{"gene":"OBSL1","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2011,"finding":"CCDC8 physically interacts with OBSL1 (but not CUL7) as shown by coimmunoprecipitation, placing CCDC8 in the same pathway as CUL7 and OBSL1 in the control of mammalian growth.","method":"Coimmunoprecipitation","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP experiment demonstrating physical interaction; supported by transcriptional co-association data but no reciprocal IP or in vitro reconstitution reported in abstract","pmids":["21737058"],"is_preprint":false},{"year":2011,"finding":"OBSL1 forms a physical complex with the scaffold protein CUL7, and this interaction localizes CUL7 to the Golgi apparatus. OBSL1 is required for Golgi morphogenesis and dendrite elaboration in neurons, acting upstream of the CUL7(Fbxw8) ubiquitin ligase. Loss of OBSL1 impairs Golgi complex morphology and secretory trafficking, and reduces dendrite growth without affecting axons.","method":"Immunoprecipitation/mass spectrometry, co-immunoprecipitation, RNAi knockdown with morphological and functional readouts in primary neurons and in vivo rat cerebellum","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal IP/MS to identify complex, functional KD with specific morphological phenotypes in vitro and in vivo, multiple orthogonal methods in single rigorous study","pmids":["21572988"],"is_preprint":false},{"year":2009,"finding":"OBSL1 is a cytoskeletal adaptor protein that localizes to the nuclear envelope, and loss of OBSL1 leads to downregulation of CUL7 protein levels, implying a role for OBSL1 in the maintenance of CUL7 and that both proteins act in the same molecular pathway.","method":"High-density genome-wide SNP mapping, mutation identification, subcellular localization (nuclear envelope), and protein level analysis in patient-derived cells","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment and functional consequence (CUL7 downregulation upon OBSL1 loss) in patient-derived cells; single lab, limited mechanistic detail in abstract","pmids":["19481195"],"is_preprint":false},{"year":2007,"finding":"OBSL1 is a cytoskeletal adaptor protein closely related to obscurin, expressed in multiple tissues, and localizes to intercalated discs, the perinuclear region, and overlying the Z lines and M bands of adult rat cardiac myocytes.","method":"Cloning, alternative splicing characterization, immunofluorescence localization in adult rat cardiac myocytes","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct subcellular localization by imaging in cardiac myocytes; characterization of isoforms by molecular cloning; single lab without functional consequence formally demonstrated","pmids":["17289344"],"is_preprint":false},{"year":2012,"finding":"In OBSL1-null fibroblasts, activation of STAT5b and MAPK in response to GH is reduced compared to controls, and activation of AKT in response to IGF1 is reduced at 5 min post-stimulation, indicating that OBSL1 is required for normal GH and IGF1 signaling.","method":"Signaling assays (phosphorylation of STAT5b, MAPK, AKT) in patient-derived OBSL1-null fibroblast cell lines following GH or IGF1 stimulation","journal":"Journal of molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional assay in patient-derived null cells with two signaling pathways tested; single lab, limited mechanistic depth on how OBSL1 engages these pathways","pmids":["23018678"],"is_preprint":false},{"year":2019,"finding":"Skeletal muscle-specific Obsl1 knockout mice have a benign phenotype similar to obscurin knockouts, but combined deletion of both Obsl1 and obscurin reveals functionally redundant roles for sarcolemmal stability and sarcoplasmic reticulum organization in skeletal muscle. Global Obsl1 knockout is embryonically lethal.","method":"Conditional and global knockout mouse models, mass spectrometry-based proteomics of muscle tissue, histological and ultrastructural analysis","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — rigorous double-knockout genetic epistasis in vivo with multiple orthogonal readouts (proteomics, histology, ultrastructure); embryonic lethality of global KO directly established","pmids":["31098411"],"is_preprint":false},{"year":2025,"finding":"In cardiac muscle, Obsl1 (together with obscurin) plays roles in sarcoplasmic reticulum structure, calcium cycling, mitochondrial architecture and function. Obsl1 interacts with Atg4 proteins (novel interactors identified), and combined loss of obscurin and Obsl1 results in abnormal mitophagy, increased unfolded protein response, decreased Chchd3 (a MICOS complex