{"gene":"FEM1C","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2021,"finding":"FEM1C is a substrate receptor of the CRL2 (Cullin2-RING) ubiquitin ligase complex that recognizes the C-terminal arginine degron (Arg/C-degron) via a semi-open binding pocket, with the extreme C-terminal arginine being the major structural determinant for recognition. Crystal structures of FEM1C in complex with the Arg/C-degron, combined with biochemical and mutagenesis studies, established this molecular mechanism.","method":"X-ray crystallography (crystal structures of FEM1C–Arg/C-degron complex), biochemical assays, site-directed mutagenesis","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation by mutagenesis and biochemical assays in a single rigorous study","pmids":["33398170"],"is_preprint":false},{"year":2023,"finding":"FEM1C recognizes proteins bearing an R/K-X-R or R/K-X-X-R motif at the C-terminus for ubiquitin-proteasome-mediated degradation. A fluorescent probe (ES148, Ki = 1.6 µM) was developed and validated by fluorescence polarization and isothermal titration calorimetry as a competitive ligand for the FEM1C substrate-binding site, confirming the binding pocket is druggable.","method":"Fluorescence polarization competition assay, isothermal titration calorimetry, synthesis and characterization of fluorescent probe ES148","journal":"Bioorganic & medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal biophysical methods (FP and ITC) in a single lab confirming ligand binding to FEM1C","pmids":["37339537"],"is_preprint":false},{"year":2023,"finding":"A de novo missense variant at the conserved Asp126 residue of FEM1C (equivalent to Asp133 in C. elegans FEM-1) impairs substrate binding in vitro and causes synaptic dysfunction (not muscle dysfunction) in a C. elegans model, as evidenced by aldicarb sensitivity but not levamisole sensitivity, placing FEM1C function at the synapse in neuronal contexts.","method":"In silico structural modeling, in vitro functional assay of FEM1C Asp126Ala variant, C. elegans locomotion assay, aldicarb/levamisole pharmacological epistasis","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro functional compromise of variant plus pharmacological epistasis in animal model, single lab","pmids":["36336956"],"is_preprint":false},{"year":2021,"finding":"Knockdown of FEM1C in colorectal cancer cells promotes cell migration, invasion, and proliferation in vitro, and enhances liver and lung metastasis in vivo, accompanied by an epithelial-to-mesenchymal transition (EMT) phenotype, indicating FEM1C acts as a suppressor of EMT-related pathways.","method":"siRNA knockdown, CCK-8 proliferation assay, colony formation assay, transwell migration/invasion assay, in vivo metastasis models, GSEA","journal":"Annals of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KD with defined cellular and in vivo phenotype, but single lab, no direct molecular mechanism of substrate identified","pmids":["34733943"],"is_preprint":false},{"year":2003,"finding":"Vertebrate FEM1C proteins (human, mouse, zebrafish) are conserved members of the FEM1 family and uniquely terminate with a C-terminal arginine residue, distinguishing them from other FEM-1 family members; human FEM1C maps to chromosome 5q22.","method":"Comparative genomic analysis, cDNA cloning, chromosomal mapping, tissue expression profiling","journal":"Gene","confidence":"Low","confidence_rationale":"Tier 3 / Moderate — sequence/mapping characterization without direct functional mechanistic experiment; replicated across species","pmids":["14527725"],"is_preprint":false},{"year":2009,"finding":"FEM1C-Z protein localizes to the cytoplasm in zebra finch fibroblast cells, consistent with cytoplasmic localization observed in C. elegans.","method":"Immunofluorescence/subcellular localization in zebra finch fibroblast cells","journal":"Chromosoma","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single localization experiment without functional consequence established, single lab","pmids":["19139913"],"is_preprint":false}],"current_model":"FEM1C is a substrate-recognition receptor of the CRL2 (Cullin2-RING) E3 ubiquitin ligase that uses a semi-open binding pocket to capture C-terminal arginine (Arg/C-degron) motifs on substrate proteins, directing them for proteasomal degradation; structural and mutagenesis studies show the extreme C-terminal arginine is the primary recognition determinant, and loss of FEM1C function—whether by missense mutation at the conserved Asp126 residue or siRNA knockdown—causes synaptic dysfunction in C. elegans and promotes EMT-driven metastasis in mammalian cancer models."