{"gene":"SCOC","run_date":"2026-06-10T07:46:29","timeline":{"discoveries":[{"year":2006,"finding":"C. elegans UNC-69 (ortholog of human SCOC) is required for axon outgrowth, guidance, fasciculation, and normal presynaptic organization. UNC-69 physically interacts with UNC-76 (ortholog of human FEZ1), and the two proteins colocalize as puncta in neuronal processes, cooperating to regulate axon extension and synapse formation. A reduction-of-function allele causes mislocalization of the synaptic vesicle marker synaptobrevin.","method":"Genetic loss-of-function analysis in C. elegans, co-immunoprecipitation/physical interaction assay, colocalization imaging, synaptobrevin mislocalization assay, chicken UNC-69 homolog RNAi knockdown","journal":"Journal of biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (genetics, physical interaction, colocalization, RNAi in vertebrate), replicated across C. elegans and chicken models","pmids":["16725058"],"is_preprint":false},{"year":2012,"finding":"SCOC is a Golgi-localized protein required for autophagosome formation during amino acid starvation. SCOC 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 with GFP-LC3 autophagosome readout, followed by validation; co-immunoprecipitation to identify SCOC-FEZ1-UVRAG trimeric complex; Golgi localization established","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide screen with stringent validation, reciprocal co-IP for complex, Golgi localization, multiple orthogonal methods in one study","pmids":["22354037"],"is_preprint":false},{"year":2013,"finding":"The crystal structure of the coiled-coil domain of human SCOC was determined at 2.7 Å resolution, revealing a parallel left-handed coiled-coil dimer with conformational flexibility due to polar/charged residues at core heptad positions. SCOC forms a stable complex with the coiled-coil domain of FEZ1, and SCOC dimerization and the surface residue R117 are important for this interaction. Core mutations (E93V/K97L or N125L/N132V) altered oligomerization state.","method":"X-ray crystallography (2.7 Å), multi-angle laser light scattering, native mass spectrometry, site-directed mutagenesis of core residues","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with mutagenesis and orthogonal biophysical methods (MALLS, native MS) in one study","pmids":["24098481"],"is_preprint":false},{"year":2013,"finding":"Structural analysis of the FEZ1/SCOC complex revealed that FEZ1 homodimerizes in an anti-parallel topology and interacts with SCOC. The FEZ1-SCOC interaction interface identified by cross-linking mass spectrometry and computational modelling is consistent with the UNC-76/UNC-69 interaction in C. elegans. SAXS data support a heterotetrameric complex model for FEZ1/SCOC.","method":"NMR, cross-linking coupled with mass spectrometry, SAXS, molecular modelling","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal structural/biophysical methods (NMR, XL-MS, SAXS) in one study, single lab","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 LIR motif by autophagy-related kinases ULK1-3 and TBK1 specifically increases binding to LC3 family members, thereby modulating ATG8 binding affinity and specificity. Flanking residues beyond the core LIR contribute to ATG8 binding, and their loss can be compensated by phosphorylation of adjacent serine residues.","method":"Structural analysis, biophysical binding assays, in vitro kinase assays with ULK1-3 and TBK1, mutagenesis of LIR domain residues, biochemical binding specificity measurements","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — comprehensive structural, biophysical, and biochemical analyses with mutagenesis and in vitro kinase assays, multiple orthogonal methods in one study","pmids":["33845085"],"is_preprint":false},{"year":2022,"finding":"SCOC, ULK1, and NBR1 can directly bind to FEZ1 protein to form a protein complex (FEZ1/SCOC/ULK1/NBR1). miR-129-5p targets FEZ1, SCOC, ULK1, and NBR1 as direct target genes, and overexpression of miR-129-5p reduces autophagy and the levels of these proteins in neuronal cells.","method":"Co-immunoprecipitation to demonstrate SCOC-FEZ1 direct binding, dual-luciferase reporter assay to confirm miR-129-5p targeting of SCOC","journal":"Bioengineered","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single Co-IP for complex, single lab, limited mechanistic follow-up for SCOC specifically","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 starvation-sensitive trimeric complex with FEZ1 and UVRAG to regulate autophagosome formation during amino acid starvation; it contains a LIR motif whose phosphorylation by ULK1-3 and TBK1 dynamically controls binding affinity and specificity toward ATG8 family members (GABARAP, LC3A/C), and its C. elegans ortholog UNC-69 cooperates with FEZ1/UNC-76 in axonal outgrowth and presynaptic vesicle organization."