{"gene":"KICS2","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2017,"finding":"C12orf66 (KICS2) is a component of the KICSTOR complex (together with KPTN, ITFG2, and SZT2) that localizes to lysosomes and recruits GATOR1 (but not GATOR2) to the lysosomal surface, making it necessary for GATOR1 to interact with its substrates (Rag GTPases) and with GATOR2; loss of KICSTOR abolishes amino acid- or glucose-deprivation-induced inhibition of mTORC1.","method":"Co-immunoprecipitation, lysosomal fractionation/localization, genetic loss-of-function (siRNA/CRISPR knockout) with mTORC1 signaling readouts in cultured human cells and SZT2-knockout mice","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, subcellular fractionation, genetic KO with defined pathway phenotype, replicated across cell lines and in vivo mouse model","pmids":["28199306"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM structural analysis revealed that within KICSTOR, SZT2 forms a crescent-shaped scaffold with repetitive tandem units, binding the ITFG2-KPTN heterodimer and C12orf66 at its C terminus; GATOR1 binds the SZT2 N-terminal domain via NPRL3; SZT2 and C12orf66 preferentially interact with negatively charged lipids, which is required for lysosomal localization of KICSTOR; disruption of the GATOR1-KICSTOR interaction hyperactivates mTORC1 and mislocalizes TFE3 independently of nutrient status.","method":"Cryo-electron microscopy, computational modeling, biochemical binding assays (lipid-binding), mutagenesis with functional mTORC1 and TFE3 localization readouts","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure combined with mutagenesis, biochemical validation, and functional downstream readouts in a single rigorous study","pmids":["41198956"],"is_preprint":false},{"year":2022,"finding":"SAMTOR interacts with the GATOR1-KICSTOR complex (which includes C12orf66/KICS2) to regulate mTORC1 activity in response to SAM; crystal structures of Drosophila SAMTOR show the MTase domain contains the GATOR1-KICSTOR-binding site, and SAM binding causes conformational change in the helical domain that modulates this interaction.","method":"Crystal structure determination (apo and SAM-bound), mutagenesis with functional mTORC1 signaling assays","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — Tier 1 method (crystal structure + mutagenesis) but C12orf66/KICS2 is referenced as part of the KICSTOR complex rather than being directly interrogated; single lab, Drosophila SAMTOR structure","pmids":["35776786"],"is_preprint":false},{"year":2025,"finding":"FBXO2 directly interacts with KPTN (a KICSTOR subunit) via its F-box-associated domain and promotes K48- and K63-linked polyubiquitination of KPTN at lysines 49, 67, 262, and 265; this ubiquitination disrupts KPTN's interaction with ITFG2 and SZT2 while enhancing its interaction with C12orf66 (KICS2), thereby impairing KICSTOR's ability to recruit GATOR1 to the lysosomal surface and promoting mTORC1 activation.","method":"Co-immunoprecipitation, ubiquitination assays (K48/K63 linkage-specific), mutagenesis of KPTN lysine residues, loss-of-function with mTORC1 signaling readouts","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ubiquitination site mutagenesis, and pathway-level functional readouts; single lab but multiple orthogonal methods","pmids":["41401028"],"is_preprint":false},{"year":2021,"finding":"CRISPR/Cas9 knockout of C12orf66 (KICS2) in PIK3CA-mutated breast cancer cells confers resistance to PI3Kα inhibition by sustaining mTORC1 signaling, confirming its role as a negative regulator of mTORC1 in this context.","method":"Genome-wide CRISPR/Cas9 knockout screen with validation, mTORC1 signaling readouts, pharmacological rescue with mTOR inhibition","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with defined cellular phenotype (drug resistance and mTOR signaling) and pharmacological rescue; single lab","pmids":["33685991"],"is_preprint":false}],"current_model":"C12orf66/KICS2 is an integral subunit of the KICSTOR complex (with KPTN, ITFG2, and SZT2) that localizes to lysosomes via lipid interactions and acts as a scaffold to recruit the GATOR1 GTPase-activating complex to the lysosomal surface, where GATOR1 can then inhibit Rag GTPases and suppress mTORC1 in response to amino acid or glucose deprivation; within KICSTOR, C12orf66 binds the C-terminus of the SZT2 scaffold, and its interaction with KPTN is modulated by FBXO2-mediated ubiquitination of KPTN, providing a regulatory mechanism for mTORC1 activation."