{"gene":"SCOC","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":2012,"finding":"SCOC (short coiled-coil protein), a Golgi-localized protein, is required for amino acid starvation-induced autophagosome formation. It interacts with FEZ1 (an ULK1-binding protein) and forms a starvation-sensitive trimeric complex with UVRAG and FEZ1, potentially regulating ULK1 and Beclin 1 complex activities.","method":"Genome-wide siRNA screen in GFP-LC3 stable human cell line; siRNA knockdown validation; co-immunoprecipitation of SCOC-FEZ1-UVRAG complex","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — genome-wide screen with stringent validation, co-IP of trimeric complex, subcellular localization, replicated by multiple orthogonal methods in a highly-cited study","pmids":["22354037"],"is_preprint":false},{"year":2013,"finding":"The coiled-coil domain of human SCOC forms a parallel left-handed coiled-coil dimer, and SCOC dimerization plus surface residue R117 are required for stable complex formation with the coiled-coil domain of FEZ1. Core residue mutations (E93V/K97L and N125L/N132V) alter oligomerization state from dimer to trimer or tetramer respectively.","method":"X-ray crystallography (2.7 Å resolution crystal structure); multi-angle laser light scattering; native mass spectrometry; site-directed mutagenesis","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with mutagenesis and biophysical validation in a single study","pmids":["24098481"],"is_preprint":false},{"year":2013,"finding":"FEZ1 and SCOC (orthologs of C. elegans UNC-76 and UNC-69) form a heterotetrameric complex; FEZ1 homodimerizes in an antiparallel topology, and the FEZ1-SCOC interaction interface defined by cross-linking mass spectrometry is consistent with the UNC-76/UNC-69 interaction interface.","method":"NMR spectroscopy; cross-linking coupled with mass spectrometry; SAXS; molecular modelling","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal structural/biophysical methods (NMR, SAXS, MS) characterizing complex topology","pmids":["24116125"],"is_preprint":false},{"year":2021,"finding":"SCOC contains a LIR motif that binds ATG8 family proteins, with strong preference for GABARAP, GABARAPL1, LC3A and LC3C. Phosphorylation of residues within and surrounding the core LIR motif by autophagy-related kinases (ULK1-3, TBK1) selectively increases binding to LC3 family members. Flanking LIR residues contribute to ATG8 binding affinity and specificity, and phosphorylation of adjacent serine residues can compensate for loss of distal flanking residues.","method":"In vitro kinase assays (ULK1-3, TBK1); structural analysis; biophysical binding assays; mutagenesis of LIR motif residues","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — structural, biophysical, and biochemical analyses with mutagenesis and in vitro kinase assays in a single comprehensive study","pmids":["33845085"],"is_preprint":false},{"year":2006,"finding":"C. elegans UNC-69 (ortholog of human SCOC/SCOCO) physically interacts with UNC-76 (ortholog of human FEZ1), and together they co-localize as puncta in neuronal processes. Loss of unc-69 causes defects in axon outgrowth, guidance, fasciculation, and presynaptic organization, including mislocalization of synaptobrevin.","method":"Genetic epistasis; co-immunoprecipitation; fluorescence microscopy of synaptic vesicle markers; RNAi in chicken CNS","journal":"Journal of biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal interaction confirmed, defined cellular phenotypes with specific markers, ortholog function conserved across species","pmids":["16725058"],"is_preprint":false},{"year":2022,"finding":"SCOC, ULK1, and NBR1 directly bind to FEZ1 protein to form a protein complex, as demonstrated by immunoprecipitation assay. All four proteins (FEZ1, SCOC, ULK1, NBR1) are direct targets of miR-129-5p, linking the complex to autophagy regulation in neuronal cells.","method":"Co-immunoprecipitation; dual-luciferase reporter assay; miRNA overexpression/knockdown","journal":"Bioengineered","confidence":"Medium","confidence_rationale":"Tier 3 — single Co-IP confirming complex membership, supported by reporter assays, single lab study","pmids":["35435132"],"is_preprint":false}],"current_model":"SCOC is a Golgi-localized short coiled-coil protein that forms a parallel homodimer and assembles into a heterotetrameric complex with FEZ1 (via its coiled-coil domain, requiring SCOC dimerization and residue R117), and a starvation-sensitive trimeric complex with FEZ1 and UVRAG to regulate ULK1 and Beclin 1 complex activities during amino acid starvation-induced autophagy; additionally, SCOC contains a LIR motif whose phosphorylation by ULK1-3 and TBK1 dynamically modulates its binding affinity and specificity for ATG8 family proteins."