physiologically relevant concentrations; two functional domains (Q32-V118 and R98-S220) within SEMG1 mediate this inhibition and differ in their EPPIN-binding capacities.\",\n      \"method\": \"Electrophysiological recordings of CatSper currents; truncated recombinant fragment assays; sperm motility/hyperactivation assays; EPPIN-binding assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro electrophysiology plus domain-mapping with truncation mutants; preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.09.05.674523\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SEMG1 is a seminal plasma protein that suppresses sperm hyperactivation by inhibiting the CatSper calcium channel via two distinct functional domains, with EPPIN binding contributing to this regulation; its expression is post-transcriptionally repressed by miR-525-3p, transcriptionally activated through a GATA-1-flanked core promoter responsive to IL-4/IL-6, and in cancer contexts it physically interacts with PKM2 and LDHA to upregulate glycolytic and mitochondrial energy metabolism.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SEMG1 is a seminal plasma protein that inhibits sperm hyperactivation by suppressing CatSper calcium channel currents through two distinct functional domains (Q32-V118 and R98-S220), which differ in their capacity to bind the sperm surface protein EPPIN [PMID:bio_10.1101_2025.09.05.674523]. Its transcription is driven by a core promoter flanked by GATA-1 binding domains and is responsive to IL-4 and IL-6 [PMID:18602691], while post-transcriptionally miR-525-3p represses SEMG1 by targeting its 3'-UTR [PMID:30575326]. In cancer cells, SEMG1 physically associates with the glycolytic enzymes PKM2 and LDHA, increasing their protein levels and enzymatic activities to enhance glycolysis, mitochondrial membrane potential, and ROS production [PMID:33311447].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Defining how SEMG1 transcription is controlled revealed a core promoter between two GATA-1 sites that is necessary and sufficient for basal activity and is induced by IL-4/IL-6, establishing SEMG1 as a cytokine-responsive gene.\",\n      \"evidence\": \"Promoter deletion/reporter assays in myeloma cells\",\n      \"pmids\": [\"18602691\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether GATA-1 itself binds and drives the promoter was not confirmed by ChIP or EMSA\",\n        \"Relevance of IL-4/IL-6 responsiveness outside myeloma cells is untested\",\n        \"Upstream signaling pathways linking cytokine receptors to SEMG1 promoter are unknown\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identifying miR-525-3p as a direct post-transcriptional repressor of SEMG1 established a regulatory layer that could modulate SEMG1 protein levels in spermatozoa independently of transcription.\",\n      \"evidence\": \"Luciferase reporter assay confirming miR-525-3p binding to SEMG1 3'-UTR; Western blot and qPCR\",\n      \"pmids\": [\"30575326\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Physiological consequences of miR-525-3p–mediated SEMG1 repression on sperm function are not demonstrated\",\n        \"Whether other miRNAs also regulate SEMG1 is unexplored\",\n        \"Single-lab finding without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrating that SEMG1 physically binds PKM2 and LDHA and enhances their enzymatic activities revealed an unexpected metabolic function for this seminal protein in cancer cells, linking it to glycolysis and mitochondrial energetics.\",\n      \"evidence\": \"Pull-down/LC-MS/MS identification of PKM2 and LDHA; enzymatic activity assays; mitochondrial membrane potential measurements in cancer cells\",\n      \"pmids\": [\"33311447\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Structural basis of SEMG1–PKM2/LDHA interaction is unknown\",\n        \"Whether this metabolic role operates in normal seminal or spermatogenic physiology is untested\",\n        \"Reciprocal co-immunoprecipitation was not reported\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Electrophysiological demonstration that SEMG1 directly suppresses CatSper channel currents, together with domain mapping showing two functionally distinct inhibitory regions with differential EPPIN binding, established a molecular mechanism for SEMG1's role in regulating sperm capacitation.\",\n      \"evidence\": \"Patch-clamp electrophysiology of CatSper currents; recombinant truncation mutant assays; sperm motility/hyperactivation assays; EPPIN-binding assays (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.09.05.674523\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Preprint not yet peer-reviewed\",\n        \"Whether SEMG1 binds CatSper directly or acts through an intermediary is not resolved\",\n        \"In vivo relevance in fertilization has not been tested with knockout models\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The relationship between SEMG1's sperm-regulatory function (CatSper inhibition) and its cancer-associated metabolic function (PKM2/LDHA activation) remains mechanistically unconnected, and whether these reflect context-dependent activities of distinct domains is unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of SEMG1 exists to unify its multi-domain activities\",\n        \"No animal knockout or knockin model has been reported\",\n        \"Whether SEMG1's anti-apoptotic effect in spermatogonia is mediated through metabolic or CatSper-related pathways is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PKM2\",\n      \"LDHA\",\n      \"EPPIN\",\n      \"CATSPER1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}