protein) levels, and diastolic dysfunction.","method":"Cardiac-specific double-knockout mouse models, biochemical fractionation, co-immunoprecipitation (Atg4 as novel OBSL1 interactors), electron microscopy, calcium imaging, metabolic assays, echocardiography","journal":"Circulation. Heart failure","confidence":"High","confidence_rationale":"Tier 2 / Strong — rigorous double-KO genetic model with multiple orthogonal methods (imaging, biochemistry, physiology, interactor identification); novel Atg4 interaction identified by co-IP","pmids":["40066567"],"is_preprint":false}],"current_model":"OBSL1 is a cytoskeletal adaptor protein that localizes to the Golgi apparatus and nuclear envelope, where it scaffolds the CUL7(Fbxw8) E3 ubiquitin ligase complex by physically binding CUL7, thereby maintaining CUL7 protein levels and enabling ubiquitin-dependent regulation of Golgi morphogenesis, dendrite patterning, and GH/IGF1 signaling; OBSL1 also physically associates with CCDC8 (but not CUL7 directly) to form a growth-regulatory pathway, interacts with Atg4 proteins to regulate mitophagy in the heart, and acts redundantly with obscurin to maintain sarcolemmal integrity, sarcoplasmic reticulum organization, and calcium cycling in striated muscle."},"narrative":{"mechanistic_narrative":"OBSL1 is a cytoskeletal adaptor protein, closely related to obscurin, that functions as a scaffold linking growth-regulatory ubiquitin ligase activity to organelle and cytoskeletal organization [PMID:17289344, PMID:21572988]. It localizes to the nuclear envelope and is required to maintain CUL7 protein levels, placing OBSL1 in a shared molecular pathway with CUL7 [PMID:19481195]. OBSL1 physically binds CUL7 and recruits it to the Golgi apparatus, acting upstream of the CUL7(Fbxw8) ubiquitin ligase to drive Golgi morphogenesis, secretory trafficking, and dendrite elaboration in neurons [PMID:21572988]; it additionally associates with CCDC8 in this growth-control pathway, though CCDC8 binds OBSL1 rather than CUL7 directly [PMID:21737058]. Consistent with a growth-regulatory role, OBSL1-null fibroblasts show reduced GH-induced STAT5b/MAPK activation and blunted IGF1-induced AKT signaling [PMID:23018678]. In striated muscle, OBSL1 acts redundantly with obscurin: single-gene loss is benign, but combined deletion impairs sarcolemmal stability and sarcoplasmic reticulum organization, while global OBSL1 knockout is embryonically lethal [PMID:31098411]. In the heart, OBSL1 and obscurin together govern sarcoplasmic reticulum structure, calcium cycling, and mitochondrial architecture, with OBSL1 binding Atg4 proteins and dual loss producing abnormal mitophagy, elevated unfolded protein response, and diastolic dysfunction [PMID:40066567].","teleology":[{"year":2007,"claim":"Established the existence and tissue distribution of OBSL1 as an obscurin-related adaptor, defining its candidate subcellular niches before any function was known.","evidence":"Molecular cloning, splice-isoform characterization, and immunofluorescence in adult rat cardiac myocytes","pmids":["17289344"],"confidence":"Medium","gaps":["No functional consequence demonstrated","Binding partners and pathway not yet defined"]},{"year":2009,"claim":"Linked OBSL1 to CUL7 by showing OBSL1 loss reduces CUL7 protein levels, establishing the two proteins act in a common pathway and OBSL1 stabilizes CUL7.","evidence":"SNP mapping, mutation identification, and localization/protein-level analysis in patient-derived cells","pmids":["19481195"],"confidence":"Medium","gaps":["Mechanism of CUL7 stabilization not resolved","Direct OBSL1–CUL7 binding not yet shown in this study"]},{"year":2011,"claim":"Resolved how OBSL1 acts on CUL7 — direct complex formation that recruits CUL7 to the Golgi and drives Golgi morphogenesis and dendrite growth — defining OBSL1 as an upstream scaffold for the CUL7(Fbxw8) ligase.","evidence":"Reciprocal IP/MS, co-IP, and RNAi knockdown with morphological/functional readouts in primary neurons and rat cerebellum","pmids":["21572988"],"confidence":"High","gaps":["Ubiquitination substrates downstream of the Golgi-localized complex not identified","How OBSL1 itself is targeted to the Golgi unresolved"]},{"year":2011,"claim":"Extended the growth-control module by showing CCDC8 binds OBSL1 (but not CUL7), defining the topology of the OBSL1–CUL7–CCDC8 pathway.","evidence":"Coimmunoprecipitation plus transcriptional co-association data","pmids":["21737058"],"confidence":"Medium","gaps":["Single Co-IP without reciprocal validation or in vitro reconstitution","Functional output of the OBSL1–CCDC8 interaction not