{"gene":"C2ORF49","run_date":"2026-06-11T12:11:54","timeline":{"discoveries":[{"year":2014,"finding":"ASW (C2ORF49) was identified as a subunit of the human tRNA splicing ligase complex (tRNA-LC), which contains RTCB as the essential catalytic subunit. The functions of ASW within the complex in the context of RNA ligation were characterized in the context of eukaryotic orthologous group analysis, placing it alongside CGI-99, FAM98B, and DDX1.","method":"Analysis of clusters of eukaryotic orthologous groups; functional studies of the tRNA ligase complex","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal functional characterization of the tRNA-LC complex, replicated across studies (PMID:24870230 and subsequent work), multiple labs","pmids":["24870230"],"is_preprint":false},{"year":2025,"finding":"ASW (C2ORF49) serves as the nuclear import factor for the tRNA ligase complex (tRNA-LC) in vertebrates. ASW contains a dual nuclear localization signal (NLS); disruption of this NLS causes retention of the tRNA-LC in the cytoplasm, impairment of pre-tRNA splicing, and accumulation of 5' tRNA fragments. ASW interacts exclusively with the FAM98B-containing form of the tRNA-LC, enabling its nuclear localization for tRNA biogenesis, while FAM98 paralogs (FAM98A, FAM98B, FAM98C) define three distinct forms of the complex with different subcellular distributions.","method":"NLS mutagenesis, subcellular fractionation/live imaging, pre-tRNA splicing assays, co-immunoprecipitation, depletion rescue experiments (NLS-tagged RTCB)","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (mutagenesis, localization, splicing assay, Co-IP) in a single preprint study, not yet peer-reviewed","pmids":["bio_10.1101_2025.08.01.668163"],"is_preprint":true},{"year":2000,"finding":"The avian ASW protein (the bird ortholog, encoded on the W chromosome) is related to the HIT (histidine triad) family of proteins, shows female-specific expression in genital ridges, and maps to the W chromosome across 17 bird species from nine families.","method":"W-chromosome linkage mapping, expression analysis in chick embryonic gonads, sequence analysis","journal":"Development genes and evolution","confidence":"Medium","confidence_rationale":"Tier 3 / Strong — localization and expression established by direct experiment, replicated across multiple avian species; however, mechanistic link to protein function is indirect","pmids":["11180828"],"is_preprint":false},{"year":2002,"finding":"The avian ASW protein is classified as a Hint family member that has evolved to lose its nucleotide binding site (15 of 16 AMP-interacting residues are altered), rendering it catalytically inactive as a nucleotide hydrolase, in contrast to the enzymatically active HINT encoded on the Z chromosome.","method":"Sequence analysis and biochemical classification of HIT superfamily members; structural/mechanistic inference from conserved residue comparison","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — sequence-based mechanistic inference supported by comparative biochemistry of HIT family; no direct enzymatic assay of ASW performed in this paper","pmids":["12119013"],"is_preprint":false},{"year":2003,"finding":"Molecular modeling predicts that avian Asw and Hint can form a heterodimer, and that Gln127 of Asw (replacing Trp123 of Hint) dominantly interferes with the remaining Hint active site. Positive cooperativity as the basis for dominant negativity was experimentally rejected. The model proposes that Asw functions as a dominant-negative dimerization partner of Hint.","method":"Molecular modeling of Asw-Hint heterodimer; experimental rejection of positive cooperativity model using enzyme activity assays","journal":"Genome biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — combination of molecular modeling and experimental rejection of one mechanistic model; direct biochemical confirmation of heterodimer and dominant-negative activity not yet shown in this paper","pmids":["12620103"],"is_preprint":false},{"year":2004,"finding":"A Hint-W123Q substitution (corresponding to Gln127 in avian Asw) reduced k(cat)/K(m) for AMP-lysine hydrolysis 17-fold while increasing specificity for AMP-para-nitroaniline hydrolysis 160-fold, resulting in a 2,700-fold switch in enzyme specificity. This experimentally supports the hypothesis that Gln127 is a key determinant of Asw's dominant-negative effect on Hint activity.","method":"In vitro enzyme kinetics assay with mutant Hint-W123Q; development of novel substrate linking AMP-lysine modification reversal to aminomethylcoumarin release","journal":"Physiological genomics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro enzymatic reconstitution and mutagenesis with quantitative kinetic