{"gene":"WDR24","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2013,"finding":"WDR24 is a subunit of the GATOR2 complex (along with Mios, WDR59, Seh1L, and Sec13), which positively regulates mTORC1 signaling upstream of the Rag GTPases. Inhibition of WDR24/GATOR2 suppresses mTORC1 signaling, and epistasis analysis shows GATOR2 negatively regulates GATOR1 (DEPDC5/Nprl2/Nprl3), which itself has GAP activity toward RagA/RagB.","method":"RNAi knockdown, epistasis analysis, Co-immunoprecipitation, mTORC1 activity assays (phospho-S6K1)","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, epistasis, multiple orthogonal methods, replicated across multiple subsequent studies","pmids":["23723238"],"is_preprint":false},{"year":2022,"finding":"Cryo-EM structure of human GATOR2 revealed a ~1.1 MDa two-fold symmetric cage-like architecture with an octagonal scaffold containing two WDR24, four MIOS, and two WDR59 subunits circularized via non-catalytic RING domains and α-solenoids. WDR24 contributes WD40 β-propeller dimers that mediate interactions with SESN2, CASTOR1, and GATOR1. SEH1L and SEC13 stabilize the complex via β-propeller blade donation.","method":"Cryo-electron microscopy, biochemical reconstitution","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure with functional validation, published in high-impact journal, replicated by subsequent structural studies","pmids":["35831510"],"is_preprint":false},{"year":2016,"finding":"Drosophila Wdr24 (ortholog of WDR24) is required for robust TORC1 activation and cellular growth in vivo. Additionally, Wdr24 has a TORC1-independent function in regulating lysosome dynamics and autophagic flux. In wdr24-/- knockout HeLa cells, Wdr24 promotes lysosome acidification and autophagic flux.","method":"Null allele characterization, genetic epistasis with GATOR1 components, biochemical fractionation, cell biological assays, HeLa knockout cell line","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — combination of genetic, biochemical, and cell biological methods in both Drosophila and mammalian cells; null allele used","pmids":["27166823"],"is_preprint":false},{"year":2020,"finding":"WDR24 is the GATOR2 component essential for the Sestrin2-GATOR2 interaction. Deleting or silencing WDR24 completely ablates Sestrin2-induced AKT activation. WDR24 bridges Sestrin2 to the GATOR2 complex, which in turn interacts with mTORC2 through WDR59 to induce AKT activation.","method":"Co-immunoprecipitation, siRNA knockdown, WDR24 deletion, in vitro kinase assay, AKT activation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, genetic deletion, in vitro kinase assay; multiple orthogonal methods in single study","pmids":["31915252"],"is_preprint":false},{"year":2023,"finding":"AMPK directly phosphorylates WDR24 at Ser155 upon glucose deprivation, disrupting the integrity of the GATOR2 complex and suppressing mTORC1 activation. Phosphomimetic Wdr24-S155D knock-in mice exhibit early embryonic lethality and reduced mTORC1 activity, while phospho-deficient Wdr24-S155A knock-in mice are more resistant to fasting and display elevated mTORC1 activity.","method":"In vitro kinase assay, phosphomimetic and phospho-deficient knock-in mice, Co-immunoprecipitation, mTORC1 activity assays","journal":"Nature metabolism","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay with site-specific mutagenesis, confirmed in vivo by knock-in mouse models with phenotypic readouts","pmids":["36732624"],"is_preprint":false},{"year":2023,"finding":"PRMT1, activated by CDK5-mediated phosphorylation at S307 in response to amino acids, translocates from nucleus to cytoplasm/lysosome and methylates WDR24, an essential GATOR2 component, to activate the mTORC1 pathway. Disruption of the CDK5-PRMT1-WDR24 axis suppresses mTORC1 signaling, HCC cell proliferation, and xenograft tumor growth.","method":"Co-immunoprecipitation, arginine methylation assays, subcellular fractionation/localization, siRNA knockdown, xenograft tumor models","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, in vitro methylation assay, and functional knockdown in single lab; specific methylation site on WDR24 not fully mapped in abstract","pmids":["36995937"],"is_preprint":false},{"year":2023,"finding":"ILF3 tethers the GATOR complexes (including WDR24-containing GATOR2) to lysosomes to control mTORC1. Adding a lysosome-targeting sequence to WDR24 directly bypasses the requirement for ILF3 in amino-acid-dependent