defined"]},{"year":2012,"claim":"Connected OBSL1 to growth-factor signaling by showing OBSL1-null cells have blunted GH and IGF1 responses, providing a cellular signaling basis for the growth phenotype.","evidence":"Phosphorylation assays for STAT5b/MAPK/AKT in patient-derived OBSL1-null fibroblasts after GH or IGF1 stimulation","pmids":["23018678"],"confidence":"Medium","gaps":["Molecular mechanism by which OBSL1 engages GH/IGF1 receptor signaling unknown","Link to CUL7 ligase activity in this context not established"]},{"year":2019,"claim":"Defined OBSL1's role in striated muscle through genetic epistasis with obscurin, revealing functional redundancy for sarcolemmal and SR integrity and establishing the gene as essential for development.","evidence":"Conditional and global knockout mice, muscle proteomics, histology, and ultrastructure","pmids":["31098411"],"confidence":"High","gaps":["Molecular basis of redundancy with obscurin unresolved","Cause of embryonic lethality of global knockout not pinpointed"]},{"year":2025,"claim":"Extended the muscle role to cardiac mitochondrial quality control, identifying Atg4 as a novel OBSL1 interactor and linking combined OBSL1/obscurin loss to defective mitophagy and diastolic dysfunction.","evidence":"Cardiac-specific double-knockout mice, fractionation, co-IP, EM, calcium imaging, metabolic assays, echocardiography","pmids":["40066567"],"confidence":"High","gaps":["Whether OBSL1–Atg4 binding is direct and functionally required for mitophagy not dissected","Relationship between cardiac mitophagy role and the CUL7 ubiquitin-ligase pathway unknown"]},{"year":null,"claim":"It remains unknown how OBSL1's distinct roles — CUL7-scaffolded ubiquitination, GH/IGF1 signaling, and obscurin-redundant muscle/mitophagy functions — are mechanistically unified or whether they share common substrates.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of OBSL1 in any complex","No identified ubiquitination substrate downstream of OBSL1–CUL7","Mechanism connecting growth signaling and cytoskeletal/organelle roles undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2,3]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[2,3]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[2]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2]}],"complexes":["CUL7(Fbxw8) E3 ubiquitin ligase complex"],"partners":["CUL7","CCDC8","OBSCN","ATG4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O75147","full_name":"Obscurin-like protein 1","aliases":[],"length_aa":1896,"mass_kda":206.9,"function":"Core component of the 3M complex, a complex required to regulate microtubule dynamics and genome integrity. It is unclear how the 3M complex regulates microtubules, it could act by controlling the level of a microtubule stabilizer (PubMed:24793695, PubMed:24793696). Acts as a regulator of the Cul7-RING(FBXW8) ubiquitin-protein ligase, playing a critical role in the ubiquitin ligase pathway that regulates Golgi morphogenesis and dendrite patterning in brain. Required to localize CUL7 to the Golgi apparatus in neurons","subcellular_location":"Cytoplasm; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Cytoplasm, perinuclear region; Golgi apparatus","url":"https://www.uniprot.org/uniprotkb/O75147/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/OBSL1","classification":"Not Classified","n_dependent_lines":35,"n_total_lines":1208,"dependency_fraction":0.028973509933774833},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CALM1","stoichiometry":0.2},{"gene":"CALM3","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CSNK2B","stoichiometry":0.2},{"gene":"VPS35","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/OBSL1","total_profiled":1310},"omim":[{"mim_id":"614205","title":"THREE M SYNDROME 3; 3M3","url":"https://www.omim.org/entry/614205"},{"mim_id":"614145","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 8; CCDC8","url":"https://www.omim.org/entry/614145"},{"mim_id":"612921","title":"THREE M SYNDROME 2; 3M2","url":"https://www.omim.org/entry/612921"},{"mim_id":"610991","title":"OBSCURIN-LIKE 1; OBSL1","url":"https://www.omim.org/entry/610991"},{"mim_id":"273750","title":"THREE M SYNDROME 1; 