},"narrative":{"mechanistic_narrative":"SCOC is a Golgi-localized short coiled-coil protein that regulates autophagosome formation during amino acid starvation, identified through a genome-wide siRNA screen as required for starvation-induced autophagy [PMID:22354037]. Mechanistically, SCOC forms a starvation-sensitive trimeric complex with the ULK1-binding protein FEZ1 and UVRAG, positioning it to modulate ULK1 and Beclin 1 complex activities [PMID:22354037]. Structurally, SCOC assembles as a parallel left-handed coiled-coil homodimer whose conformational flexibility and surface residue R117 underpin its stable interaction with the coiled-coil domain of FEZ1, which itself homodimerizes in an anti-parallel topology to yield a heterotetrameric FEZ1/SCOC assembly [PMID:24098481, PMID:24116125]. SCOC additionally carries a LIR motif that binds ATG8-family proteins with preference for GABARAP, GABARAPL1, LC3A, and LC3C, and phosphorylation within and around this motif by the autophagy kinases ULK1-3 and TBK1 tunes its affinity and specificity toward LC3 family members [PMID:33845085]. The function is conserved: the C. elegans ortholog UNC-69 cooperates with the FEZ1 ortholog UNC-76 to control axon outgrowth, guidance, fasciculation, and presynaptic vesicle organization [PMID:16725058].","teleology":[{"year":2006,"claim":"Established the first physiological role and a conserved binding partner for the SCOC ortholog, showing it is not an orphan coiled-coil protein but a neuronal regulator acting with FEZ1.","evidence":"C. elegans loss-of-function genetics, co-immunoprecipitation, colocalization imaging, and vertebrate RNAi knockdown","pmids":["16725058"],"confidence":"High","gaps":["Molecular mechanism by which the UNC-69/UNC-76 complex directs axon outgrowth not defined","Relationship to autophagy not yet recognized","Human SCOC function not directly tested"]},{"year":2012,"claim":"Connected SCOC to autophagy, answering what cellular pathway it operates in by placing it in a starvation-sensitive trimeric complex with FEZ1 and UVRAG required for autophagosome formation.","evidence":"Genome-wide siRNA screen with GFP-LC3 readout and reciprocal co-immunoprecipitation, Golgi localization","pmids":["22354037"],"confidence":"High","gaps":["Direct enzymatic effect on ULK1 or Beclin 1 complexes not demonstrated","How starvation sensitizes complex assembly unresolved","Stoichiometry of the trimeric complex not defined"]},{"year":2013,"claim":"Resolved the molecular architecture of SCOC and its FEZ1 interaction, showing how a flexible parallel coiled-coil homodimer engages an anti-parallel FEZ1 dimer to form a heterotetramer.","evidence":"X-ray crystallography, MALLS, native MS, NMR, cross-linking MS, SAXS, and core/surface residue mutagenesis across two studies","pmids":["24098481","24116125"],"confidence":"High","gaps":["Structure of the full SCOC/FEZ1/UVRAG trimeric complex not determined","Functional consequence of conformational flexibility in cells not tested","How UVRAG joins the assembly unknown"]},{"year":2021,"claim":"Identified SCOC as a direct ATG8 effector through a LIR motif and showed that autophagy-kinase phosphorylation dynamically controls its ATG8 selectivity, providing a regulatory switch linking it to membrane-associated ATG8 proteins.","evidence":"Structural and biophysical binding assays, in vitro kinase assays with ULK1-3 and TBK1, and LIR mutagenesis","pmids":["33845085"],"confidence":"High","gaps":["In-cell relevance of phospho-regulated ATG8 binding to autophagosome formation not established","Which kinase acts on SCOC under physiological starvation unclear","Link between LIR-mediated ATG8 binding and the FEZ1/UVRAG complex unresolved"]},{"year":2022,"claim":"Extended