mTORC1 signalling, demonstrating that lysosomal localization of GATOR2 via WDR24 is functionally sufficient.","method":"Genome-wide CRISPR/Cas9 screen, lysosome-targeting sequence rescue experiment, mTORC1 activity assays (pS6 FACS)","journal":"Nature cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic rescue experiment with lysosome-targeting WDR24 construct, supported by CRISPR screen; single lab","pmids":["37037994"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM structures of GATOR2 bound to Sestrin2 or CASTOR1 revealed that Sestrin2 interacts with the WDR24-Seh1L subcomplex, inducing conformational changes, while CASTOR1 engages Mios WD40 β-propellers. Binding of either sensor restricts the dynamic WDR24 β-propeller, a domain essential for nutrient-dependent mTORC1 activation. Amino acid binding triggers structural rearrangements in sensors that cause their dissociation from GATOR2.","method":"Cryo-electron microscopy, site-directed mutagenesis of binding interfaces, functional mTORC1 signaling assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structures with mutagenesis of interface residues validated functionally; replicated by contemporaneous Cell Reports structural study","pmids":["40836086"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM structures of GATOR2 in three inhibitory states (CASTOR1-bound, Sestrin2-bound, dual-bound) confirmed that Sestrin2 interacts with the WDR24-Seh1L subcomplex while CASTOR1 engages Mios WD40 β-propellers. HDX-MS revealed dynamic motions in apo-GATOR2 and its sensor complexes.","method":"Cryo-electron microscopy, hydrogen-deuterium exchange mass spectrometry (HDX-MS)","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — independent cryo-EM structural study with HDX-MS, corroborating contemporaneous Nature structural paper","pmids":["40742811"],"is_preprint":false},{"year":2024,"finding":"D-serine produced by Mycobacterium tuberculosis interacts with WDR24 and inhibits mTORC1 activation in CD8+ T cells, decreasing T-bet expression and reducing IFN-γ production.","method":"Metabolomic, proteomic and genetic approaches; direct interaction assay between D-serine and WDR24; mTORC1 activity assays in CD8+ T cells","journal":"Nature microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction between D-serine and WDR24 with functional mTORC1 readout; single lab, abstract does not fully detail binding assay method","pmids":["38806671"],"is_preprint":false},{"year":2022,"finding":"In mammalian HeLa cells, Wdr59 (another GATOR2 component) prevents the proteolytic destruction of GATOR2 proteins Mio and Wdr24. In Wdr59 knockout HeLa cells, reduced Wdr24 protein levels correlated with reduced TORC1 activity, which was restored along with Wdr24 levels upon proteasome inhibition.","method":"Wdr59 knockout HeLa cells, proteasome inhibition rescue, immunoblot for Wdr24 protein levels, mTORC1 activity assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with proteasome inhibitor rescue, multiple readouts; single lab","pmids":["36577058"],"is_preprint":false},{"year":2025,"finding":"Radiation-induced AMPK activation phosphorylates WDR24, which promotes NPRL2 dissociation from the GATOR1 complex and facilitates NPRL2 nuclear translocation. Nuclear NPRL2 then inactivates E3 ubiquitin ligases HERC2 and RNF8 to enhance DNA repair. AMPK inhibition blocks this cascade, impairing DNA repair and radiosensitizing CRC cells.","method":"Co-immunoprecipitation, nuclear fractionation, AMPK inhibition, in vitro and in vivo radiosensitization assays","journal":"Acta pharmaceutica Sinica. B","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway established by Co-IP and fractionation with functional rescue; single lab, single study","pmids":["41584340"],"is_preprint":false}],"current_model":"WDR24 is a core scaffold subunit of the GATOR2 complex (with MIOS, WDR59, SEH1L, SEC13) that forms a ~1.1 MDa cage-like structure at the lysosome; its WD40 β-propeller domain engages the leucine sensor Sestrin2 (and is restricted by sensor binding), mediates GATOR2 interactions with GATOR1 and mTORC2, and is subject to activating arginine methylation by PRMT1 and inhibitory phosphorylation at Ser155 by AMPK, thereby serving as a convergence point for amino acid and glucose signals that tune mTORC1 activity."