3M1","url":"https://www.omim.org/entry/273750"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Centrosome","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"ovary","ntpm":329.2}],"url":"https://www.proteinatlas.org/search/OBSL1"},"hgnc":{"alias_symbol":["KIAA0657"],"prev_symbol":[]},"alphafold":{"accession":"O75147","domains":[{"cath_id":"2.60.40.10","chopping":"11-103","consensus_level":"high","plddt":83.1056,"start":11,"end":103},{"cath_id":"2.60.40.10","chopping":"131-228","consensus_level":"medium","plddt":79.8722,"start":131,"end":228},{"cath_id":"2.60.40.10","chopping":"251-339","consensus_level":"medium","plddt":79.4907,"start":251,"end":339},{"cath_id":"2.60.40.10","chopping":"342-429","consensus_level":"medium","plddt":84.5165,"start":342,"end":429},{"cath_id":"2.60.40.10","chopping":"437-515","consensus_level":"medium","plddt":81.0553,"start":437,"end":515},{"cath_id":"-","chopping":"534-584_595-601","consensus_level":"medium","plddt":81.2648,"start":534,"end":601},{"cath_id":"2.60.40.10","chopping":"619-659_697-710","consensus_level":"high","plddt":82.6107,"start":619,"end":710},{"cath_id":"2.60.40.10","chopping":"718-803","consensus_level":"high","plddt":84.7401,"start":718,"end":803},{"cath_id":"2.60.40.10","chopping":"809-894","consensus_level":"high","plddt":82.3084,"start":809,"end":894},{"cath_id":"2.60.40.10","chopping":"991-1009_1022-1076","consensus_level":"high","plddt":82.7692,"start":991,"end":1076},{"cath_id":"2.60.40.10","chopping":"1080-1170","consensus_level":"medium","plddt":81.4916,"start":1080,"end":1170},{"cath_id":"2.60.40.10","chopping":"1192-1259","consensus_level":"high","plddt":76.1794,"start":1192,"end":1259},{"cath_id":"2.60.40.10","chopping":"1370-1445","consensus_level":"high","plddt":79.7833,"start":1370,"end":1445},{"cath_id":"2.60.40.10","chopping":"1452-1537","consensus_level":"high","plddt":83.1774,"start":1452,"end":1537},{"cath_id":"2.60.40.10","chopping":"1543-1626","consensus_level":"high","plddt":83.213,"start":1543,"end":1626},{"cath_id":"2.60.40.10","chopping":"1630-1718","consensus_level":"medium","plddt":83.1166,"start":1630,"end":1718},{"cath_id":"2.60.40.10","chopping":"1722-1805","consensus_level":"high","plddt":84.5581,"start":1722,"end":1805},{"cath_id":"2.60.40.10","chopping":"1811-1895","consensus_level":"high","plddt":85.8688,"start":1811,"end":1895}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75147","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75147-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75147-F1-predicted_aligned_error_v6.png","plddt_mean":79.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=OBSL1","jax_strain_url":"https://www.jax.org/strain/search?query=OBSL1"},"sequence":{"accession":"O75147","fasta_url":"https://rest.uniprot.org/uniprotkb/O75147.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75147/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75147"}},"corpus_meta":[{"pmid":"21737058","id":"PMC_21737058","title":"Exome sequencing identifies CCDC8 mutations in 3-M syndrome, suggesting that CCDC8 contributes in a pathway with CUL7 and OBSL1 to control human growth.","date":"2011","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21737058","citation_count":95,"is_preprint":false},{"pmid":"21572988","id":"PMC_21572988","title":"An OBSL1-Cul7Fbxw8 ubiquitin ligase signaling mechanism regulates Golgi morphology and dendrite patterning.","date":"2011","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/21572988","citation_count":86,"is_preprint":false},{"pmid":"19481195","id":"PMC_19481195","title":"The primordial growth disorder 3-M syndrome connects ubiquitination to the cytoskeletal adaptor OBSL1.","date":"2009","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19481195","citation_count":84,"is_preprint":false},{"pmid":"17289344","id":"PMC_17289344","title":"Obscurin-like 1, OBSL1, is a novel cytoskeletal protein related to obscurin.","date":"2007","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/17289344","citation_count":73,"is_preprint":false},{"pmid":"23018678","id":"PMC_23018678","title":"Mutations in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling.","date":"2012","source":"Journal of molecular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/23018678","citation_count":50,"is_preprint":false},{"pmid":"31098411","id":"PMC_31098411","title":"Murine obscurin and Obsl1 have functionally redundant roles in sarcolemmal integrity, sarcoplasmic reticulum organization, and muscle metabolism.","date":"2019","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/31098411","citation_count":27,"is_preprint":false},{"pmid":"27796265","id":"PMC_27796265","title":"A Rare Cause of Short Stature: 3M Syndrome in a Patient with Novel Mutation in OBSL1 Gene.","date":"2016","source":"Journal of clinical research in pediatric endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/27796265","citation_count":17,"is_preprint":false},{"pmid":"23457316","id":"PMC_23457316","title":"Severe short stature due to 3-M