{"gene":"KLHDC1","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2020,"finding":"KLHDC1 functions as a substrate receptor for a Cul5-type ubiquitin ligase complex that targets truncated SELENOS (a selenoprotein lacking selenocysteine due to failed UGA/Sec decoding) for proteasomal degradation. Knockdown of KLHDC1 in U2OS cells decreased ER stress-induced cell death and altered ROS levels, linking KLHDC1-mediated degradation to maintenance of oxidoreductase activity and ROS homeostasis.","method":"siRNA knockdown in U2OS cells with cell death and ROS level readouts; identification of KLHDC1 as Cul5-type ubiquitin ligase component targeting truncated SELENOS for proteasomal degradation","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotypes (cell death, ROS) and pathway placement in Cul5-type ubiquitin ligase complex, single lab but two orthogonal readouts","pmids":["32200094"],"is_preprint":false},{"year":2006,"finding":"KLHDC1 localizes predominantly to the cytoplasm (in contrast to its paralog KLHDC2, which is nuclear), does not bind actin, and is unable to inhibit LZIP/CREB3-mediated transcriptional activation, distinguishing it functionally from KLHDC2.","method":"Subcellular fractionation and immunofluorescence microscopy for localization; actin-binding assay; transcriptional reporter assay for LZIP inhibition activity","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization experiment with functional activity assays, single lab, multiple orthogonal methods","pmids":["16964437"],"is_preprint":false},{"year":2024,"finding":"KLHDC1, together with the related E3 ligases KLHDC3 and KLHDC10, does not bind the C-degron ligands that engage KLHDC2, indicating that KLHDC1's substrate-binding pocket is distinct from KLHDC2's U-shaped C-degron binding site and cannot support cooperative ternary complex formation with BET-family neo-substrates.","method":"Selectivity profiling of KLHDC2-targeting ligands against related E3s (KLHDC1, KLHDC3, KLHDC10) in binding and degradation assays; structure-based ligand design","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — negative selectivity result established by in vitro ubiquitylation and cell-based degradation assays in a single rigorous study; finding is informative about KLHDC1 substrate-binding specificity","pmids":["39396041"],"is_preprint":false}],"current_model":"KLHDC1 is a cytoplasmic substrate receptor for a Cul5-type ubiquitin ligase complex that targets truncated, oxidoreductase-inactive selenoproteins (specifically SELENOS lacking selenocysteine) for proteasomal degradation, thereby maintaining cellular ROS levels; its substrate-binding pocket is distinct from the C-degron-binding pocket of its paralog KLHDC2, and it neither binds actin nor inhibits LZIP/CREB3-mediated transcription."},"narrative":{"mechanistic_narrative":"KLHDC1 is a cytoplasmic substrate receptor for a Cul5-type ubiquitin ligase complex that targets truncated SELENOS—a selenoprotein that fails UGA/Sec decoding and therefore lacks its catalytic selenocysteine—for proteasomal degradation, coupling protein quality control of defective selenoproteins to ROS homeostasis [PMID:32200094]. Loss of KLHDC1 decreases ER stress-induced cell death and alters cellular ROS levels, placing its degradative activity within the maintenance of oxidoreductase capacity [PMID:32200094]. KLHDC1 localizes predominantly to the cytoplasm, distinguishing it from its nuclear paralog KLHDC2; it neither binds actin nor inhibits LZIP/CREB3-mediated transcription [PMID:16964437]. Its substrate-binding pocket is functionally distinct from the U-shaped C-degron binding site of KLHDC2, as KLHDC1 does not engage the C-degron ligands recognized by KLHDC2 [PMID:39396041].","teleology":[{"year":2006,"claim":"Established that KLHDC1 is functionally distinct from its paralog KLHDC2, resolving whether the two paralogs share localization and activity.","evidence":"Subcellular fractionation, immunofluorescence, actin-binding and transcriptional reporter assays","pmids":["16964437"],"confidence":"Medium","gaps":["Did not identify a positive molecular function or substrate for KLHDC1","No interacting partners or complex membership defined","Cellular role left unassigned"]},{"year":2020,"claim":"Assigned KLHDC1 a concrete molecular role as the substrate-receptor subunit of a Cul5-type ubiquitin ligase that degrades truncated, Sec-lacking SELENOS, linking selenoprotein quality control to ROS homeostasis.","evidence":"siRNA knockdown in U2OS cells with cell death and ROS readouts; identification as a Cul5-type ligase component targeting truncated SELENOS","pmids":["32200094"],"confidence":"Medium","gaps":["Single-lab study; degradation mechanism not reconstituted in vitro","Scope of substrate repertoire beyond SELENOS unknown","Structural basis of truncated-SELENOS recognition undefined"]},{"year":2024,"claim":"Demonstrated that KLHDC1's substrate-binding pocket does not recognize the C-degron ligands engaged by KLHDC2, defining its specificity as mechanistically separate from the KLHDC2 C-degron pathway.","evidence":"Selectivity profiling of KLHDC2-targeting ligands against KLHDC1/KLHDC3/KLHDC10 in binding