analysis; single lab but rigorous biochemical methods","pmids":["15507519"],"is_preprint":false}],"current_model":"C2ORF49 (Ashwin/ASW) is a vertebrate-specific subunit of the tRNA ligase complex (tRNA-LC) that acts as the nuclear import factor for the complex via a dual NLS, directing the FAM98B-containing form of tRNA-LC to the nucleus for pre-tRNA splicing; loss of ASW or its NLS causes cytoplasmic retention of the complex, impaired tRNA splicing, and 5' tRNA fragment accumulation, while the avian ortholog (also called ASW) is an inactive, dominant-negative Hint dimerization partner whose key catalytic residues have been specifically altered in evolution (notably Gln127 replacing Trp123), reducing Hint AMP-lysine hydrolase activity and implicated in avian sex determination."},"narrative":{"mechanistic_narrative":"C2ORF49 (ASW/Ashwin) is a vertebrate-specific subunit of the tRNA splicing ligase complex (tRNA-LC), the multiprotein assembly built around the catalytic ligase RTCB together with FAM98B, DDX1, and CGI-99 [PMID:24870230]. Within this complex, ASW functions as the dedicated nuclear import factor: it carries a dual nuclear localization signal, and disruption of this NLS causes cytoplasmic retention of the tRNA-LC, impaired pre-tRNA splicing, and accumulation of 5' tRNA fragments [PMID:bio_10.1101_2025.08.01.668163]. ASW associates selectively with the FAM98B-containing form of the complex, directing that particular assembly to the nucleus for tRNA biogenesis, whereas FAM98A- and FAM98C-containing forms occupy distinct subcellular compartments [PMID:bio_10.1101_2025.08.01.668163]. In birds, a W-chromosome-encoded ASW ortholog represents a divergent branch of the protein: it is a HIT (histidine triad) family relative that has lost its nucleotide-binding site through alteration of nearly all AMP-contacting residues, rendering it catalytically inactive, and is expressed female-specifically in embryonic gonads [PMID:11180828, PMID:12119013]. This avian ASW acts as a dominant-negative dimerization partner of the active Z-chromosome-encoded Hint, with the Gln127-for-Trp123 substitution being a key determinant: an equivalent Hint-W123Q substitution causes a 2,700-fold switch in enzyme specificity and a 17-fold reduction in AMP-lysine hydrolysis [PMID:12620103, PMID:15507519].","teleology":[{"year":2014,"claim":"Establishing that ASW is a bona fide component of the human tRNA-LC placed an otherwise uncharacterized open reading frame within a defined RNA-processing machine alongside RTCB, FAM98B, DDX1, and CGI-99.","evidence":"Eukaryotic orthologous group analysis combined with functional characterization of the tRNA ligase complex","pmids":["24870230"],"confidence":"High","gaps":["Did not define ASW's specific role within the complex","No localization or import function assigned"]},{"year":2025,"claim":"Assigning ASW as the nuclear import factor of the tRNA-LC answered why the complex reaches the nucleus, linking a dual NLS in ASW to pre-tRNA splicing and revealing FAM98 paralog-defined complex forms with distinct distributions.","evidence":"NLS mutagenesis, subcellular fractionation/live imaging, pre-tRNA splicing assays, co-immunoprecipitation, and depletion rescue with NLS-tagged RTCB (preprint)","pmids":["bio_10.1101_2025.08.01.668163"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Structural basis of ASW-FAM98B selectivity not resolved","Mechanism by which the dual NLS engages import machinery undefined"]},{"year":2000,"claim":"Identifying the avian W-chromosome ASW ortholog as a female-specific, gonad-expressed HIT-family relative conserved across birds raised the question of its role in sex determination.","evidence":"W-chromosome linkage mapping, expression analysis in chick embryonic gonads, and sequence analysis across 17 bird species","pmids":["11180828"],"confidence":"Medium","gaps":["Mechanistic function not determined","Causal role in sex determination not demonstrated"]},{"year":2002,"claim":"Showing that avian ASW has lost nearly all AMP-interacting residues established it as a catalytically dead member of the HIT family, distinguishing it from the active Z-encoded Hint.","evidence":"Sequence analysis and comparative biochemical classification of HIT superfamily members","pmids":["12119013"],"confidence":"Medium","gaps":["No direct enzymatic assay of ASW performed","Functional consequence of inactivity not yet shown"]},{"year":2003,"claim":"Modeling an Asw-Hint heterodimer and rejecting positive cooperativity reframed avian ASW as a dominant-negative dimerization partner acting through the Gln127 substitution rather than via cooperative interference.","evidence":"Molecular modeling of the Asw-Hint heterodimer with experimental rejection of the positive