},"narrative":{"mechanistic_narrative":"WDR24 is a core scaffold subunit of the GATOR2 complex that acts as a positive regulator of amino acid signaling to mTORC1 upstream of the Rag GTPases, where GATOR2 negatively regulates the GATOR1 GAP complex (DEPDC5/NPRL2/NPRL3) toward RagA/RagB [PMID:23723238]. Within the ~1.1 MDa two-fold symmetric, cage-like GATOR2 architecture, WDR24 contributes WD40 β-propeller dimers to an octagonal scaffold built from WDR24, MIOS, and WDR59 circularized through non-catalytic RING domains and α-solenoids, with SEH1L and SEC13 stabilizing the assembly by β-propeller blade donation [PMID:35831510]. The WDR24 β-propeller is the docking site for the leucine sensor Sestrin2, engaging it via the WDR24-SEH1L subcomplex; sensor binding restricts the dynamic WDR24 propeller that is essential for nutrient-dependent mTORC1 activation, and amino-acid-induced conformational changes drive sensor dissociation to relieve this restraint [PMID:40836086, PMID:40742811]. WDR24 is also the GATOR2 component required for the Sestrin2-GATOR2 interaction that couples to mTORC2 through WDR59 to activate AKT [PMID:31915252], and lysosomal localization of GATOR2 imparted through WDR24 is sufficient for amino-acid-dependent mTORC1 signaling [PMID:37037994]. The complex serves as a signal convergence point regulated by post-translational modification: PRMT1-mediated arginine methylation activates the WDR24/mTORC1 axis in response to amino acids [PMID:36995937], whereas AMPK directly phosphorylates WDR24 at Ser155 upon glucose deprivation to disrupt GATOR2 integrity and suppress mTORC1, a regulatory event essential in vivo as phosphomimetic knock-in mice are embryonic-lethal [PMID:36732624]. WDR24 protein stability within the complex depends on WDR59, which protects it from proteasomal degradation [PMID:36577058]. Beyond mTORC1, WDR24 has a TORC1-independent role in lysosome acidification and autophagic flux [PMID:27166823].","teleology":[{"year":2013,"claim":"Established WDR24's foundational identity as a GATOR2 subunit and placed it in the amino-acid-sensing hierarchy upstream of mTORC1, defining the double-negative GATOR2→GATOR1→Rag logic.","evidence":"RNAi knockdown, reciprocal Co-IP, and epistasis with phospho-S6K1 mTORC1 readouts","pmids":["23723238"],"confidence":"High","gaps":["Mechanism by which GATOR2 represses GATOR1 not resolved","Structural basis of subunit assembly unknown at this stage","How amino acid signals are received not addressed"]},{"year":2016,"claim":"Demonstrated that WDR24 is required for TORC1 activation in vivo while also carrying a TORC1-independent function in lysosome dynamics, separating its growth-signaling and organelle roles.","evidence":"Drosophila null allele characterization, genetic epistasis with GATOR1, and HeLa knockout cell lysosome/autophagy assays","pmids":["27166823"],"confidence":"High","gaps":["Molecular basis of the TORC1-independent lysosomal function unknown","Direct effector of lysosome acidification not identified"]},{"year":2020,"claim":"Identified WDR24 as the obligate bridge linking the leucine sensor Sestrin2 to GATOR2 and, via WDR59, to mTORC2/AKT, extending GATOR2 signaling beyond mTORC1.","evidence":"Co-IP, siRNA knockdown, WDR24 deletion, and in vitro kinase/AKT activation assays","pmids":["31915252"],"confidence":"High","gaps":["Structural interface of Sestrin2-WDR24 not defined here","Direct vs scaffold role of WDR24 in mTORC2 activation unclear"]},{"year":2022,"claim":"Resolved the GATOR2 cage architecture, showing WDR24 contributes WD40 β-propeller dimers that form the interaction platform for SESN2, CASTOR1, and GATOR1.","evidence":"Cryo-EM structure with biochemical reconstitution","pmids":["35831510"],"confidence":"High","gaps":["Static structure does not capture sensor-induced conformational dynamics","Mechanism of GATOR1 regulation by GATOR2 still structurally unresolved"]},{"year":2022,"claim":"Showed WDR24 protein abundance within GATOR2 is maintained by WDR59, which shields it from proteasomal turnover, linking complex assembly to subunit stability and TORC1 output.","evidence":"WDR59 knockout HeLa cells with proteasome-inhibitor rescue and WDR24 immunoblot","pmids":["36577058"],"confidence":"Medium","gaps":["E3 ligase targeting WDR24 not identified","Single lab, single cell system"]},{"year":2023,"claim":"Defined AMPK as a direct glucose-sensitive negative regulator that phosphorylates WDR24 Ser155 to disassemble GATOR2 and suppress mTORC1, validated by knock-in mouse phenotypes.","evidence":"In vitro kinase assay with site-specific mutagenesis and