and degradation assays with structure-based ligand design","pmids":["39396041"],"confidence":"Medium","gaps":["A negative selectivity result; positive degron specificity of KLHDC1 not mapped","No KLHDC1 structure provided","Does not define how truncated SELENOS is recognized"]},{"year":null,"claim":"The structural basis of KLHDC1 substrate recognition and the full repertoire of its physiological substrates remain undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of the KLHDC1 substrate-binding pocket","Substrate degron and recognition determinants for truncated SELENOS unmapped","Composition of the full Cul5-type ligase complex not characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0]}],"complexes":["Cul5-type ubiquitin ligase complex"],"partners":["CUL5","SELENOS"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8N7A1","full_name":"Kelch domain-containing protein 1","aliases":[],"length_aa":406,"mass_kda":46.7,"function":"Substrate-recognition component of a Cul5-RING (CRL5) 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:32200094). 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:32200094). The CRL5(KLHDC1) complex mediates ubiquitination and degradation of truncated SELENOS selenoprotein produced by failed UGA/Sec decoding, which ends with a glycine (PubMed:32200094)","subcellular_location":"Cytoplasm, cytosol","url":"https://www.uniprot.org/uniprotkb/Q8N7A1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KLHDC1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KLHDC1","total_profiled":1310},"omim":[{"mim_id":"611281","title":"KELCH DOMAIN-CONTAINING PROTEIN 1; KLHDC1","url":"https://www.omim.org/entry/611281"},{"mim_id":"611280","title":"KELCH DOMAIN-CONTAINING PROTEIN 2; KLHDC2","url":"https://www.omim.org/entry/611280"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KLHDC1"},"hgnc":{"alias_symbol":["MST025"],"prev_symbol":[]},"alphafold":{"accession":"Q8N7A1","domains":[{"cath_id":"2.120.10.80","chopping":"18-341","consensus_level":"medium","plddt":95.6869,"start":18,"end":341},{"cath_id":"-","chopping":"346-406","consensus_level":"high","plddt":85.7595,"start":346,"end":406}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N7A1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N7A1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N7A1-F1-predicted_aligned_error_v6.png","plddt_mean":93.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KLHDC1","jax_strain_url":"https://www.jax.org/strain/search?query=KLHDC1"},"sequence":{"accession":"Q8N7A1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N7A1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N7A1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N7A1"}},"corpus_meta":[{"pmid":"32200094","id":"PMC_32200094","title":"Cul5-type Ubiquitin Ligase KLHDC1 Contributes to the Elimination of Truncated SELENOS Produced by Failed UGA/Sec Decoding.","date":"2020","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/32200094","citation_count":19,"is_preprint":false},{"pmid":"39396041","id":"PMC_39396041","title":"Principles of paralog-specific targeted protein degradation engaging the C-degron E3 KLHDC2.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39396041","citation_count":17,"is_preprint":false},{"pmid":"16964437","id":"PMC_16964437","title":"Differential subcellular localization and activity of kelch repeat proteins KLHDC1 and KLHDC2.","date":"2006","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16964437","citation_count":16,"is_preprint":false},{"pmid":"24498620","id":"PMC_24498620","title":"Identification of novel point mutations in splicing sites integrating whole-exome and RNA-seq data in myeloproliferative diseases.","date":"2013","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24498620","citation_count":13,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4230,"output_tokens":942,"usd":0.01341,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7419,"output_tokens":1557,"usd":0.03801,"stage2_stop_reason":"end_turn"},"total_usd":0.05142,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"KLHDC1 functions as a substrate receptor for a Cul5-type ubiquitin ligase complex that targets truncated SELENOS (a selenoprotein lacking selenocysteine due to failed UGA/Sec decoding) for proteasomal degradation. Knockdown of KLHDC1 in U2OS cells decreased ER stress-induced cell death and altered ROS levels, linking KLHDC1-mediated degradation to maintenance of oxidoreductase activity and ROS homeostasis.\",\n      \"method\": \"siRNA knockdown in U2OS cells with cell death and ROS level readouts; identification of KLHDC1 as Cul5-type ubiquitin ligase component targeting truncated SELENOS for proteasomal degradation\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotypes (cell death, ROS) and pathway placement in Cul5-type ubiquitin ligase complex, single lab but two orthogonal readouts\",\n      \"pmids\": [\"32200094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"KLHDC1 localizes predominantly to the cytoplasm (in contrast to its paralog KLHDC2, which is nuclear), does not bind actin, and is unable to inhibit LZIP/CREB3-mediated transcriptional activation, distinguishing it functionally from KLHDC2.