},"narrative":{"mechanistic_narrative":"KICS2 (C12orf66) is an integral subunit of the KICSTOR complex that couples nutrient availability to mTORC1 activity by recruiting the GATOR1 GTPase-activating complex to the lysosomal surface [PMID:28199306]. Within KICSTOR, KICS2 assembles with the SZT2 scaffold at its C terminus alongside the ITFG2-KPTN heterodimer, while GATOR1 docks onto the SZT2 N-terminal domain via NPRL3; both SZT2 and KICS2 bind negatively charged lipids, an interaction required for lysosomal localization of the complex [PMID:41198956]. By positioning GATOR1 at the lysosome, KICSTOR enables GATOR1 to act on Rag GTPases and thereby suppress mTORC1 during amino acid or glucose deprivation, so loss of the complex abolishes nutrient-deprivation-induced mTORC1 inhibition and mislocalizes the downstream transcription factor TFE3 [PMID:28199306, PMID:41198956]. Consistent with this negative-regulatory role, CRISPR knockout of KICS2 sustains mTORC1 signaling and confers resistance to PI3Kα inhibition in PIK3CA-mutant breast cancer cells [PMID:33685991]. The complex is itself regulated: FBXO2-mediated polyubiquitination of the KPTN subunit enhances KPTN's interaction with KICS2 while disrupting its association with ITFG2 and SZT2, impairing GATOR1 recruitment and promoting mTORC1 activation [PMID:41401028].","teleology":[{"year":2017,"claim":"Established that KICS2 is a bona fide subunit of a lysosomal complex (KICSTOR) whose function is to recruit GATOR1, defining how the nutrient-sensing machinery is physically organized at the lysosome.","evidence":"Co-IP, lysosomal fractionation, and CRISPR/siRNA loss-of-function with mTORC1 readouts in human cells and SZT2-knockout mice","pmids":["28199306"],"confidence":"High","gaps":["Did not resolve the structural arrangement of subunits","Specific lipid determinants of lysosomal targeting not defined"]},{"year":2021,"claim":"Demonstrated a cellular consequence of losing KICS2 — sustained mTORC1 signaling driving drug resistance — confirming its role as a negative mTORC1 regulator in a cancer context.","evidence":"Genome-wide CRISPR/Cas9 knockout screen with validation and pharmacological mTOR-inhibitor rescue in PIK3CA-mutant breast cancer cells","pmids":["33685991"],"confidence":"Medium","gaps":["Single cell-type context","Does not address KICS2's molecular contribution within the complex versus other subunits"]},{"year":2022,"claim":"Placed KICSTOR (including KICS2) downstream of an additional input by showing SAMTOR engages the GATOR1-KICSTOR complex to couple SAM levels to mTORC1.","evidence":"Apo and SAM-bound crystal structures of Drosophila SAMTOR with mutagenesis and mTORC1 signaling assays","pmids":["35776786"],"confidence":"Medium","gaps":["KICS2 referenced as a complex member but not directly interrogated","Drosophila structure; human KICS2-SAMTOR contacts undefined"]},{"year":2025,"claim":"Resolved the architecture of KICSTOR, showing how KICS2 binds the SZT2 C-terminus, how GATOR1 docks via NPRL3, and that lipid binding by SZT2 and KICS2 drives lysosomal localization.","evidence":"Cryo-EM structure with computational modeling, lipid-binding assays, and mutagenesis tied to mTORC1 and TFE3 localization readouts","pmids":["41198956"],"confidence":"High","gaps":["KICS2's specific lipid-binding residues not separately dissected from SZT2","No structure of the full assembly bound to active GATOR1 substrates"]},{"year":2025,"claim":"Identified a post-translational regulatory layer in which FBXO2 ubiquitination of KPTN remodels intra-complex interactions, including enhancing the KPTN-KICS2 association while weakening GATOR1 recruitment.","evidence":"Co-IP, linkage-specific ubiquitination assays, lysine-site mutagenesis, and loss-of-function with mTORC1 readouts","pmids":["41401028"],"confidence":"Medium","gaps":["Functional meaning of the strengthened KPTN-KICS2 interaction not fully resolved","Single lab; physiological triggers of FBXO2 activity undefined"]},{"year":null,"claim":"The distinct molecular contribution of KICS2 relative to the other KICSTOR subunits — and whether it carries any catalytic or signaling function beyond lipid-anchored scaffolding — remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No KICS2-specific separation-of-function studies","No KICS2 disease association established