S155D/S155A knock-in mice with mTORC1 and fasting phenotypes","pmids":["36732624"],"confidence":"High","gaps":["Structural consequence of Ser155 phosphorylation on the cage not visualized","How disassembly is reversed upon glucose restoration unknown"]},{"year":2023,"claim":"Identified arginine methylation of WDR24 by PRMT1, driven by a CDK5-PRMT1 amino-acid-responsive axis, as an activating modification promoting mTORC1 and tumor growth.","evidence":"Co-IP, arginine methylation assays, subcellular fractionation, knockdown, and HCC xenograft models","pmids":["36995937"],"confidence":"Medium","gaps":["Specific WDR24 methylation site not mapped","Mechanistic link between methylation and complex activation undefined"]},{"year":2023,"claim":"Established that lysosomal recruitment of GATOR2, mediated through WDR24, is the rate-limiting step for amino-acid-dependent mTORC1, with ILF3 as the tether.","evidence":"Genome-wide CRISPR screen and lysosome-targeting WDR24 construct rescue with pS6 FACS","pmids":["37037994"],"confidence":"Medium","gaps":["Direct WDR24-ILF3 contact not structurally defined","Regulation of the tethering step by nutrients unclear"]},{"year":2024,"claim":"Revealed WDR24 as a target of pathogen-derived metabolite signaling, where M. tuberculosis D-serine binds WDR24 to suppress mTORC1 in CD8+ T cells and dampen IFN-γ.","evidence":"Metabolomic/proteomic/genetic approaches with direct D-serine–WDR24 interaction assay and mTORC1 readouts in CD8+ T cells","pmids":["38806671"],"confidence":"Medium","gaps":["Binding site of D-serine on WDR24 not mapped","Structural mechanism of inhibition unknown","Single lab"]},{"year":2025,"claim":"Cryo-EM and HDX-MS of sensor-bound GATOR2 pinpointed the WDR24-SEH1L subcomplex as the Sestrin2 interface and showed sensor binding restricts the dynamic WDR24 β-propeller required for activation.","evidence":"Cryo-EM structures in apo and inhibitory states, interface mutagenesis, and HDX-MS with functional mTORC1 assays","pmids":["40836086","40742811"],"confidence":"High","gaps":["Coupling of WDR24 propeller dynamics to downstream GATOR1 regulation not fully resolved","Active (sensor-free) signaling conformation not captured"]},{"year":2025,"claim":"Extended WDR24 signaling into the DNA damage response, showing radiation-induced AMPK phosphorylation of WDR24 drives NPRL2 release and nuclear translocation to enhance DNA repair.","evidence":"Co-IP, nuclear fractionation, AMPK inhibition, and radiosensitization assays in CRC cells in vitro and in vivo","pmids":["41584340"],"confidence":"Medium","gaps":["Phosphorylation site mediating this effect not specified","Direct WDR24 contribution vs upstream GATOR2 disassembly not separated","Single study"]},{"year":null,"claim":"How the multiple WDR24 post-translational and metabolite inputs (Ser155 phosphorylation, PRMT1 methylation, D-serine binding) are structurally integrated on the GATOR2 cage to set a graded mTORC1 output remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of a modified WDR24 within GATOR2","Quantitative hierarchy among amino acid, glucose, and metabolite signals undefined","Mechanism converting WDR24 propeller dynamics into GATOR1 inhibition unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[7,9]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,4]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[1,6]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,4]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[2]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[4,7]}],"complexes":["GATOR2"],"partners":["MIOS","WDR59","SEH1L","SEC13","SESN2","PRMT1","ILF3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96S15","full_name":"GATOR2 complex protein WDR24","aliases":["WD repeat-containing protein 24"],"length_aa":790,"mass_kda":88.2,"function":"Catalytic component of the GATOR2 complex, a multiprotein complex that acts as an activator of the amino acid-sensing branch of the mTORC1 signaling pathway (PubMed:23723238, PubMed:26449471, PubMed:26586190, PubMed:27487210, PubMed:35831510, PubMed:36528027, PubMed:36732624). The GATOR2 complex indirectly activates mTORC1 through the inhibition of the GATOR1 subcomplex (PubMed:23723238, PubMed:26449471, PubMed:26586190, PubMed:27487210, PubMed:35831510, PubMed:36528027, PubMed:36732624). GATOR2 probably acts as an E3 ubiquitin-protein ligase toward GATOR1 (PubMed:36528027, PubMed:36732624). In the presence of abundant amino