},"narrative":{"mechanistic_narrative":"FEM1C is a substrate-recognition receptor of the CRL2 (Cullin2-RING) E3 ubiquitin ligase that targets proteins bearing C-terminal arginine degrons (Arg/C-degrons) for proteasomal degradation [PMID:33398170]. Crystal structures of FEM1C bound to its degron, together with biochemical and mutagenesis studies, established that the receptor uses a semi-open binding pocket in which the extreme C-terminal arginine is the principal recognition determinant, and that the pocket extends to accept R/K-X-R and R/K-X-X-R C-terminal motifs [PMID:33398170, PMID:37339537]. The conserved Asp126 residue is required for substrate engagement, as a de novo missense variant at this position impairs substrate binding in vitro and produces synaptic dysfunction in a C. elegans model, linking FEM1C activity to neuronal function [PMID:36336956]. Loss of FEM1C by knockdown in colorectal cancer cells drives migration, invasion, proliferation, and an epithelial-to-mesenchymal transition phenotype with enhanced metastasis in vivo, identifying it as a suppressor of EMT-related pathways [PMID:34733943]. The specific physiological substrates degraded through FEM1C in these neuronal and cancer contexts have not been identified in the available corpus.","teleology":[{"year":2003,"claim":"Before any function was known, it was unclear how vertebrate FEM1C related to the broader FEM1 family; sequence analysis showed it uniquely terminates in a C-terminal arginine, a feature later central to its mechanism.","evidence":"comparative genomics, cDNA cloning, chromosomal mapping in human/mouse/zebrafish","pmids":["14527725"],"confidence":"Low","gaps":["no functional mechanism established","no link to ubiquitin ligase activity at this stage","expression profiling does not define cellular role"]},{"year":2009,"claim":"The subcellular compartment in which FEM1C acts was undefined; localization studies placed the protein in the cytoplasm, consistent across species.","evidence":"immunofluorescence in zebra finch fibroblasts","pmids":["19139913"],"confidence":"Low","gaps":["single localization experiment","no functional consequence tied to localization","human FEM1C localization not directly tested"]},{"year":2021,"claim":"The molecular function of FEM1C was unknown until structures showed it is a CRL2 substrate receptor that captures C-terminal arginine degrons through a semi-open pocket, defining how it selects substrates for degradation.","evidence":"X-ray crystallography of FEM1C–Arg/C-degron complex with biochemical and mutagenesis validation","pmids":["33398170"],"confidence":"High","gaps":["physiological substrates not identified","in vivo CRL2 assembly with FEM1C not characterized in this work","scope of degron motifs beyond Arg terminus not fully mapped"]},{"year":2023,"claim":"It was unclear whether the FEM1C pocket tolerated extended degron motifs or could be chemically targeted; biophysical work mapped recognition of R/K-X-R and R/K-X-X-R C-terminal motifs and showed the pocket is druggable.","evidence":"fluorescence polarization competition and ITC with synthetic probe ES148 (Ki = 1.6 µM)","pmids":["37339537"],"confidence":"Medium","gaps":["single-lab biophysical characterization","no cellular degradation demonstrated with the probe","endogenous substrates bearing these motifs not enumerated"]},{"year":2023,"claim":"Whether a disease-associated variant disrupts FEM1C function was unknown; an Asp126 missense variant impaired substrate binding and caused synaptic, not muscle, dysfunction, placing FEM1C activity at the neuronal synapse.","evidence":"in vitro Asp126Ala functional assay and C. elegans aldicarb/levamisole pharmacological epistasis","pmids":["36336956"],"confidence":"Medium","gaps":["synaptic substrate of FEM1C not identified","single animal model","no formal Mendelian disease gene assignment established in this entry"]},{"year":2021,"claim":"The cellular role of FEM1C in cancer was undefined; knockdown promoted EMT, migration, invasion, and metastasis, identifying it as a suppressor of EMT-related pathways.","evidence":"siRNA knockdown with proliferation, migration/invasion assays, in vivo metastasis models, and GSEA in colorectal cancer cells","pmids":["34733943"],"confidence":"Medium","gaps":["no degradation substrate linking FEM1C to EMT identified","single lab","mechanistic connection between ligase activity and EMT not established"]},{"year":null,"claim":"The endogenous physiological substrates degraded by FEM1C-CRL2 in neuronal and cancer contexts remain unidentified, leaving the link between its degron-recognition activity and its synaptic and EMT-suppressive phenotypes mechanistically incomplete.","evidence":"","pmids":[],"confidence":"Medium","gaps":["no validated cellular substrate reported","substrate connecting FEM1C to EMT suppression unknown","substrate underlying synaptic dysfunction unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1]},{"term_id":"GO:0140097","term_label":"catalytic activity, acting on DNA","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0]}],"complexes":["CRL2 (Cullin2-RING ubiquitin ligase)"],"partners":["CUL2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96JP0","full_name":"Protein fem-1 homolog C","aliases":["FEM1-gamma"],"length_aa":617,"mass_kda":68.7,"function":"Substrate-recognition component of a Cul2-RING (CRL2) E3 ubiquitin-protein ligase complex of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation (PubMed:29775578, PubMed:29779948, PubMed:33398168, PubMed:33398170, PubMed:38326650). The C-degron recognized by the DesCEND pathway is usually a motif of less than ten residues and can be present in full-length proteins, truncated proteins or proteolytically cleaved forms (PubMed:29775578, PubMed:29779948, PubMed:33398168, PubMed:33398170). The CRL2(FEM1C) complex specifically recognizes proteins with an arginine at the C-terminus: recognizes and binds proteins ending with -Lys/Arg-Xaa-Arg and -Lys/Arg-Xaa-Xaa-Arg C-degrons, such as SIL1 or OR51B2, leading to their ubiquitination and degradation (PubMed:33398168, PubMed:33398170, PubMed:38326650). The CRL2(FEM1C) complex mediates ubiquitination and degradation of truncated MSRB1/SEPX1 selenoproteins produced by failed UGA/Sec decoding (PubMed:26138980). Promotes ubiquitination and degradation of SLBP (PubMed:28118078)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q96JP0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FEM1C","classification":"Not Classified","n_dependent_lines":28,"n_total_lines":1208,"dependency_fraction":0.023178807947019868},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FEM1C","total_profiled":1310},"omim":[{"mim_id":"608767","title":"FEM1 HOMOLOG C; FEM1C","url":"https://www.omim.org/entry/608767"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":59.6}],"url":"https://www.proteinatlas.org/search/FEM1C"},"hgnc":{"alias_symbol":["KIAA1785","EUROIMAGE686608","EUROIMAGE783647","FEM1A"],"prev_symbol":[]},"alphafold":{"accession":"Q96JP0","domains":[{"cath_id":"1.10.750","chopping":"585-617","consensus_level":"medium","plddt":87.7236,"start":585,"end":617}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96JP0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96JP0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96JP0-F1-predicted_aligned_error_v6.png","plddt_mean":94.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FEM1C","jax_strain_url":"https://www.jax.org/strain/search?query=FEM1C"},"sequence":{"accession":"Q96JP0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96JP0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96JP0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96JP0"}},"corpus_meta":[{"pmid":"33398170","id":"PMC_33398170","title":"Molecular basis for ubiquitin ligase CRL2FEM1C-mediated recognition of C-degron.","date":"2021","source":"Nature chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/33398170","citation_count":33,"is_preprint":false},{"pmid":"14527725","id":"PMC_14527725","title":"The Fem1c genes: conserved members of the Fem1 gene family in vertebrates.","date":"2003","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/14527725","citation_count":23,"is_preprint":false},{"pmid":"15082774","id":"PMC_15082774","title":"Insertion of the beta Geo promoter trap into the Fem1c gene of ROSA3 mice.","date":"2004","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15082774","citation_count":11,"is_preprint":false},{"pmid":"37339537","id":"PMC_37339537","title":"Design and synthesis of a fluorescent probe to develop a fluorescence polarization assay for the E3 ligase FEM1C.","date":"2023","source":"Bioorganic & medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37339537","citation_count":8,"is_preprint":false},{"pmid":"19139913","id":"PMC_19139913","title":"Disruption of FEM1C-W gene in zebra finch: evolutionary insights on avian ZW genes.","date":"2009","source":"Chromosoma","url":"https://pubmed.ncbi.nlm.nih.gov/19139913","citation_count":7,"is_preprint":false},{"pmid":"34733943","id":"PMC_34733943","title":"Downregulation of FEM1C enhances metastasis and proliferation in colorectal cancer.","date":"2021","source":"Annals of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34733943","citation_count":4,"is_preprint":false},{"pmid":"37889731","id":"PMC_37889731","title":"Eriocheir sinensis feminization-1c (Fem-1c) and Its Predicted miRNAs Involved in Sexual Development and Regulation.","date":"2023","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/37889731","citation_count":3,"is_preprint":false},{"pmid":"36336956","id":"PMC_36336956","title":"A novel de novo FEM1C variant is linked to neurodevelopmental disorder with absent speech, pyramidal signs and limb ataxia.","date":"2023","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36336956","citation_count":2,"is_preprint":false},{"pmid":"40992847","id":"PMC_40992847","title":"Fluorescence polarization binding assays for the E3 ligase FEM1C.","date":"2025","source":"Methods in enzymology","url":"https://pubmed.ncbi.nlm.nih.gov/40992847","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":5981,"output_tokens":1510,"usd":0.020296,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8287,"output_tokens":2343,"usd":0.050005,"stage2_stop_reason":"end_turn"},"total_usd":0.070301,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"FEM1C is a substrate receptor of the CRL2 (Cullin2-RING) ubiquitin ligase complex that recognizes the C-terminal arginine degron (Arg/C-degron) via a semi-open binding pocket, with the extreme C-terminal arginine being the major structural determinant for recognition. Crystal structures of FEM1C in complex with the Arg/C-degron, combined with biochemical and mutagenesis studies, established this molecular mechanism.