\",\n      \"method\": \"Subcellular fractionation and immunofluorescence microscopy for localization; actin-binding assay; transcriptional reporter assay for LZIP inhibition activity\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization experiment with functional activity assays, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"16964437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KLHDC1, together with the related E3 ligases KLHDC3 and KLHDC10, does not bind the C-degron ligands that engage KLHDC2, indicating that KLHDC1's substrate-binding pocket is distinct from KLHDC2's U-shaped C-degron binding site and cannot support cooperative ternary complex formation with BET-family neo-substrates.\",\n      \"method\": \"Selectivity profiling of KLHDC2-targeting ligands against related E3s (KLHDC1, KLHDC3, KLHDC10) in binding and degradation assays; structure-based ligand design\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — negative selectivity result established by in vitro ubiquitylation and cell-based degradation assays in a single rigorous study; finding is informative about KLHDC1 substrate-binding specificity\",\n      \"pmids\": [\"39396041\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KLHDC1 is a cytoplasmic substrate receptor for a Cul5-type ubiquitin ligase complex that targets truncated, oxidoreductase-inactive selenoproteins (specifically SELENOS lacking selenocysteine) for proteasomal degradation, thereby maintaining cellular ROS levels; its substrate-binding pocket is distinct from the C-degron-binding pocket of its paralog KLHDC2, and it neither binds actin nor inhibits LZIP/CREB3-mediated transcription.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KLHDC1 is a cytoplasmic substrate receptor for a Cul5-type ubiquitin ligase complex that targets truncated SELENOS—a selenoprotein that fails UGA/Sec decoding and therefore lacks its catalytic selenocysteine—for proteasomal degradation, coupling protein quality control of defective selenoproteins to ROS homeostasis [#0]. Loss of KLHDC1 decreases ER stress-induced cell death and alters cellular ROS levels, placing its degradative activity within the maintenance of oxidoreductase capacity [#0]. KLHDC1 localizes predominantly to the cytoplasm, distinguishing it from its nuclear paralog KLHDC2; it neither binds actin nor inhibits LZIP/CREB3-mediated transcription [#1]. Its substrate-binding pocket is functionally distinct from the U-shaped C-degron binding site of KLHDC2, as KLHDC1 does not engage the C-degron ligands recognized by KLHDC2 [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established that KLHDC1 is functionally distinct from its paralog KLHDC2, resolving whether the two paralogs share localization and activity.\",\n      \"evidence\": \"Subcellular fractionation, immunofluorescence, actin-binding and transcriptional reporter assays\",\n      \"pmids\": [\"16964437\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Did not identify a positive molecular function or substrate for KLHDC1\",\n        \"No interacting partners or complex membership defined\",\n        \"Cellular role left unassigned\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Assigned KLHDC1 a concrete molecular role as the substrate-receptor subunit of a Cul5-type ubiquitin ligase that degrades truncated, Sec-lacking SELENOS, linking selenoprotein quality control to ROS homeostasis.\",\n      \"evidence\": \"siRNA knockdown in U2OS cells with cell death and ROS readouts; identification as a Cul5-type ligase component targeting truncated SELENOS\",\n      \"pmids\": [\"32200094\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study; degradation mechanism not reconstituted in vitro\",\n        \"Scope of substrate repertoire beyond SELENOS unknown\",\n        \"Structural basis of truncated-SELENOS recognition undefined\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated that KLHDC1's substrate-binding pocket does not recognize the C-degron ligands engaged by KLHDC2, defining its specificity as mechanistically separate from the KLHDC2 C-degron pathway.\",\n      \"evidence\": \"Selectivity profiling of KLHDC2-targeting ligands against KLHDC1/KLHDC3/KLHDC10 in binding and degradation assays with structure-based ligand design\",\n      \"pmids\": [\"39396041\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"A negative selectivity result; positive degron specificity of KLHDC1 not mapped\",\n        \"No KLHDC1 structure provided\",\n        \"Does not define how truncated SELENOS is recognized\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of KLHDC1 substrate recognition and the full repertoire of its physiological substrates remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structure of the KLHDC1 substrate-binding pocket\",\n        \"Substrate degron and recognition determinants for truncated SELENOS unmapped\",\n        \"Composition of the full Cul5-type ligase complex not characterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"Cul5-type ubiquitin ligase complex\"],\n    \"partners\": [\"CUL5\", \"SELENOS\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}