the SCOC interaction network to a larger FEZ1/SCOC/ULK1/NBR1 complex and placed it under microRNA control in neuronal cells.","evidence":"Co-immunoprecipitation and dual-luciferase reporter assay for miR-129-5p targeting","pmids":["35435132"],"confidence":"Medium","gaps":["Single Co-IP without reciprocal validation for the four-protein complex","Direct versus indirect SCOC contacts within the complex not dissected","Functional autophagy consequence attributable specifically to SCOC not isolated"]},{"year":null,"claim":"Whether SCOC's LIR-mediated ATG8 binding, its FEZ1/UVRAG complex, and its conserved neuronal role are mechanistically integrated into a single regulatory step in autophagosome biogenesis remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structure of the assembled multiprotein complex with ATG8","Causal in-cell pathway from SCOC phosphorylation to autophagosome formation not traced","Direct biochemical effect on ULK1/Beclin 1 activity untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,3,4]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,2,3]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[1,4]}],"complexes":["SCOC/FEZ1/UVRAG trimeric complex","FEZ1/SCOC heterotetramer","FEZ1/SCOC/ULK1/NBR1 complex"],"partners":["FEZ1","UVRAG","ULK1","NBR1","GABARAP","GABARAPL1","LC3A","LC3C"],"other_free_text":[]}},"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":33,"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":"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":"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":"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":9,"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":"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":"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":"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":12233,"output_tokens":2038,"usd":0.033634,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8613,"output_tokens":2384,"usd":0.051333,"stage2_stop_reason":"end_turn"},"total_usd":0.084967,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to distinguish between:\n1. Human/mammalian SCOC (short coiled-coil protein, also known as SCOCO/UNC-69) - the query gene\n2. Bacterial ScoC from Bacillus subtilis/Geobacillus - a completely different protein (MarR family transcriptional regulator) that is a symbol collision\n\nPapers 2, 3, 5, 7, 8, 12, 14, 15, 16, 17, 19, 20, 21, 22 are about bacterial ScoC - EXCLUDE.\nPaper 13 is about a lncRNA (SCOC-AS1) - EXCLUDE.\n\nRelevant papers about human/mammalian SCOC: 1, 4, 6, 9, 10, 11, 18\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"C. elegans UNC-69 (ortholog of human SCOC) is required for axon outgrowth, guidance, fasciculation, and normal presynaptic organization. UNC-69 physically interacts with UNC-76 (ortholog of human FEZ1), and the two proteins colocalize as puncta in neuronal processes, cooperating to regulate axon extension and synapse formation. A reduction-of-function allele causes mislocalization of the synaptic vesicle marker synaptobrevin.\",\n      \"method\": \"Genetic loss-of-function analysis in C. elegans, co-immunoprecipitation/physical interaction assay, colocalization imaging, synaptobrevin mislocalization assay, chicken UNC-69 homolog RNAi knockdown\",\n      \"journal\": \"Journal of biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genetics, physical interaction, colocalization, RNAi in vertebrate), replicated across C. elegans and chicken models\",\n      \"pmids\": [\"16725058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SCOC is a Golgi-localized protein required for autophagosome formation during amino acid starvation. SCOC 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 with GFP-LC3 autophagosome readout, followed by validation; co-immunoprecipitation to identify SCOC-FEZ1-UVRAG trimeric complex; Golgi localization established\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide screen with stringent validation, reciprocal co-IP for complex, Golgi localization, multiple orthogonal methods in one study\",\n      \"pmids\": [\"22354037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The crystal structure of the coiled-coil domain of human SCOC was determined at 2.7 Å resolution, revealing a parallel left-handed coiled-coil dimer with conformational flexibility due to polar/charged residues at core heptad positions. SCOC forms a stable complex with the coiled-coil domain of FEZ1, and SCOC dimerization and the surface residue R117 are important for this interaction. Core mutations (E93V/K97L or N125L/N132V) altered oligomerization state.