cooperativity model via enzyme activity assays","pmids":["12620103"],"confidence":"Medium","gaps":["Heterodimer formation not biochemically confirmed","Dominant-negative activity not directly demonstrated in this study"]},{"year":2004,"claim":"Direct enzyme kinetics on Hint-W123Q (mimicking Asw Gln127) confirmed that this single residue is a key determinant of altered HIT activity, supporting the dominant-negative model.","evidence":"In vitro enzyme kinetics with mutant Hint-W123Q using a novel AMP-para-nitroaniline/AMP-lysine substrate system","pmids":["15507519"],"confidence":"High","gaps":["Tested in Hint, not in native avian Asw protein","Physiological consequence for sex determination not established"]},{"year":null,"claim":"How the vertebrate tRNA-LC import function of C2ORF49 relates to the divergent avian sex-determination role of its W-chromosome ortholog remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying functional model linking the tRNA-LC role and the HIT/Hint dominant-negative role","In vivo phenotype of ASW loss in vertebrates not characterized","Causal mechanism in avian sex determination undemonstrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,5]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1]}],"complexes":["tRNA ligase complex (tRNA-LC)"],"partners":["RTCB","FAM98B","DDX1","CGI-99","HINT"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BVC5","full_name":"tRNA-splicing ligase complex subunit ASW","aliases":[],"length_aa":232,"mass_kda":25.9,"function":"Accessory subunit of the tRNA-splicing ligase complex that acts by directly joining spliced tRNA halves to mature-sized tRNAs by incorporating the precursor-derived splice junction phosphate into the mature tRNA as a canonical 3',5'-phosphodiester. May act as an RNA ligase with broad substrate specificity and may function toward other RNAs","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9BVC5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/C2ORF49"},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DDX39B","stoichiometry":0.2},{"gene":"RTCB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/C2ORF49","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/C2ORF49"},"hgnc":{"alias_symbol":["MGC5509","asw"],"prev_symbol":[]},"alphafold":{"accession":"Q9BVC5","domains":[{"cath_id":"1.10.720","chopping":"13-83","consensus_level":"medium","plddt":85.2011,"start":13,"end":83}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BVC5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BVC5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BVC5-F1-predicted_aligned_error_v6.png","plddt_mean":65.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=C2ORF49","jax_strain_url":"https://www.jax.org/strain/search?query=C2ORF49"},"sequence":{"accession":"Q9BVC5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BVC5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BVC5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BVC5"}},"corpus_meta":[{"pmid":"31948481","id":"PMC_31948481","title":"A benchmark of 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The functions of ASW within the complex in the context of RNA ligation were characterized in the context of eukaryotic orthologous group analysis, placing it alongside CGI-99, FAM98B, and DDX1.\",\n      \"method\": \"Analysis of clusters of eukaryotic orthologous groups; functional studies of the tRNA ligase complex\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal functional characterization of the tRNA-LC complex, replicated across studies (PMID:24870230 and subsequent work), multiple labs\",\n      \"pmids\": [\"24870230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ASW (C2ORF49) serves as the nuclear import factor for the tRNA ligase complex (tRNA-LC) in vertebrates. ASW contains a dual nuclear localization signal (NLS); disruption of this NLS causes retention of the tRNA-LC in the cytoplasm, impairment of pre-tRNA splicing, and accumulation of 5' tRNA fragments. ASW interacts exclusively with the FAM98B-containing form of the tRNA-LC, enabling its nuclear localization for tRNA biogenesis, while FAM98 paralogs (FAM98A, FAM98B, FAM98C) define three distinct forms of the complex with different subcellular distributions.\",\n      \"method\": \"NLS mutagenesis, subcellular fractionation/live imaging, pre-tRNA splicing assays, co-immunoprecipitation, depletion rescue experiments (NLS-tagged RTCB)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (mutagenesis, localization, splicing assay, Co-IP) in a single preprint study, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.08.01.668163\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The avian ASW protein (the bird ortholog, encoded on the W chromosome) is related to the HIT (histidine triad) family of proteins, shows female-specific expression in genital ridges, and maps to the W chromosome across 17 bird species from nine families.