in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,4]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[0]}],"complexes":["KICSTOR"],"partners":["SZT2","KPTN","ITFG2","NPRL3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96MD2","full_name":"KICSTOR subunit 2","aliases":["KICSTOR complex protein C12orf66"],"length_aa":445,"mass_kda":50.4,"function":"As part of the KICSTOR complex functions in the amino acid-sensing branch of the TORC1 signaling pathway. Recruits, in an amino acid-independent manner, the GATOR1 complex to the lysosomal membranes and allows its interaction with GATOR2 and the RAG GTPases. Functions upstream of the RAG GTPases and is required to negatively regulate mTORC1 signaling in absence of amino acids. In absence of the KICSTOR complex mTORC1 is constitutively localized to the lysosome and activated. The KICSTOR complex is also probably involved in the regulation of mTORC1 by glucose","subcellular_location":"Lysosome membrane","url":"https://www.uniprot.org/uniprotkb/Q96MD2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KICS2","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/KICS2","total_profiled":1310},"omim":[{"mim_id":"621100","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 83; MRT83","url":"https://www.omim.org/entry/621100"},{"mim_id":"617420","title":"KICSTOR SUBUNIT 2; KICS2","url":"https://www.omim.org/entry/617420"},{"mim_id":"613639","title":"ADHESION G PROTEIN-COUPLED RECEPTOR D1; ADGRD1","url":"https://www.omim.org/entry/613639"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Lysosomes","reliability":"Approved"},{"location":"Cytokinetic bridge","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KICS2"},"hgnc":{"alias_symbol":["FLJ32549"],"prev_symbol":["C12orf66"]},"alphafold":{"accession":"Q96MD2","domains":[{"cath_id":"1.10.3450.30","chopping":"14-77_86-239_251-264","consensus_level":"medium","plddt":91.4174,"start":14,"end":264},{"cath_id":"3.30.450.240","chopping":"296-332_340-436","consensus_level":"high","plddt":92.3097,"start":296,"end":436}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96MD2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96MD2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96MD2-F1-predicted_aligned_error_v6.png","plddt_mean":88.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KICS2","jax_strain_url":"https://www.jax.org/strain/search?query=KICS2"},"sequence":{"accession":"Q96MD2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96MD2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96MD2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96MD2"}},"corpus_meta":[{"pmid":"28199306","id":"PMC_28199306","title":"KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28199306","citation_count":272,"is_preprint":false},{"pmid":"35776786","id":"PMC_35776786","title":"Molecular mechanism of S-adenosylmethionine sensing by SAMTOR in mTORC1 signaling.","date":"2022","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/35776786","citation_count":34,"is_preprint":false},{"pmid":"33685991","id":"PMC_33685991","title":"Genomic Alterations in PIK3CA-Mutated Breast Cancer Result in mTORC1 Activation and Limit the Sensitivity to PI3Kα Inhibitors.","date":"2021","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/33685991","citation_count":33,"is_preprint":false},{"pmid":"41198956","id":"PMC_41198956","title":"Architecture of the human KICSTOR and GATOR1-KICSTOR complexes.","date":"2025","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/41198956","citation_count":2,"is_preprint":false},{"pmid":"41401028","id":"PMC_41401028","title":"FBXO2-mediated KPTN ubiquitination promotes amino acid-dependent mTORC1 signaling and tumor growth.","date":"2025","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/41401028","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4679,"output_tokens":1653,"usd":0.019416,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8333,"output_tokens":2213,"usd":0.048495,"stage2_stop_reason":"end_turn"},"total_usd":0.067911,"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\": 2017,\n      \"finding\": \"C12orf66 (KICS2) is a component of the KICSTOR complex (together with KPTN, ITFG2, and SZT2) that localizes to lysosomes and recruits GATOR1 (but not GATOR2) to the lysosomal surface, making it necessary for GATOR1 to interact with its substrates (Rag GTPases) and with GATOR2; loss of KICSTOR abolishes amino acid- or glucose-deprivation-induced inhibition of mTORC1.