{"gene":"C2ORF76","run_date":"2026-06-09T22:02:45","timeline":{"discoveries":[{"year":2023,"finding":"The highly conserved Aim29 protein (C2ORF76) acts as a co-chaperone for Zpr1, an ATP-independent chaperone dedicated to folding of eukaryotic translation elongation factor 1A (eEF1A). Aim29 recognizes eEF1A in the GTP-bound, pre-hydrolysis conformation, dampens Zpr1·eEF1A GTPase activity, and facilitates client exit from the folding cycle, thereby enabling Zpr1 recycling.","method":"Yeast genetics and microscopy, biochemical reconstitution, and structural modeling","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — biochemical reconstitution plus yeast genetic epistasis plus structural modeling in a single rigorous study with multiple orthogonal methods","pmids":["37597513"],"is_preprint":false}],"current_model":"C2ORF76 (AIM29) is a conserved co-chaperone that works with the ATP-independent chaperone Zpr1 to fold eEF1A: it binds eEF1A in the GTP-bound pre-hydrolysis state, dampens GTPase activity of the Zpr1·eEF1A complex, and promotes client release to allow Zpr1 recycling."},"narrative":{"mechanistic_narrative":"C2ORF76 (Aim29) is a conserved co-chaperone that functions in the folding cycle of eukaryotic translation elongation factor 1A (eEF1A), acting through the ATP-independent chaperone Zpr1 [PMID:37597513]. It recognizes eEF1A specifically in the GTP-bound, pre-hydrolysis conformation, dampens the GTPase activity of the Zpr1·eEF1A complex, and facilitates client exit from the folding cycle, thereby enabling Zpr1 to be recycled [PMID:37597513]. Beyond this single characterized role in the Zpr1-dependent folding of eEF1A, no further mechanistic detail has been characterized in the available corpus.","teleology":[{"year":2023,"claim":"Established that the conserved orphan protein C2ORF76/Aim29 is not a standalone factor but a co-chaperone that couples conformational sensing of eEF1A to the Zpr1 folding cycle, explaining how a dedicated client is released and the chaperone recycled.","evidence":"yeast genetics and microscopy, in vitro biochemical reconstitution, and structural modeling","pmids":["37597513"],"confidence":"High","gaps":["Human C2ORF76 function shown largely through the yeast Aim29 ortholog; cellular role in human cells not directly tested","No high-resolution experimental structure of the Aim29·Zpr1·eEF1A complex","Physiological consequences of disrupting this co-chaperone in metazoan translation and cell growth unresolved"]},{"year":null,"claim":"Whether C2ORF76 has roles beyond eEF1A folding, and how its activity is regulated or integrated with translation in human cells, remains open.","evidence":"no further discoveries in the available corpus","pmids":[],"confidence":"High","gaps":["No human disease association documented in the corpus","Regulation, expression control, and tissue context uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[0]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0]}],"localization":[],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0]}],"complexes":["Zpr1·eEF1A folding complex"],"partners":["ZPR1","EEF1A1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q3KRA6","full_name":"UPF0538 protein C2orf76","aliases":[],"length_aa":126,"mass_kda":14.6,"function":"","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q3KRA6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/C2ORF76"},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/C2ORF76","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Endoplasmic reticulum","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/C2ORF76"},"hgnc":{"alias_symbol":["MGC104437","LOC130355","AIM29"],"prev_symbol":[]},"alphafold":{"accession":"Q3KRA6","domains":[{"cath_id":"3.10.20.90","chopping":"6-121","consensus_level":"high","plddt":92.1629,"start":6,"end":121}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q3KRA6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q3KRA6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q3KRA6-F1-predicted_aligned_error_v6.png","plddt_mean":92.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=C2ORF76","jax_strain_url":"https://www.jax.org/strain/search?query=C2ORF76"},"sequence":{"accession":"Q3KRA6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q3KRA6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q3KRA6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q3KRA6"}},"corpus_meta":[{"pmid":"24009515","id":"PMC_24009515","title":"Comparative anatomy of chromosomal domains with imprinted and non-imprinted allele-specific DNA methylation.","date":"2013","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24009515","citation_count":33,"is_preprint":false},{"pmid":"37371794","id":"PMC_37371794","title":"Transcriptomic Context of RUNX3 Expression in Monocytes: A Cross-Sectional Analysis.","date":"2023","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/37371794","citation_count":4,"is_preprint":false},{"pmid":"37597513","id":"PMC_37597513","title":"A Zpr1 co-chaperone mediates folding of eukaryotic translation elongation factor 1A via a GTPase cycle.","date":"2023","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/37597513","citation_count":4,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4049,"output_tokens":382,"usd":0.008939,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6623,"output_tokens":949,"usd":0.02842,"stage2_stop_reason":"end_turn"},"total_usd":0.037359,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2023,\n      \"finding\": \"The highly conserved Aim29 protein (C2ORF76) acts as a co-chaperone for Zpr1, an ATP-independent chaperone dedicated to folding of eukaryotic translation elongation factor 1A (eEF1A). Aim29 recognizes eEF1A in the GTP-bound, pre-hydrolysis conformation, dampens Zpr1·eEF1A GTPase activity, and facilitates client exit from the folding cycle, thereby enabling Zpr1 recycling.\",\n      \"method\": \"Yeast genetics and microscopy, biochemical reconstitution, and structural modeling\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — biochemical reconstitution plus yeast genetic epistasis plus structural modeling in a single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"37597513\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"C2ORF76 (AIM29) is a conserved co-chaperone that works with the ATP-independent chaperone Zpr1 to fold eEF1A: it binds eEF1A in the GTP-bound pre-hydrolysis state, dampens GTPase activity of the Zpr1·eEF1A complex, and promotes client release to allow Zpr1 recycling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"C2ORF76 (Aim29) is a conserved co-chaperone that functions in the folding cycle of eukaryotic translation elongation factor 1A (eEF1A), acting through the ATP-independent chaperone Zpr1 [#0]. It recognizes eEF1A specifically in the GTP-bound, pre-hydrolysis conformation, dampens the GTPase activity of the Zpr1·eEF1A complex, and facilitates client exit from the folding cycle, thereby enabling Zpr1 to be recycled [#0]. Beyond this single characterized role in the Zpr1-dependent folding of eEF1A, no further mechanistic detail has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2023,\n      \"claim\": \"Established that the conserved orphan protein C2ORF76/Aim29 is not a standalone factor but a co-chaperone that couples conformational sensing of eEF1A to the Zpr1 folding cycle, explaining how a dedicated client is released and the chaperone recycled.\",\n      \"evidence\": \"yeast genetics and microscopy, in vitro biochemical reconstitution, and structural modeling\",\n      \"pmids\": [\"37597513\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Human C2ORF76 function shown largely through the yeast Aim29 ortholog; cellular role in human cells not directly tested\",\n        \"No high-resolution experimental structure of the Aim29·Zpr1·eEF1A complex\",\n        \"Physiological consequences of disrupting this co-chaperone in metazoan translation and cell growth unresolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether C2ORF76 has roles beyond eEF1A folding, and how its activity is regulated or integrated with translation in human cells, remains open.\",\n      \"evidence\": \"no further discoveries in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No human disease association documented in the corpus\",\n        \"Regulation, expression control, and tissue context uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"Zpr1\\u00b7eEF1A folding complex\"],\n    \"partners\": [\"ZPR1\", \"EEF1A1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":1,"faith_total":2,"faith_pct":50.0}}