\",\n      \"method\": \"W-chromosome linkage mapping, expression analysis in chick embryonic gonads, sequence analysis\",\n      \"journal\": \"Development genes and evolution\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Strong — localization and expression established by direct experiment, replicated across multiple avian species; however, mechanistic link to protein function is indirect\",\n      \"pmids\": [\"11180828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The avian ASW protein is classified as a Hint family member that has evolved to lose its nucleotide binding site (15 of 16 AMP-interacting residues are altered), rendering it catalytically inactive as a nucleotide hydrolase, in contrast to the enzymatically active HINT encoded on the Z chromosome.\",\n      \"method\": \"Sequence analysis and biochemical classification of HIT superfamily members; structural/mechanistic inference from conserved residue comparison\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — sequence-based mechanistic inference supported by comparative biochemistry of HIT family; no direct enzymatic assay of ASW performed in this paper\",\n      \"pmids\": [\"12119013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Molecular modeling predicts that avian Asw and Hint can form a heterodimer, and that Gln127 of Asw (replacing Trp123 of Hint) dominantly interferes with the remaining Hint active site. Positive cooperativity as the basis for dominant negativity was experimentally rejected. The model proposes that Asw functions as a dominant-negative dimerization partner of Hint.\",\n      \"method\": \"Molecular modeling of Asw-Hint heterodimer; experimental rejection of positive cooperativity model using enzyme activity assays\",\n      \"journal\": \"Genome biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — combination of molecular modeling and experimental rejection of one mechanistic model; direct biochemical confirmation of heterodimer and dominant-negative activity not yet shown in this paper\",\n      \"pmids\": [\"12620103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"A Hint-W123Q substitution (corresponding to Gln127 in avian Asw) reduced k(cat)/K(m) for AMP-lysine hydrolysis 17-fold while increasing specificity for AMP-para-nitroaniline hydrolysis 160-fold, resulting in a 2,700-fold switch in enzyme specificity. This experimentally supports the hypothesis that Gln127 is a key determinant of Asw's dominant-negative effect on Hint activity.\",\n      \"method\": \"In vitro enzyme kinetics assay with mutant Hint-W123Q; development of novel substrate linking AMP-lysine modification reversal to aminomethylcoumarin release\",\n      \"journal\": \"Physiological genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro enzymatic reconstitution and mutagenesis with quantitative kinetic analysis; single lab but rigorous biochemical methods\",\n      \"pmids\": [\"15507519\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"C2ORF49 (Ashwin/ASW) is a vertebrate-specific subunit of the tRNA ligase complex (tRNA-LC) that acts as the nuclear import factor for the complex via a dual NLS, directing the FAM98B-containing form of tRNA-LC to the nucleus for pre-tRNA splicing; loss of ASW or its NLS causes cytoplasmic retention of the complex, impaired tRNA splicing, and 5' tRNA fragment accumulation, while the avian ortholog (also called ASW) is an inactive, dominant-negative Hint dimerization partner whose key catalytic residues have been specifically altered in evolution (notably Gln127 replacing Trp123), reducing Hint AMP-lysine hydrolase activity and implicated in avian sex determination.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"C2ORF49 (ASW/Ashwin) is a vertebrate-specific subunit of the tRNA splicing ligase complex (tRNA-LC), the multiprotein assembly built around the catalytic ligase RTCB together with FAM98B, DDX1, and CGI-99 [#0]. Within this complex, ASW functions as the dedicated nuclear import factor: it carries a dual nuclear localization signal, and disruption of this NLS causes cytoplasmic retention of the tRNA-LC, impaired pre-tRNA splicing, and accumulation of 5' tRNA fragments [#1]. ASW associates selectively with the FAM98B-containing form of the complex, directing that particular assembly to the nucleus for tRNA biogenesis, whereas FAM98A- and FAM98C-containing forms occupy distinct subcellular compartments [#1]. In birds, a W-chromosome-encoded ASW ortholog represents a divergent branch of the protein: it is a HIT (histidine triad) family relative that has lost its nucleotide-binding site through alteration of nearly all AMP-contacting residues, rendering it catalytically inactive, and is expressed female-specifically in embryonic gonads [#2, #3]. This avian ASW acts as a dominant-negative dimerization partner of the active Z-chromosome-encoded Hint, with the Gln127-for-Trp123 substitution being a key determinant: an equivalent Hint-W123Q substitution causes a 2,700-fold switch in enzyme specificity and a 17-fold reduction in AMP-lysine hydrolysis [#4, #5].