\",\n      \"method\": \"Co-immunoprecipitation, lysosomal fractionation/localization, genetic loss-of-function (siRNA/CRISPR knockout) with mTORC1 signaling readouts in cultured human cells and SZT2-knockout mice\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, subcellular fractionation, genetic KO with defined pathway phenotype, replicated across cell lines and in vivo mouse model\",\n      \"pmids\": [\"28199306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structural analysis revealed that within KICSTOR, SZT2 forms a crescent-shaped scaffold with repetitive tandem units, binding the ITFG2-KPTN heterodimer and C12orf66 at its C terminus; GATOR1 binds the SZT2 N-terminal domain via NPRL3; SZT2 and C12orf66 preferentially interact with negatively charged lipids, which is required for lysosomal localization of KICSTOR; disruption of the GATOR1-KICSTOR interaction hyperactivates mTORC1 and mislocalizes TFE3 independently of nutrient status.\",\n      \"method\": \"Cryo-electron microscopy, computational modeling, biochemical binding assays (lipid-binding), mutagenesis with functional mTORC1 and TFE3 localization readouts\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure combined with mutagenesis, biochemical validation, and functional downstream readouts in a single rigorous study\",\n      \"pmids\": [\"41198956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SAMTOR interacts with the GATOR1-KICSTOR complex (which includes C12orf66/KICS2) to regulate mTORC1 activity in response to SAM; crystal structures of Drosophila SAMTOR show the MTase domain contains the GATOR1-KICSTOR-binding site, and SAM binding causes conformational change in the helical domain that modulates this interaction.\",\n      \"method\": \"Crystal structure determination (apo and SAM-bound), mutagenesis with functional mTORC1 signaling assays\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — Tier 1 method (crystal structure + mutagenesis) but C12orf66/KICS2 is referenced as part of the KICSTOR complex rather than being directly interrogated; single lab, Drosophila SAMTOR structure\",\n      \"pmids\": [\"35776786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FBXO2 directly interacts with KPTN (a KICSTOR subunit) via its F-box-associated domain and promotes K48- and K63-linked polyubiquitination of KPTN at lysines 49, 67, 262, and 265; this ubiquitination disrupts KPTN's interaction with ITFG2 and SZT2 while enhancing its interaction with C12orf66 (KICS2), thereby impairing KICSTOR's ability to recruit GATOR1 to the lysosomal surface and promoting mTORC1 activation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays (K48/K63 linkage-specific), mutagenesis of KPTN lysine residues, loss-of-function with mTORC1 signaling readouts\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ubiquitination site mutagenesis, and pathway-level functional readouts; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"41401028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CRISPR/Cas9 knockout of C12orf66 (KICS2) in PIK3CA-mutated breast cancer cells confers resistance to PI3Kα inhibition by sustaining mTORC1 signaling, confirming its role as a negative regulator of mTORC1 in this context.\",\n      \"method\": \"Genome-wide CRISPR/Cas9 knockout screen with validation, mTORC1 signaling readouts, pharmacological rescue with mTOR inhibition\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with defined cellular phenotype (drug resistance and mTOR signaling) and pharmacological rescue; single lab\",\n      \"pmids\": [\"33685991\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"C12orf66/KICS2 is an integral subunit of the KICSTOR complex (with KPTN, ITFG2, and SZT2) that localizes to lysosomes via lipid interactions and acts as a scaffold to recruit the GATOR1 GTPase-activating complex to the lysosomal surface, where GATOR1 can then inhibit Rag GTPases and suppress mTORC1 in response to amino acid or glucose deprivation; within KICSTOR, C12orf66 binds the C-terminus of the SZT2 scaffold, and its interaction with KPTN is modulated by FBXO2-mediated ubiquitination of KPTN, providing a regulatory mechanism for mTORC1 activation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KICS2 (C12orf66) is an integral subunit of the KICSTOR complex that couples nutrient availability to mTORC1 activity by recruiting the GATOR1 GTPase-activating complex to the lysosomal surface [#0]. Within KICSTOR, KICS2 assembles with the SZT2 scaffold at its C