\",\n      \"method\": \"X-ray crystallography (2.7 Å), multi-angle laser light scattering, native mass spectrometry, site-directed mutagenesis of core residues\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with mutagenesis and orthogonal biophysical methods (MALLS, native MS) in one study\",\n      \"pmids\": [\"24098481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Structural analysis of the FEZ1/SCOC complex revealed that FEZ1 homodimerizes in an anti-parallel topology and interacts with SCOC. The FEZ1-SCOC interaction interface identified by cross-linking mass spectrometry and computational modelling is consistent with the UNC-76/UNC-69 interaction in C. elegans. SAXS data support a heterotetrameric complex model for FEZ1/SCOC.\",\n      \"method\": \"NMR, cross-linking coupled with mass spectrometry, SAXS, molecular modelling\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal structural/biophysical methods (NMR, XL-MS, SAXS) in one study, single lab\",\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 LIR motif by autophagy-related kinases ULK1-3 and TBK1 specifically increases binding to LC3 family members, thereby modulating ATG8 binding affinity and specificity. Flanking residues beyond the core LIR contribute to ATG8 binding, and their loss can be compensated by phosphorylation of adjacent serine residues.\",\n      \"method\": \"Structural analysis, biophysical binding assays, in vitro kinase assays with ULK1-3 and TBK1, mutagenesis of LIR domain residues, biochemical binding specificity measurements\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — comprehensive structural, biophysical, and biochemical analyses with mutagenesis and in vitro kinase assays, multiple orthogonal methods in one study\",\n      \"pmids\": [\"33845085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SCOC, ULK1, and NBR1 can directly bind to FEZ1 protein to form a protein complex (FEZ1/SCOC/ULK1/NBR1). miR-129-5p targets FEZ1, SCOC, ULK1, and NBR1 as direct target genes, and overexpression of miR-129-5p reduces autophagy and the levels of these proteins in neuronal cells.\",\n      \"method\": \"Co-immunoprecipitation to demonstrate SCOC-FEZ1 direct binding, dual-luciferase reporter assay to confirm miR-129-5p targeting of SCOC\",\n      \"journal\": \"Bioengineered\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP for complex, single lab, limited mechanistic follow-up for SCOC specifically\",\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 starvation-sensitive trimeric complex with FEZ1 and UVRAG to regulate autophagosome formation during amino acid starvation; it contains a LIR motif whose phosphorylation by ULK1-3 and TBK1 dynamically controls binding affinity and specificity toward ATG8 family members (GABARAP, LC3A/C), and its C. elegans ortholog UNC-69 cooperates with FEZ1/UNC-76 in axonal outgrowth and presynaptic vesicle organization.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SCOC is a Golgi-localized short coiled-coil protein that regulates autophagosome formation during amino acid starvation, identified through a genome-wide siRNA screen as required for starvation-induced autophagy [#1]. Mechanistically, SCOC forms a starvation-sensitive trimeric complex with the ULK1-binding protein FEZ1 and UVRAG, positioning it to modulate ULK1 and Beclin 1 complex activities [#1]. Structurally, SCOC assembles as a parallel left-handed coiled-coil homodimer whose conformational flexibility and surface residue R117 underpin its stable interaction with the coiled-coil domain of FEZ1, which itself homodimerizes in an anti-parallel topology to yield a heterotetrameric FEZ1/SCOC assembly [#2, #3]. SCOC additionally carries a LIR motif that binds ATG8-family proteins with preference for GABARAP, GABARAPL1, LC3A, and LC3C, and phosphorylation within and around this motif by the autophagy kinases ULK1-3 and TBK1 tunes its affinity and specificity toward LC3 family members [#4]. The function is conserved: the C. elegans ortholog UNC-69 cooperates with the FEZ1 ortholog UNC-76 to control axon outgrowth, guidance, fasciculation, and presynaptic vesicle organization [#0].