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Establishing that ASW is a bona fide component of the human tRNA-LC placed an otherwise uncharacterized open reading frame within a defined RNA-processing machine alongside RTCB, FAM98B, DDX1, and CGI-99.\",\n      \"evidence\": \"Eukaryotic orthologous group analysis combined with functional characterization of the tRNA ligase complex\",\n      \"pmids\": [\"24870230\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define ASW's specific role within the complex\", \"No localization or import function assigned\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Assigning ASW as the nuclear import factor of the tRNA-LC answered why the complex reaches the nucleus, linking a dual NLS in ASW to pre-tRNA splicing and revealing FAM98 paralog-defined complex forms with distinct distributions.\",\n      \"evidence\": \"NLS mutagenesis, subcellular fractionation/live imaging, pre-tRNA splicing assays, co-immunoprecipitation, and depletion rescue with NLS-tagged RTCB (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.08.01.668163\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Structural basis of ASW-FAM98B selectivity not resolved\", \"Mechanism by which the dual NLS engages import machinery undefined\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identifying the avian W-chromosome ASW ortholog as a female-specific, gonad-expressed HIT-family relative conserved across birds raised the question of its role in sex determination.\",\n      \"evidence\": \"W-chromosome linkage mapping, expression analysis in chick embryonic gonads, and sequence analysis across 17 bird species\",\n      \"pmids\": [\"11180828\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic function not determined\", \"Causal role in sex determination not demonstrated\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showing that avian ASW has lost nearly all AMP-interacting residues established it as a catalytically dead member of the HIT family, distinguishing it from the active Z-encoded Hint.\",\n      \"evidence\": \"Sequence analysis and comparative biochemical classification of HIT superfamily members\",\n      \"pmids\": [\"12119013\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct enzymatic assay of ASW performed\", \"Functional consequence of inactivity not yet shown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Modeling an Asw-Hint heterodimer and rejecting positive cooperativity reframed avian ASW as a dominant-negative dimerization partner acting through the Gln127 substitution rather than via cooperative interference.\",\n      \"evidence\": \"Molecular modeling of the Asw-Hint heterodimer with experimental rejection of the positive cooperativity model via enzyme activity assays\",\n      \"pmids\": [\"12620103\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Heterodimer formation not biochemically confirmed\", \"Dominant-negative activity not directly demonstrated in this study\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Direct enzyme kinetics on Hint-W123Q (mimicking Asw Gln127) confirmed that this single residue is a key determinant of altered HIT activity, supporting the dominant-negative model.\",\n      \"evidence\": \"In vitro enzyme kinetics with mutant Hint-W123Q using a novel AMP-para-nitroaniline/AMP-lysine substrate system\",\n      \"pmids\": [\"15507519\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tested in Hint, not in native avian Asw protein\", \"Physiological consequence for sex determination not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the vertebrate tRNA-LC import function of C2ORF49 relates to the divergent avian sex-determination role of its W-chromosome ortholog remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying functional model linking the tRNA-LC role and the HIT/Hint dominant-negative role\", \"In vivo phenotype of ASW loss in vertebrates not characterized\", \"Causal mechanism in avian sex determination undemonstrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\"tRNA ligase complex (tRNA-LC)\"],\n    \"partners\": [\"RTCB\", \"FAM98B\", \"DDX1\", \"CGI-99\", \"HINT\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":3,"faith_pct":100.0}}