terminus alongside the ITFG2-KPTN heterodimer, while GATOR1 docks onto the SZT2 N-terminal domain via NPRL3; both SZT2 and KICS2 bind negatively charged lipids, an interaction required for lysosomal localization of the complex [#1]. By positioning GATOR1 at the lysosome, KICSTOR enables GATOR1 to act on Rag GTPases and thereby suppress mTORC1 during amino acid or glucose deprivation, so loss of the complex abolishes nutrient-deprivation-induced mTORC1 inhibition and mislocalizes the downstream transcription factor TFE3 [#0, #1]. Consistent with this negative-regulatory role, CRISPR knockout of KICS2 sustains mTORC1 signaling and confers resistance to PI3Kα inhibition in PIK3CA-mutant breast cancer cells [#4]. The complex is itself regulated: FBXO2-mediated polyubiquitination of the KPTN subunit enhances KPTN's interaction with KICS2 while disrupting its association with ITFG2 and SZT2, impairing GATOR1 recruitment and promoting mTORC1 activation [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"Established that KICS2 is a bona fide subunit of a lysosomal complex (KICSTOR) whose function is to recruit GATOR1, defining how the nutrient-sensing machinery is physically organized at the lysosome.\",\n      \"evidence\": \"Co-IP, lysosomal fractionation, and CRISPR/siRNA loss-of-function with mTORC1 readouts in human cells and SZT2-knockout mice\",\n      \"pmids\": [\"28199306\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural arrangement of subunits\", \"Specific lipid determinants of lysosomal targeting not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated a cellular consequence of losing KICS2 — sustained mTORC1 signaling driving drug resistance — confirming its role as a negative mTORC1 regulator in a cancer context.\",\n      \"evidence\": \"Genome-wide CRISPR/Cas9 knockout screen with validation and pharmacological mTOR-inhibitor rescue in PIK3CA-mutant breast cancer cells\",\n      \"pmids\": [\"33685991\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cell-type context\", \"Does not address KICS2's molecular contribution within the complex versus other subunits\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed KICSTOR (including KICS2) downstream of an additional input by showing SAMTOR engages the GATOR1-KICSTOR complex to couple SAM levels to mTORC1.\",\n      \"evidence\": \"Apo and SAM-bound crystal structures of Drosophila SAMTOR with mutagenesis and mTORC1 signaling assays\",\n      \"pmids\": [\"35776786\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"KICS2 referenced as a complex member but not directly interrogated\", \"Drosophila structure; human KICS2-SAMTOR contacts undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved the architecture of KICSTOR, showing how KICS2 binds the SZT2 C-terminus, how GATOR1 docks via NPRL3, and that lipid binding by SZT2 and KICS2 drives lysosomal localization.\",\n      \"evidence\": \"Cryo-EM structure with computational modeling, lipid-binding assays, and mutagenesis tied to mTORC1 and TFE3 localization readouts\",\n      \"pmids\": [\"41198956\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"KICS2's specific lipid-binding residues not separately dissected from SZT2\", \"No structure of the full assembly bound to active GATOR1 substrates\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified a post-translational regulatory layer in which FBXO2 ubiquitination of KPTN remodels intra-complex interactions, including enhancing the KPTN-KICS2 association while weakening GATOR1 recruitment.\",\n      \"evidence\": \"Co-IP, linkage-specific ubiquitination assays, lysine-site mutagenesis, and loss-of-function with mTORC1 readouts\",\n      \"pmids\": [\"41401028\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional meaning of the strengthened KPTN-KICS2 interaction not fully resolved\", \"Single lab; physiological triggers of FBXO2 activity undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The distinct molecular contribution of KICS2 relative to the other KICSTOR subunits — and whether it carries any catalytic or signaling function beyond lipid-anchored scaffolding — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No KICS2-specific separation-of-function studies\", \"No KICS2 disease association established in the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"KICSTOR\"],\n    \"partners\": [\"SZT2\", \"KPTN\", \"ITFG2\", \"NPRL3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}