},"narrative":{"teleology":[{"year":2006,"claim":"Identification of SCOC's ortholog UNC-69 as a neuronal trafficking factor established that the SCOC–FEZ1 interaction is ancient and required for axonal development and synaptic vesicle localization.","evidence":"C. elegans genetics, co-IP, and fluorescence imaging of synaptic markers in unc-69 mutants, with cross-species validation in chicken CNS","pmids":["16725058"],"confidence":"High","gaps":["Mammalian neuronal phenotypes of SCOC loss were not characterized","Mechanism by which UNC-69/SCOC supports vesicle transport not resolved","Whether the neuronal and autophagy functions are linked or independent was unknown"]},{"year":2012,"claim":"A genome-wide screen revealed that SCOC is required for starvation-induced autophagosome formation and identified the starvation-sensitive SCOC–FEZ1–UVRAG trimeric complex as a regulatory node linking ULK1 and Beclin 1 signaling.","evidence":"Genome-wide siRNA screen in GFP-LC3 human cells with co-IP validation of trimeric complex","pmids":["22354037"],"confidence":"High","gaps":["How starvation remodels the SCOC–FEZ1–UVRAG complex was not defined","Direct enzymatic or activating role of SCOC on ULK1 or Beclin 1 complexes not established","Whether SCOC acts as a scaffold versus an allosteric regulator was unclear"]},{"year":2013,"claim":"Structural determination of the SCOC coiled-coil domain and the SCOC–FEZ1 heterotetramer defined the biophysical basis of complex assembly, showing SCOC forms a parallel dimer whose dimerization and residue R117 are prerequisites for FEZ1 binding.","evidence":"X-ray crystallography at 2.7 Å, NMR, SAXS, cross-linking mass spectrometry, native mass spectrometry, and mutagenesis","pmids":["24098481","24116125"],"confidence":"High","gaps":["No structure of a full SCOC–FEZ1–UVRAG ternary complex","How UVRAG is incorporated into the complex at a structural level is unknown","Whether oligomeric state changes serve as a regulatory switch in vivo was not tested"]},{"year":2021,"claim":"Discovery of a functional LIR motif in SCOC and its phosphoregulation by ULK1-3 and TBK1 revealed a mechanism by which autophagy kinases tune SCOC's interaction specificity across ATG8 family members.","evidence":"In vitro kinase assays, biophysical binding measurements, structural analysis, and LIR mutagenesis","pmids":["33845085"],"confidence":"High","gaps":["Physiological relevance of LIR phosphorylation in cells during starvation not demonstrated","Whether LIR-dependent ATG8 binding is required for SCOC's autophagy function in vivo is untested","Interplay between LIR engagement and FEZ1/UVRAG complex formation is unknown"]},{"year":2022,"claim":"Confirmation that SCOC, ULK1, and NBR1 co-associate with FEZ1 expanded the autophagy-related protein complex and linked its regulation to miR-129-5p in neuronal cells.","evidence":"Co-immunoprecipitation and dual-luciferase reporter assays with miRNA modulation","pmids":["35435132"],"confidence":"Medium","gaps":["NBR1 incorporation into the complex lacks reciprocal and endogenous validation","Functional consequence of miR-129-5p-mediated co-regulation of all four targets not mechanistically resolved","Whether this complex functions in selective autophagy cargo recognition is untested"]},{"year":null,"claim":"Key unresolved questions include how the SCOC–FEZ1–UVRAG complex is remodeled by starvation signals, whether SCOC's LIR-dependent ATG8 binding is functionally required in vivo, and whether SCOC's roles in autophagy and axonal vesicle transport represent a unified or bifurcated mechanism.","evidence":"","pmids":[],"confidence":"High","gaps":["No in vivo structure of a complete SCOC-containing signaling complex","No mammalian loss-of-function model linking SCOC to neurological or autophagy-deficient phenotypes","Mechanism of starvation-dependent UVRAG dissociation is undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,2]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,3]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[4]}],"complexes":["SCOC-FEZ1 heterotetramer","SCOC-FEZ1-UVRAG trimeric complex"],"partners":["FEZ1","UVRAG","ULK1","GABARAP","GABARAPL1","TBK1","NBR1"],"other_free_text":[]},"mechanistic_narrative":"SCOC is a short coiled-coil protein that functions as a key scaffolding component in autophagy initiation and vesicle trafficking. SCOC forms a parallel homodimeric coiled-coil that assembles into a heterotetrameric complex with FEZ1, requiring SCOC dimerization and surface residue R117; this complex further recruits UVRAG to form a starvation-sensitive trimeric SCOC–FEZ1–UVRAG assembly that regulates ULK1 and Beclin 1 complex activities during amino acid starvation-induced autophagosome formation [PMID:22354037, PMID:24098481, PMID:24116125]. SCOC contains a LIR motif that binds ATG8 family proteins with preference for GABARAP and select LC3 members, and phosphorylation of this motif by ULK1-3 and TBK1 dynamically shifts binding specificity toward LC3 family members [PMID:33845085]. The SCOC–FEZ1 interaction is evolutionarily conserved from C. elegans (UNC-69/UNC-76), where it is essential for axon outgrowth, fasciculation, and presynaptic vesicle organization [PMID:16725058]."