\",\n      \"method\": \"X-ray crystallography (crystal structures of FEM1C–Arg/C-degron complex), biochemical assays, site-directed mutagenesis\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation by mutagenesis and biochemical assays in a single rigorous study\",\n      \"pmids\": [\"33398170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FEM1C recognizes proteins bearing an R/K-X-R or R/K-X-X-R motif at the C-terminus for ubiquitin-proteasome-mediated degradation. A fluorescent probe (ES148, Ki = 1.6 µM) was developed and validated by fluorescence polarization and isothermal titration calorimetry as a competitive ligand for the FEM1C substrate-binding site, confirming the binding pocket is druggable.\",\n      \"method\": \"Fluorescence polarization competition assay, isothermal titration calorimetry, synthesis and characterization of fluorescent probe ES148\",\n      \"journal\": \"Bioorganic & medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal biophysical methods (FP and ITC) in a single lab confirming ligand binding to FEM1C\",\n      \"pmids\": [\"37339537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A de novo missense variant at the conserved Asp126 residue of FEM1C (equivalent to Asp133 in C. elegans FEM-1) impairs substrate binding in vitro and causes synaptic dysfunction (not muscle dysfunction) in a C. elegans model, as evidenced by aldicarb sensitivity but not levamisole sensitivity, placing FEM1C function at the synapse in neuronal contexts.\",\n      \"method\": \"In silico structural modeling, in vitro functional assay of FEM1C Asp126Ala variant, C. elegans locomotion assay, aldicarb/levamisole pharmacological epistasis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro functional compromise of variant plus pharmacological epistasis in animal model, single lab\",\n      \"pmids\": [\"36336956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Knockdown of FEM1C in colorectal cancer cells promotes cell migration, invasion, and proliferation in vitro, and enhances liver and lung metastasis in vivo, accompanied by an epithelial-to-mesenchymal transition (EMT) phenotype, indicating FEM1C acts as a suppressor of EMT-related pathways.\",\n      \"method\": \"siRNA knockdown, CCK-8 proliferation assay, colony formation assay, transwell migration/invasion assay, in vivo metastasis models, GSEA\",\n      \"journal\": \"Annals of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KD with defined cellular and in vivo phenotype, but single lab, no direct molecular mechanism of substrate identified\",\n      \"pmids\": [\"34733943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Vertebrate FEM1C proteins (human, mouse, zebrafish) are conserved members of the FEM1 family and uniquely terminate with a C-terminal arginine residue, distinguishing them from other FEM-1 family members; human FEM1C maps to chromosome 5q22.\",\n      \"method\": \"Comparative genomic analysis, cDNA cloning, chromosomal mapping, tissue expression profiling\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — sequence/mapping characterization without direct functional mechanistic experiment; replicated across species\",\n      \"pmids\": [\"14527725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"FEM1C-Z protein localizes to the cytoplasm in zebra finch fibroblast cells, consistent with cytoplasmic localization observed in C. elegans.\",\n      \"method\": \"Immunofluorescence/subcellular localization in zebra finch fibroblast cells\",\n      \"journal\": \"Chromosoma\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single localization experiment without functional consequence established, single lab\",\n      \"pmids\": [\"19139913\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FEM1C is a substrate-recognition receptor of the CRL2 (Cullin2-RING) E3 ubiquitin ligase that uses a semi-open binding pocket to capture C-terminal arginine (Arg/C-degron) motifs on substrate proteins, directing them for proteasomal degradation; structural and mutagenesis studies show the extreme C-terminal arginine is the primary recognition determinant, and loss of FEM1C function—whether by missense mutation at the conserved Asp126 residue or siRNA knockdown—causes synaptic dysfunction in C. elegans and promotes EMT-driven metastasis in mammalian cancer models.