syndrome with a novel OBSL1 gene mutation.","date":"2013","source":"Journal of pediatric endocrinology & metabolism : JPEM","url":"https://pubmed.ncbi.nlm.nih.gov/23457316","citation_count":14,"is_preprint":false},{"pmid":"25923536","id":"PMC_25923536","title":"Whole-exome analysis of foetal autopsy tissue reveals a frameshift mutation in OBSL1, consistent with a diagnosis of 3-M Syndrome.","date":"2015","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/25923536","citation_count":8,"is_preprint":false},{"pmid":"40066567","id":"PMC_40066567","title":"Combined Loss of Obsc and Obsl1 in Murine Hearts Results in Diastolic Dysfunction, Altered Metabolism, and Deregulated Mitophagy.","date":"2025","source":"Circulation. Heart failure","url":"https://pubmed.ncbi.nlm.nih.gov/40066567","citation_count":5,"is_preprint":false},{"pmid":"37780995","id":"PMC_37780995","title":"Expanding OBSL1 Mutation Phenotype: Disproportionate Short Stature, Barrel Chest, Thoracic Kyphoscoliosis, Hypogonadism, and Hypospadias.","date":"2023","source":"The Yale journal of biology and medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37780995","citation_count":3,"is_preprint":false},{"pmid":"38407006","id":"PMC_38407006","title":"Novel OBSL1 Variant in a Chinese Patient with 3M Syndrome: The c.458dupG Mutation May Be a Potential Hotspot Mutation in the Chinese Population.","date":"2024","source":"Journal of clinical research in pediatric endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/38407006","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7506,"output_tokens":1901,"usd":0.025517,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8843,"output_tokens":2773,"usd":0.05677,"stage2_stop_reason":"end_turn"},"total_usd":0.082287,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"CCDC8 physically interacts with OBSL1 (but not CUL7) as shown by coimmunoprecipitation, placing CCDC8 in the same pathway as CUL7 and OBSL1 in the control of mammalian growth.\",\n      \"method\": \"Coimmunoprecipitation\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP experiment demonstrating physical interaction; supported by transcriptional co-association data but no reciprocal IP or in vitro reconstitution reported in abstract\",\n      \"pmids\": [\"21737058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"OBSL1 forms a physical complex with the scaffold protein CUL7, and this interaction localizes CUL7 to the Golgi apparatus. OBSL1 is required for Golgi morphogenesis and dendrite elaboration in neurons, acting upstream of the CUL7(Fbxw8) ubiquitin ligase. Loss of OBSL1 impairs Golgi complex morphology and secretory trafficking, and reduces dendrite growth without affecting axons.\",\n      \"method\": \"Immunoprecipitation/mass spectrometry, co-immunoprecipitation, RNAi knockdown with morphological and functional readouts in primary neurons and in vivo rat cerebellum\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal IP/MS to identify complex, functional KD with specific morphological phenotypes in vitro and in vivo, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"21572988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"OBSL1 is a cytoskeletal adaptor protein that localizes to the nuclear envelope, and loss of OBSL1 leads to downregulation of CUL7 protein levels, implying a role for OBSL1 in the maintenance of CUL7 and that both proteins act in the same molecular pathway.\",\n      \"method\": \"High-density genome-wide SNP mapping, mutation identification, subcellular localization (nuclear envelope), and protein level analysis in patient-derived cells\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment and functional consequence (CUL7 downregulation upon OBSL1 loss) in patient-derived cells; single lab, limited mechanistic detail in abstract\",\n      \"pmids\": [\"19481195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"OBSL1 is a cytoskeletal adaptor protein closely related to obscurin, expressed in multiple tissues, and localizes to intercalated discs, the perinuclear region, and overlying the Z lines and M bands of adult rat cardiac myocytes.\",\n      \"method\": \"Cloning, alternative splicing characterization, immunofluorescence localization in adult rat cardiac myocytes\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct subcellular localization by imaging in cardiac myocytes; characterization of isoforms by molecular cloning; single lab without functional consequence formally demonstrated\",\n      \"pmids\": [\"17289344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In OBSL1-null fibroblasts, activation of STAT5b and MAPK in response to GH is reduced compared to controls, and activation of AKT in response to IGF1 is reduced at 5 min post-stimulation, indicating that OBSL1 is required for normal GH and IGF1 signaling.