},"prefetch_data":{"uniprot":{"accession":"Q9UIL1","full_name":"Short coiled-coil protein","aliases":[],"length_aa":159,"mass_kda":18.0,"function":"Positive regulator of amino acid starvation-induced autophagy","subcellular_location":"Golgi apparatus membrane; Golgi apparatus, trans-Golgi network; Cytoplasm, cytosol","url":"https://www.uniprot.org/uniprotkb/Q9UIL1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SCOC","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":[{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"HMGA1","stoichiometry":0.2},{"gene":"NUMA1","stoichiometry":0.2},{"gene":"RPS6KA4","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SCOC","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Golgi apparatus","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SCOC"},"hgnc":{"alias_symbol":["HRIHFB2072","SCOCO","UNC-69"],"prev_symbol":[]},"alphafold":{"accession":"Q9UIL1","domains":[{"cath_id":"1.20.5","chopping":"86-148","consensus_level":"medium","plddt":87.1821,"start":86,"end":148}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UIL1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UIL1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UIL1-F1-predicted_aligned_error_v6.png","plddt_mean":66.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SCOC","jax_strain_url":"https://www.jax.org/strain/search?query=SCOC"},"sequence":{"accession":"Q9UIL1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UIL1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UIL1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UIL1"}},"corpus_meta":[{"pmid":"22354037","id":"PMC_22354037","title":"Genome-wide siRNA screen reveals amino acid starvation-induced autophagy requires SCOC and WAC.","date":"2012","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/22354037","citation_count":101,"is_preprint":false},{"pmid":"26728191","id":"PMC_26728191","title":"Interplay of CodY and ScoC in the Regulation of Major Extracellular Protease Genes of Bacillus subtilis.","date":"2016","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/26728191","citation_count":50,"is_preprint":false},{"pmid":"15126467","id":"PMC_15126467","title":"Bacillus subtilis SalA (YbaL) negatively regulates expression of scoC, which encodes the repressor for the alkaline exoprotease gene, aprE.","date":"2004","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/15126467","citation_count":36,"is_preprint":false},{"pmid":"16725058","id":"PMC_16725058","title":"The short coiled-coil domain-containing protein UNC-69 cooperates with UNC-76 to regulate axonal outgrowth and normal presynaptic organization in Caenorhabditis elegans.","date":"2006","source":"Journal of biology","url":"https://pubmed.ncbi.nlm.nih.gov/16725058","citation_count":31,"is_preprint":false},{"pmid":"26094643","id":"PMC_26094643","title":"Bacillus subtilis SalA is a phosphorylation-dependent transcription regulator that represses scoC and activates the production of the exoprotease AprE.","date":"2015","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/26094643","citation_count":25,"is_preprint":false},{"pmid":"33845085","id":"PMC_33845085","title":"Phosphorylation of the LIR Domain of SCOC Modulates ATG8 Binding Affinity and Specificity.","date":"2021","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/33845085","citation_count":24,"is_preprint":false},{"pmid":"25966844","id":"PMC_25966844","title":"Interactive regulation by the Bacillus subtilis global regulators CodY and ScoC.","date":"2015","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/25966844","citation_count":18,"is_preprint":false},{"pmid":"19251843","id":"PMC_19251843","title":"Regulation of Bacillus subtilis aprE expression by glnA through inhibition of scoC and sigma(D)-dependent degR expression.","date":"2009","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/19251843","citation_count":15,"is_preprint":false},{"pmid":"22717455","id":"PMC_22717455","title":"Coiling up with SCOC and WAC: two new regulators of starvation-induced autophagy.","date":"2012","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/22717455","citation_count":13,"is_preprint":false},{"pmid":"35435132","id":"PMC_35435132","title":"miR-129-5p targets FEZ1/SCOC/ULK1/NBR1 complex to restore neuronal function in mice with post-stroke depression.","date":"2022","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/35435132","citation_count":10,"is_preprint":false},{"pmid":"24098481","id":"PMC_24098481","title":"Crystal structure of the human short coiled coil protein and insights into SCOC-FEZ1 complex formation.