acids, the GATOR2 complex mediates ubiquitination of the NPRL2 core component of the GATOR1 complex, leading to GATOR1 inactivation (PubMed:36528027, PubMed:36732624). In the absence of amino acids, GATOR2 is inhibited, activating the GATOR1 complex (PubMed:26449471, PubMed:26586190, PubMed:27487210). In addition to its role in regulation of the mTORC1 complex, promotes the acidification of lysosomes and facilitates autophagic flux (PubMed:27166823). Within the GATOR2 complex, WDR24 constitutes the catalytic subunit that mediates 'Lys-6'-linked ubiquitination of NPRL2 (PubMed:36528027, PubMed:36732624)","subcellular_location":"Lysosome membrane","url":"https://www.uniprot.org/uniprotkb/Q96S15/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/WDR24","classification":"Common Essential","n_dependent_lines":771,"n_total_lines":1208,"dependency_fraction":0.6382450331125827},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPZB","stoichiometry":0.2},{"gene":"HSP90B1","stoichiometry":0.2},{"gene":"SEC13","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/WDR24","total_profiled":1310},"omim":[{"mim_id":"620307","title":"WD REPEAT-CONTAINING PROTEIN 24; WDR24","url":"https://www.omim.org/entry/620307"},{"mim_id":"617418","title":"WD REPEAT-CONTAINING PROTEIN 59; WDR59","url":"https://www.omim.org/entry/617418"},{"mim_id":"617034","title":"CELLULAR ARGININE SENSOR FOR MTORC1 PROTEIN 1; CASTOR1","url":"https://www.omim.org/entry/617034"},{"mim_id":"615359","title":"MEIOSIS REGULATOR FOR OOCYTE DEVELOPMENT; MIOS","url":"https://www.omim.org/entry/615359"},{"mim_id":"614191","title":"DEP DOMAIN-CONTAINING PROTEIN 5; DEPDC5","url":"https://www.omim.org/entry/614191"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/WDR24"},"hgnc":{"alias_symbol":["DKFZp434F054","JFP7"],"prev_symbol":["C16orf21"]},"alphafold":{"accession":"Q96S15","domains":[{"cath_id":"-","chopping":"719-790","consensus_level":"medium","plddt":80.9688,"start":719,"end":790},{"cath_id":"2.130.10.10","chopping":"20-335","consensus_level":"high","plddt":92.9057,"start":20,"end":335},{"cath_id":"-","chopping":"341-399","consensus_level":"high","plddt":62.4473,"start":341,"end":399},{"cath_id":"-","chopping":"408-456_630-713","consensus_level":"medium","plddt":91.689,"start":408,"end":713}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96S15","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96S15-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96S15-F1-predicted_aligned_error_v6.png","plddt_mean":73.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=WDR24","jax_strain_url":"https://www.jax.org/strain/search?query=WDR24"},"sequence":{"accession":"Q96S15","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96S15.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96S15/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96S15"}},"corpus_meta":[{"pmid":"23723238","id":"PMC_23723238","title":"A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1.","date":"2013","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/23723238","citation_count":888,"is_preprint":false},{"pmid":"27173016","id":"PMC_27173016","title":"Involvement of GATOR complex genes in familial focal epilepsies and focal cortical dysplasia.","date":"2016","source":"Epilepsia","url":"https://pubmed.ncbi.nlm.nih.gov/27173016","citation_count":140,"is_preprint":false},{"pmid":"35831510","id":"PMC_35831510","title":"Structure of the nutrient-sensing hub GATOR2.","date":"2022","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/35831510","citation_count":71,"is_preprint":false},{"pmid":"36410445","id":"PMC_36410445","title":"Dysregulated Amino Acid Sensing Drives Colorectal Cancer Growth and Metabolic Reprogramming Leading to Chemoresistance.","date":"2022","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/36410445","citation_count":62,"is_preprint":false},{"pmid":"31915252","id":"PMC_31915252","title":"The GATOR2-mTORC2 axis mediates Sestrin2-induced AKT Ser/Thr kinase activation.","date":"2020","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31915252","citation_count":52,"is_preprint":false},{"pmid":"27166823","id":"PMC_27166823","title":"The GATOR2 Component Wdr24 Regulates TORC1 Activity and Lysosome Function.","date":"2016","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27166823","citation_count":45,"is_preprint":false},{"pmid":"36732624","id":"PMC_36732624","title":"AMPK-dependent phosphorylation of the GATOR2 component