\",\n      \"method\": \"Signaling assays (phosphorylation of STAT5b, MAPK, AKT) in patient-derived OBSL1-null fibroblast cell lines following GH or IGF1 stimulation\",\n      \"journal\": \"Journal of molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional assay in patient-derived null cells with two signaling pathways tested; single lab, limited mechanistic depth on how OBSL1 engages these pathways\",\n      \"pmids\": [\"23018678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Skeletal muscle-specific Obsl1 knockout mice have a benign phenotype similar to obscurin knockouts, but combined deletion of both Obsl1 and obscurin reveals functionally redundant roles for sarcolemmal stability and sarcoplasmic reticulum organization in skeletal muscle. Global Obsl1 knockout is embryonically lethal.\",\n      \"method\": \"Conditional and global knockout mouse models, mass spectrometry-based proteomics of muscle tissue, histological and ultrastructural analysis\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — rigorous double-knockout genetic epistasis in vivo with multiple orthogonal readouts (proteomics, histology, ultrastructure); embryonic lethality of global KO directly established\",\n      \"pmids\": [\"31098411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In cardiac muscle, Obsl1 (together with obscurin) plays roles in sarcoplasmic reticulum structure, calcium cycling, mitochondrial architecture and function. Obsl1 interacts with Atg4 proteins (novel interactors identified), and combined loss of obscurin and Obsl1 results in abnormal mitophagy, increased unfolded protein response, decreased Chchd3 (a MICOS complex protein) levels, and diastolic dysfunction.\",\n      \"method\": \"Cardiac-specific double-knockout mouse models, biochemical fractionation, co-immunoprecipitation (Atg4 as novel OBSL1 interactors), electron microscopy, calcium imaging, metabolic assays, echocardiography\",\n      \"journal\": \"Circulation. Heart failure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — rigorous double-KO genetic model with multiple orthogonal methods (imaging, biochemistry, physiology, interactor identification); novel Atg4 interaction identified by co-IP\",\n      \"pmids\": [\"40066567\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"OBSL1 is a cytoskeletal adaptor protein that localizes to the Golgi apparatus and nuclear envelope, where it scaffolds the CUL7(Fbxw8) E3 ubiquitin ligase complex by physically binding CUL7, thereby maintaining CUL7 protein levels and enabling ubiquitin-dependent regulation of Golgi morphogenesis, dendrite patterning, and GH/IGF1 signaling; OBSL1 also physically associates with CCDC8 (but not CUL7 directly) to form a growth-regulatory pathway, interacts with Atg4 proteins to regulate mitophagy in the heart, and acts redundantly with obscurin to maintain sarcolemmal integrity, sarcoplasmic reticulum organization, and calcium cycling in striated muscle.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"OBSL1 is a cytoskeletal adaptor protein, closely related to obscurin, that functions as a scaffold linking growth-regulatory ubiquitin ligase activity to organelle and cytoskeletal organization [#3, #1]. It localizes to the nuclear envelope and is required to maintain CUL7 protein levels, placing OBSL1 in a shared molecular pathway with CUL7 [#2]. OBSL1 physically binds CUL7 and recruits it to the Golgi apparatus, acting upstream of the CUL7(Fbxw8) ubiquitin ligase to drive Golgi morphogenesis, secretory trafficking, and dendrite elaboration in neurons [#1]; it additionally associates with CCDC8 in this growth-control pathway, though CCDC8 binds OBSL1 rather than CUL7 directly [#0]. Consistent with a growth-regulatory role, OBSL1-null fibroblasts show reduced GH-induced STAT5b/MAPK activation and blunted IGF1-induced AKT signaling [#4]. In striated muscle, OBSL1 acts redundantly with obscurin: single-gene loss is benign, but combined deletion impairs sarcolemmal stability and sarcoplasmic reticulum organization, while global OBSL1 knockout is embryonically lethal [#5]. In the heart, OBSL1 and obscurin together govern sarcoplasmic reticulum structure, calcium cycling, and mitochondrial architecture, with OBSL1 binding Atg4 proteins and dual loss producing abnormal mitophagy, elevated unfolded protein response, and diastolic dysfunction [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established the existence and tissue distribution of OBSL1 as an obscurin-related adaptor, defining its candidate subcellular niches before any function was known.