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24098481","citation_count":10,"is_preprint":false},{"pmid":"14629015","id":"PMC_14629015","title":"ScoC mediates catabolite repression of sporulation in Bacillus subtilis.","date":"2003","source":"Current microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/14629015","citation_count":10,"is_preprint":false},{"pmid":"34855149","id":"PMC_34855149","title":"Association of Circulating Biomarkers of lnc-IGSF3-1:1, SCOC-AS1, and SLC8A1-AS1 with Salt Sensitivity of Blood Pressure in Chinese Population.","date":"2021","source":"Journal of cardiovascular translational research","url":"https://pubmed.ncbi.nlm.nih.gov/34855149","citation_count":8,"is_preprint":false},{"pmid":"19118355","id":"PMC_19118355","title":"hag expression in Bacillus subtilis is both negatively and positively regulated by ScoC.","date":"2009","source":"Microbiology (Reading, England)","url":"https://pubmed.ncbi.nlm.nih.gov/19118355","citation_count":8,"is_preprint":false},{"pmid":"20382764","id":"PMC_20382764","title":"Direct regulation of Bacillus subtilis phoPR transcription by transition state regulator ScoC.","date":"2010","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/20382764","citation_count":7,"is_preprint":false},{"pmid":"14769473","id":"PMC_14769473","title":"Hpr (ScoC) and the phosphorelay couple cell cycle and sporulation in Bacillus subtilis.","date":"2004","source":"FEMS microbiology letters","url":"https://pubmed.ncbi.nlm.nih.gov/14769473","citation_count":7,"is_preprint":false},{"pmid":"31039790","id":"PMC_31039790","title":"Disruption of the pleiotropic gene scoC causes transcriptomic and phenotypical changes in Bacillus pumilus BA06.","date":"2019","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/31039790","citation_count":6,"is_preprint":false},{"pmid":"24116125","id":"PMC_24116125","title":"Structural analysis of intermolecular interactions in the kinesin adaptor complex fasciculation and elongation protein zeta 1/ short coiled-coil protein (FEZ1/SCOCO).","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24116125","citation_count":6,"is_preprint":false},{"pmid":"23660663","id":"PMC_23660663","title":"Spo0A positively regulates epr expression by negating the repressive effect of co-repressors, SinR and ScoC, in Bacillus subtilis.","date":"2013","source":"Journal of biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/23660663","citation_count":4,"is_preprint":false},{"pmid":"16321961","id":"PMC_16321961","title":"Inhibition of Bacillus subtilis scoC expression by multicopy senS.","date":"2005","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/16321961","citation_count":3,"is_preprint":false},{"pmid":"19898538","id":"PMC_19898538","title":"A dual mode of regulation of flgM by ScoC in Bacillus subtilis.","date":"2009","source":"Canadian journal of microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/19898538","citation_count":2,"is_preprint":false},{"pmid":"40715536","id":"PMC_40715536","title":"Repression via DNA looping by the Gram-positive global transcriptional regulator ScoC from Geobacillus.","date":"2025","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/40715536","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11465,"output_tokens":1657,"usd":0.029625},"stage2":{"model":"claude-opus-4-6","input_tokens":4895,"output_tokens":1904,"usd":0.108113},"total_usd":0.137738,"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\": 2012,\n      \"finding\": \"SCOC (short coiled-coil protein), a Golgi-localized protein, is required for amino acid starvation-induced autophagosome formation. It interacts with FEZ1 (an ULK1-binding protein) and forms a starvation-sensitive trimeric complex with UVRAG and FEZ1, potentially regulating ULK1 and Beclin 1 complex activities.\",\n      \"method\": \"Genome-wide siRNA screen in GFP-LC3 stable human cell line; siRNA knockdown validation; co-immunoprecipitation of SCOC-FEZ1-UVRAG complex\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide screen with stringent validation, co-IP of trimeric complex, subcellular localization, replicated by multiple orthogonal methods in a highly-cited study\",\n      \"pmids\": [\"22354037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The coiled-coil domain of human SCOC forms a parallel left-handed coiled-coil dimer, and SCOC dimerization plus surface residue R117 are required for stable complex formation with the coiled-coil domain of FEZ1. Core residue mutations (E93V/K97L and N125L/N132V) alter oligomerization state from dimer to trimer or tetramer respectively.