WDR24 suppresses glucose-mediated mTORC1 activation.","date":"2023","source":"Nature metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/36732624","citation_count":38,"is_preprint":false},{"pmid":"37037994","id":"PMC_37037994","title":"Genome-wide CRISPR screens identify ILF3 as a mediator of mTORC1-dependent amino acid sensing.","date":"2023","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/37037994","citation_count":30,"is_preprint":false},{"pmid":"31780813","id":"PMC_31780813","title":"Pre-clinical activity of combined LSD1 and mTORC1 inhibition in MLL-translocated acute myeloid leukaemia.","date":"2019","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/31780813","citation_count":29,"is_preprint":false},{"pmid":"36995937","id":"PMC_36995937","title":"CDK5-PRMT1-WDR24 signaling cascade promotes mTORC1 signaling and tumor growth.","date":"2023","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/36995937","citation_count":28,"is_preprint":false},{"pmid":"38806671","id":"PMC_38806671","title":"Mycobacterium tuberculosis produces D-serine under hypoxia to limit CD8+ T cell-dependent immunity in mice.","date":"2024","source":"Nature microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/38806671","citation_count":28,"is_preprint":false},{"pmid":"40836086","id":"PMC_40836086","title":"Structural basis for the dynamic regulation of mTORC1 by amino acids.","date":"2025","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/40836086","citation_count":11,"is_preprint":false},{"pmid":"40742811","id":"PMC_40742811","title":"Cryo-EM structures of amino acid sensors bound to the human GATOR2 complex.","date":"2025","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/40742811","citation_count":9,"is_preprint":false},{"pmid":"38372438","id":"PMC_38372438","title":"New insights into GATOR2-dependent interactions and its conformational changes in amino acid sensing.","date":"2024","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/38372438","citation_count":7,"is_preprint":false},{"pmid":"36577058","id":"PMC_36577058","title":"Wdr59 promotes or inhibits TORC1 activity depending on cellular context.","date":"2022","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/36577058","citation_count":7,"is_preprint":false},{"pmid":"36716920","id":"PMC_36716920","title":"Identification of Epigenetically Regulated Genes Distinguishing Intracranial from Extracranial Melanoma Metastases.","date":"2023","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/36716920","citation_count":4,"is_preprint":false},{"pmid":"39145096","id":"PMC_39145096","title":"Identifying key pathogenic mechanisms and potential intervention targets for recurrence after laryngeal cancer treatment through bioinformatics screening.","date":"2024","source":"Translational cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/39145096","citation_count":1,"is_preprint":false},{"pmid":"41584340","id":"PMC_41584340","title":"Radiation-induced nuclear translocation of NPRL2 hijacks E3 ubiquitin ligases to enhance DNA repair via the AMPK/WDR24 axis, contributing to CRC radioresistance.","date":"2025","source":"Acta pharmaceutica Sinica. B","url":"https://pubmed.ncbi.nlm.nih.gov/41584340","citation_count":0,"is_preprint":false},{"pmid":"38193103","id":"PMC_38193103","title":"The Challenge of Somatic Variants in Focal Cortical Dysplasia.","date":"2023","source":"Innovations in clinical neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/38193103","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12370,"output_tokens":3231,"usd":0.042787,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10623,"output_tokens":4016,"usd":0.076758,"stage2_stop_reason":"end_turn"},"total_usd":0.119545,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"WDR24 is a subunit of the GATOR2 complex (along with Mios, WDR59, Seh1L, and Sec13), which positively regulates mTORC1 signaling upstream of the Rag GTPases. Inhibition of WDR24/GATOR2 suppresses mTORC1 signaling, and epistasis analysis shows GATOR2 negatively regulates GATOR1 (DEPDC5/Nprl2/Nprl3), which itself has GAP activity toward RagA/RagB.