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FEM1C is a substrate-recognition receptor of the CRL2 (Cullin2-RING) E3 ubiquitin ligase that targets proteins bearing C-terminal arginine degrons (Arg/C-degrons) for proteasomal degradation [#0]. Crystal structures of FEM1C bound to its degron, together with biochemical and mutagenesis studies, established that the receptor uses a semi-open binding pocket in which the extreme C-terminal arginine is the principal recognition determinant, and that the pocket extends to accept R/K-X-R and R/K-X-X-R C-terminal motifs [#0, #1]. The conserved Asp126 residue is required for substrate engagement, as a de novo missense variant at this position impairs substrate binding in vitro and produces synaptic dysfunction in a C. elegans model, linking FEM1C activity to neuronal function [#2]. Loss of FEM1C by knockdown in colorectal cancer cells drives migration, invasion, proliferation, and an epithelial-to-mesenchymal transition phenotype with enhanced metastasis in vivo, identifying it as a suppressor of EMT-related pathways [#3]. The specific physiological substrates degraded through FEM1C in these neuronal and cancer contexts have not been identified in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Before any function was known, it was unclear how vertebrate FEM1C related to the broader FEM1 family; sequence analysis showed it uniquely terminates in a C-terminal arginine, a feature later central to its mechanism.\",\n      \"evidence\": \"comparative genomics, cDNA cloning, chromosomal mapping in human/mouse/zebrafish\",\n      \"pmids\": [\"14527725\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"no functional mechanism established\", \"no link to ubiquitin ligase activity at this stage\", \"expression profiling does not define cellular role\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"The subcellular compartment in which FEM1C acts was undefined; localization studies placed the protein in the cytoplasm, consistent across species.\",\n      \"evidence\": \"immunofluorescence in zebra finch fibroblasts\",\n      \"pmids\": [\"19139913\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"single localization experiment\", \"no functional consequence tied to localization\", \"human FEM1C localization not directly tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The molecular function of FEM1C was unknown until structures showed it is a CRL2 substrate receptor that captures C-terminal arginine degrons through a semi-open pocket, defining how it selects substrates for degradation.\",\n      \"evidence\": \"X-ray crystallography of FEM1C–Arg/C-degron complex with biochemical and mutagenesis validation\",\n      \"pmids\": [\"33398170\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"physiological substrates not identified\", \"in vivo CRL2 assembly with FEM1C not characterized in this work\", \"scope of degron motifs beyond Arg terminus not fully mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"It was unclear whether the FEM1C pocket tolerated extended degron motifs or could be chemically targeted; biophysical work mapped recognition of R/K-X-R and R/K-X-X-R C-terminal motifs and showed the pocket is druggable.\",\n      \"evidence\": \"fluorescence polarization competition and ITC with synthetic probe ES148 (Ki = 1.6 µM)\",\n      \"pmids\": [\"37339537\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"single-lab biophysical characterization\", \"no cellular degradation demonstrated with the probe\", \"endogenous substrates bearing these motifs not enumerated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Whether a disease-associated variant disrupts FEM1C function was unknown; an Asp126 missense variant impaired substrate binding and caused synaptic, not muscle, dysfunction, placing FEM1C activity at the neuronal synapse.\",\n      \"evidence\": \"in vitro Asp126Ala functional assay and C. elegans aldicarb/levamisole pharmacological epistasis\",\n      \"pmids\": [\"36336956\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"synaptic substrate of FEM1C not identified\", \"single animal model\", \"no formal Mendelian disease gene assignment established in this entry\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The cellular role of FEM1C in cancer was undefined; knockdown promoted EMT, migration, invasion, and metastasis, identifying it as a suppressor of EMT-related pathways.\",\n      \"evidence\": \"siRNA knockdown with proliferation, migration/invasion assays, in vivo metastasis models, and GSEA in colorectal cancer cells\",\n      \"pmids\": [\"34733943\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"no degradation substrate linking FEM1C to EMT identified\", \"single lab\", \"mechanistic connection between ligase activity and EMT not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The endogenous physiological substrates degraded by FEM1C-CRL2 in neuronal and cancer contexts remain unidentified, leaving the link between its degron-recognition activity and its synaptic and EMT-suppressive phenotypes mechanistically incomplete.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"no validated cellular substrate reported\", \"substrate connecting FEM1C to EMT suppression unknown\", \"substrate underlying synaptic dysfunction unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"CRL2 (Cullin2-RING ubiquitin ligase)\"],\n    \"partners\": [\"CUL2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}