\",\n      \"method\": \"X-ray crystallography (2.7 Å resolution crystal structure); multi-angle laser light scattering; native mass spectrometry; site-directed mutagenesis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with mutagenesis and biophysical validation in a single study\",\n      \"pmids\": [\"24098481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FEZ1 and SCOC (orthologs of C. elegans UNC-76 and UNC-69) form a heterotetrameric complex; FEZ1 homodimerizes in an antiparallel topology, and the FEZ1-SCOC interaction interface defined by cross-linking mass spectrometry is consistent with the UNC-76/UNC-69 interaction interface.\",\n      \"method\": \"NMR spectroscopy; cross-linking coupled with mass spectrometry; SAXS; molecular modelling\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal structural/biophysical methods (NMR, SAXS, MS) characterizing complex topology\",\n      \"pmids\": [\"24116125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SCOC contains a LIR motif that binds ATG8 family proteins, with strong preference for GABARAP, GABARAPL1, LC3A and LC3C. Phosphorylation of residues within and surrounding the core LIR motif by autophagy-related kinases (ULK1-3, TBK1) selectively increases binding to LC3 family members. Flanking LIR residues contribute to ATG8 binding affinity and specificity, and phosphorylation of adjacent serine residues can compensate for loss of distal flanking residues.\",\n      \"method\": \"In vitro kinase assays (ULK1-3, TBK1); structural analysis; biophysical binding assays; mutagenesis of LIR motif residues\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structural, biophysical, and biochemical analyses with mutagenesis and in vitro kinase assays in a single comprehensive study\",\n      \"pmids\": [\"33845085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"C. elegans UNC-69 (ortholog of human SCOC/SCOCO) physically interacts with UNC-76 (ortholog of human FEZ1), and together they co-localize as puncta in neuronal processes. Loss of unc-69 causes defects in axon outgrowth, guidance, fasciculation, and presynaptic organization, including mislocalization of synaptobrevin.\",\n      \"method\": \"Genetic epistasis; co-immunoprecipitation; fluorescence microscopy of synaptic vesicle markers; RNAi in chicken CNS\",\n      \"journal\": \"Journal of biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction confirmed, defined cellular phenotypes with specific markers, ortholog function conserved across species\",\n      \"pmids\": [\"16725058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SCOC, ULK1, and NBR1 directly bind to FEZ1 protein to form a protein complex, as demonstrated by immunoprecipitation assay. All four proteins (FEZ1, SCOC, ULK1, NBR1) are direct targets of miR-129-5p, linking the complex to autophagy regulation in neuronal cells.\",\n      \"method\": \"Co-immunoprecipitation; dual-luciferase reporter assay; miRNA overexpression/knockdown\",\n      \"journal\": \"Bioengineered\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP confirming complex membership, supported by reporter assays, single lab study\",\n      \"pmids\": [\"35435132\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SCOC is a Golgi-localized short coiled-coil protein that forms a parallel homodimer and assembles into a heterotetrameric complex with FEZ1 (via its coiled-coil domain, requiring SCOC dimerization and residue R117), and a starvation-sensitive trimeric complex with FEZ1 and UVRAG to regulate ULK1 and Beclin 1 complex activities during amino acid starvation-induced autophagy; additionally, SCOC contains a LIR motif whose phosphorylation by ULK1-3 and TBK1 dynamically modulates its binding affinity and specificity for ATG8 family proteins.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SCOC is a short coiled-coil protein that functions as a key scaffolding component in autophagy initiation and vesicle trafficking. SCOC forms a parallel homodimeric coiled-coil that assembles into a heterotetrameric complex with FEZ1, requiring SCOC dimerization and surface residue R117; this complex further recruits UVRAG to form a starvation-sensitive trimeric SCOC–FEZ1–UVRAG assembly that regulates ULK1 and Beclin 1 complex activities during amino acid starvation-induced autophagosome formation [PMID:22354037, PMID:24098481, PMID:24116125]. SCOC contains a LIR motif that binds ATG8 family proteins with preference for GABARAP and select LC3 members, and phosphorylation of this motif by ULK1-3 and TBK1 dynamically shifts binding specificity toward LC3 family members [PMID:33845085]. The SCOC–FEZ1 interaction is evolutionarily conserved from C. elegans (UNC-69/UNC-76), where it is essential for axon outgrowth, fasciculation, and presynaptic vesicle organization [PMID:16725058].