\",\n      \"evidence\": \"Molecular cloning, splice-isoform characterization, and immunofluorescence in adult rat cardiac myocytes\",\n      \"pmids\": [\"17289344\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional consequence demonstrated\", \"Binding partners and pathway not yet defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Linked OBSL1 to CUL7 by showing OBSL1 loss reduces CUL7 protein levels, establishing the two proteins act in a common pathway and OBSL1 stabilizes CUL7.\",\n      \"evidence\": \"SNP mapping, mutation identification, and localization/protein-level analysis in patient-derived cells\",\n      \"pmids\": [\"19481195\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of CUL7 stabilization not resolved\", \"Direct OBSL1\\u2013CUL7 binding not yet shown in this study\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolved how OBSL1 acts on CUL7 — direct complex formation that recruits CUL7 to the Golgi and drives Golgi morphogenesis and dendrite growth — defining OBSL1 as an upstream scaffold for the CUL7(Fbxw8) ligase.\",\n      \"evidence\": \"Reciprocal IP/MS, co-IP, and RNAi knockdown with morphological/functional readouts in primary neurons and rat cerebellum\",\n      \"pmids\": [\"21572988\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitination substrates downstream of the Golgi-localized complex not identified\", \"How OBSL1 itself is targeted to the Golgi unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended the growth-control module by showing CCDC8 binds OBSL1 (but not CUL7), defining the topology of the OBSL1\\u2013CUL7\\u2013CCDC8 pathway.\",\n      \"evidence\": \"Coimmunoprecipitation plus transcriptional co-association data\",\n      \"pmids\": [\"21737058\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation or in vitro reconstitution\", \"Functional output of the OBSL1\\u2013CCDC8 interaction not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected OBSL1 to growth-factor signaling by showing OBSL1-null cells have blunted GH and IGF1 responses, providing a cellular signaling basis for the growth phenotype.\",\n      \"evidence\": \"Phosphorylation assays for STAT5b/MAPK/AKT in patient-derived OBSL1-null fibroblasts after GH or IGF1 stimulation\",\n      \"pmids\": [\"23018678\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which OBSL1 engages GH/IGF1 receptor signaling unknown\", \"Link to CUL7 ligase activity in this context not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined OBSL1's role in striated muscle through genetic epistasis with obscurin, revealing functional redundancy for sarcolemmal and SR integrity and establishing the gene as essential for development.\",\n      \"evidence\": \"Conditional and global knockout mice, muscle proteomics, histology, and ultrastructure\",\n      \"pmids\": [\"31098411\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of redundancy with obscurin unresolved\", \"Cause of embryonic lethality of global knockout not pinpointed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended the muscle role to cardiac mitochondrial quality control, identifying Atg4 as a novel OBSL1 interactor and linking combined OBSL1/obscurin loss to defective mitophagy and diastolic dysfunction.\",\n      \"evidence\": \"Cardiac-specific double-knockout mice, fractionation, co-IP, EM, calcium imaging, metabolic assays, echocardiography\",\n      \"pmids\": [\"40066567\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether OBSL1\\u2013Atg4 binding is direct and functionally required for mitophagy not dissected\", \"Relationship between cardiac mitophagy role and the CUL7 ubiquitin-ligase pathway unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how OBSL1's distinct roles — CUL7-scaffolded ubiquitination, GH/IGF1 signaling, and obscurin-redundant muscle/mitophagy functions — are mechanistically unified or whether they share common substrates.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of OBSL1 in any complex\", \"No identified ubiquitination substrate downstream of OBSL1\\u2013CUL7\", \"Mechanism connecting growth signaling and cytoskeletal/organelle roles undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2, 3]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [\"CUL7(Fbxw8) E3 ubiquitin ligase complex\"],\n    \"partners\": [\"CUL7\", \"CCDC8\", \"OBSCN\", \"ATG4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}