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established the first physiological role and a conserved binding partner for the SCOC ortholog, showing it is not an orphan coiled-coil protein but a neuronal regulator acting with FEZ1.\",\n      \"evidence\": \"C. elegans loss-of-function genetics, co-immunoprecipitation, colocalization imaging, and vertebrate RNAi knockdown\",\n      \"pmids\": [\"16725058\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which the UNC-69/UNC-76 complex directs axon outgrowth not defined\", \"Relationship to autophagy not yet recognized\", \"Human SCOC function not directly tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected SCOC to autophagy, answering what cellular pathway it operates in by placing it in a starvation-sensitive trimeric complex with FEZ1 and UVRAG required for autophagosome formation.\",\n      \"evidence\": \"Genome-wide siRNA screen with GFP-LC3 readout and reciprocal co-immunoprecipitation, Golgi localization\",\n      \"pmids\": [\"22354037\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct enzymatic effect on ULK1 or Beclin 1 complexes not demonstrated\", \"How starvation sensitizes complex assembly unresolved\", \"Stoichiometry of the trimeric complex not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved the molecular architecture of SCOC and its FEZ1 interaction, showing how a flexible parallel coiled-coil homodimer engages an anti-parallel FEZ1 dimer to form a heterotetramer.\",\n      \"evidence\": \"X-ray crystallography, MALLS, native MS, NMR, cross-linking MS, SAXS, and core/surface residue mutagenesis across two studies\",\n      \"pmids\": [\"24098481\", \"24116125\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the full SCOC/FEZ1/UVRAG trimeric complex not determined\", \"Functional consequence of conformational flexibility in cells not tested\", \"How UVRAG joins the assembly unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified SCOC as a direct ATG8 effector through a LIR motif and showed that autophagy-kinase phosphorylation dynamically controls its ATG8 selectivity, providing a regulatory switch linking it to membrane-associated ATG8 proteins.\",\n      \"evidence\": \"Structural and biophysical binding assays, in vitro kinase assays with ULK1-3 and TBK1, and LIR mutagenesis\",\n      \"pmids\": [\"33845085\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In-cell relevance of phospho-regulated ATG8 binding to autophagosome formation not established\", \"Which kinase acts on SCOC under physiological starvation unclear\", \"Link between LIR-mediated ATG8 binding and the FEZ1/UVRAG complex unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended the SCOC interaction network to a larger FEZ1/SCOC/ULK1/NBR1 complex and placed it under microRNA control in neuronal cells.\",\n      \"evidence\": \"Co-immunoprecipitation and dual-luciferase reporter assay for miR-129-5p targeting\",\n      \"pmids\": [\"35435132\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation for the four-protein complex\", \"Direct versus indirect SCOC contacts within the complex not dissected\", \"Functional autophagy consequence attributable specifically to SCOC not isolated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether SCOC's LIR-mediated ATG8 binding, its FEZ1/UVRAG complex, and its conserved neuronal role are mechanistically integrated into a single regulatory step in autophagosome biogenesis remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of the assembled multiprotein complex with ATG8\", \"Causal in-cell pathway from SCOC phosphorylation to autophagosome formation not traced\", \"Direct biochemical effect on ULK1/Beclin 1 activity untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 3, 4]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"complexes\": [\"SCOC/FEZ1/UVRAG trimeric complex\", \"FEZ1/SCOC heterotetramer\", \"FEZ1/SCOC/ULK1/NBR1 complex\"],\n    \"partners\": [\"FEZ1\", \"UVRAG\", \"ULK1\", \"NBR1\", \"GABARAP\", \"GABARAPL1\", \"LC3A\", \"LC3C\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}