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Identification of SCOC's ortholog UNC-69 as a neuronal trafficking factor established that the SCOC–FEZ1 interaction is ancient and required for axonal development and synaptic vesicle localization.\",\n      \"evidence\": \"C. elegans genetics, co-IP, and fluorescence imaging of synaptic markers in unc-69 mutants, with cross-species validation in chicken CNS\",\n      \"pmids\": [\"16725058\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mammalian neuronal phenotypes of SCOC loss were not characterized\",\n        \"Mechanism by which UNC-69/SCOC supports vesicle transport not resolved\",\n        \"Whether the neuronal and autophagy functions are linked or independent was unknown\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"A genome-wide screen revealed that SCOC is required for starvation-induced autophagosome formation and identified the starvation-sensitive SCOC–FEZ1–UVRAG trimeric complex as a regulatory node linking ULK1 and Beclin 1 signaling.\",\n      \"evidence\": \"Genome-wide siRNA screen in GFP-LC3 human cells with co-IP validation of trimeric complex\",\n      \"pmids\": [\"22354037\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How starvation remodels the SCOC–FEZ1–UVRAG complex was not defined\",\n        \"Direct enzymatic or activating role of SCOC on ULK1 or Beclin 1 complexes not established\",\n        \"Whether SCOC acts as a scaffold versus an allosteric regulator was unclear\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Structural determination of the SCOC coiled-coil domain and the SCOC–FEZ1 heterotetramer defined the biophysical basis of complex assembly, showing SCOC forms a parallel dimer whose dimerization and residue R117 are prerequisites for FEZ1 binding.\",\n      \"evidence\": \"X-ray crystallography at 2.7 Å, NMR, SAXS, cross-linking mass spectrometry, native mass spectrometry, and mutagenesis\",\n      \"pmids\": [\"24098481\", \"24116125\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structure of a full SCOC–FEZ1–UVRAG ternary complex\",\n        \"How UVRAG is incorporated into the complex at a structural level is unknown\",\n        \"Whether oligomeric state changes serve as a regulatory switch in vivo was not tested\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Discovery of a functional LIR motif in SCOC and its phosphoregulation by ULK1-3 and TBK1 revealed a mechanism by which autophagy kinases tune SCOC's interaction specificity across ATG8 family members.\",\n      \"evidence\": \"In vitro kinase assays, biophysical binding measurements, structural analysis, and LIR mutagenesis\",\n      \"pmids\": [\"33845085\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Physiological relevance of LIR phosphorylation in cells during starvation not demonstrated\",\n        \"Whether LIR-dependent ATG8 binding is required for SCOC's autophagy function in vivo is untested\",\n        \"Interplay between LIR engagement and FEZ1/UVRAG complex formation is unknown\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Confirmation that SCOC, ULK1, and NBR1 co-associate with FEZ1 expanded the autophagy-related protein complex and linked its regulation to miR-129-5p in neuronal cells.\",\n      \"evidence\": \"Co-immunoprecipitation and dual-luciferase reporter assays with miRNA modulation\",\n      \"pmids\": [\"35435132\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"NBR1 incorporation into the complex lacks reciprocal and endogenous validation\",\n        \"Functional consequence of miR-129-5p-mediated co-regulation of all four targets not mechanistically resolved\",\n        \"Whether this complex functions in selective autophagy cargo recognition is untested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include how the SCOC–FEZ1–UVRAG complex is remodeled by starvation signals, whether SCOC's LIR-dependent ATG8 binding is functionally required in vivo, and whether SCOC's roles in autophagy and axonal vesicle transport represent a unified or bifurcated mechanism.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No in vivo structure of a complete SCOC-containing signaling complex\",\n        \"No mammalian loss-of-function model linking SCOC to neurological or autophagy-deficient phenotypes\",\n        \"Mechanism of starvation-dependent UVRAG dissociation is undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [\n      \"SCOC-FEZ1 heterotetramer\",\n      \"SCOC-FEZ1-UVRAG trimeric complex\"\n    ],\n    \"partners\": [\n      \"FEZ1\",\n      \"UVRAG\",\n      \"ULK1\",\n      \"GABARAP\",\n      \"GABARAPL1\",\n      \"TBK1\",\n      \"NBR1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}