\",\n      \"method\": \"RNAi knockdown, epistasis analysis, Co-immunoprecipitation, mTORC1 activity assays (phospho-S6K1)\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, epistasis, multiple orthogonal methods, replicated across multiple subsequent studies\",\n      \"pmids\": [\"23723238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cryo-EM structure of human GATOR2 revealed a ~1.1 MDa two-fold symmetric cage-like architecture with an octagonal scaffold containing two WDR24, four MIOS, and two WDR59 subunits circularized via non-catalytic RING domains and α-solenoids. WDR24 contributes WD40 β-propeller dimers that mediate interactions with SESN2, CASTOR1, and GATOR1. SEH1L and SEC13 stabilize the complex via β-propeller blade donation.\",\n      \"method\": \"Cryo-electron microscopy, biochemical reconstitution\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure with functional validation, published in high-impact journal, replicated by subsequent structural studies\",\n      \"pmids\": [\"35831510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Drosophila Wdr24 (ortholog of WDR24) is required for robust TORC1 activation and cellular growth in vivo. Additionally, Wdr24 has a TORC1-independent function in regulating lysosome dynamics and autophagic flux. In wdr24-/- knockout HeLa cells, Wdr24 promotes lysosome acidification and autophagic flux.\",\n      \"method\": \"Null allele characterization, genetic epistasis with GATOR1 components, biochemical fractionation, cell biological assays, HeLa knockout cell line\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — combination of genetic, biochemical, and cell biological methods in both Drosophila and mammalian cells; null allele used\",\n      \"pmids\": [\"27166823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"WDR24 is the GATOR2 component essential for the Sestrin2-GATOR2 interaction. Deleting or silencing WDR24 completely ablates Sestrin2-induced AKT activation. WDR24 bridges Sestrin2 to the GATOR2 complex, which in turn interacts with mTORC2 through WDR59 to induce AKT activation.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, WDR24 deletion, in vitro kinase assay, AKT activation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, genetic deletion, in vitro kinase assay; multiple orthogonal methods in single study\",\n      \"pmids\": [\"31915252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"AMPK directly phosphorylates WDR24 at Ser155 upon glucose deprivation, disrupting the integrity of the GATOR2 complex and suppressing mTORC1 activation. Phosphomimetic Wdr24-S155D knock-in mice exhibit early embryonic lethality and reduced mTORC1 activity, while phospho-deficient Wdr24-S155A knock-in mice are more resistant to fasting and display elevated mTORC1 activity.\",\n      \"method\": \"In vitro kinase assay, phosphomimetic and phospho-deficient knock-in mice, Co-immunoprecipitation, mTORC1 activity assays\",\n      \"journal\": \"Nature metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay with site-specific mutagenesis, confirmed in vivo by knock-in mouse models with phenotypic readouts\",\n      \"pmids\": [\"36732624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PRMT1, activated by CDK5-mediated phosphorylation at S307 in response to amino acids, translocates from nucleus to cytoplasm/lysosome and methylates WDR24, an essential GATOR2 component, to activate the mTORC1 pathway. Disruption of the CDK5-PRMT1-WDR24 axis suppresses mTORC1 signaling, HCC cell proliferation, and xenograft tumor growth.\",\n      \"method\": \"Co-immunoprecipitation, arginine methylation assays, subcellular fractionation/localization, siRNA knockdown, xenograft tumor models\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, in vitro methylation assay, and functional knockdown in single lab; specific methylation site on WDR24 not fully mapped in abstract\",\n      \"pmids\": [\"36995937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ILF3 tethers the GATOR complexes (including WDR24-containing GATOR2) to lysosomes to control mTORC1. Adding a lysosome-targeting sequence to WDR24 directly bypasses the requirement for ILF3 in amino-acid-dependent mTORC1 signalling, demonstrating that lysosomal localization of GATOR2 via WDR24 is functionally sufficient.\",\n      \"method\": \"Genome-wide CRISPR/Cas9 screen, lysosome-targeting sequence rescue experiment, mTORC1 activity assays (pS6 FACS)\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic rescue experiment with lysosome-targeting WDR24 construct, supported by CRISPR screen; single lab\",\n      \"pmids\": [\"37037994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structures of GATOR2 bound to Sestrin2 or CASTOR1 revealed that Sestrin2 interacts with the WDR24-Seh1L subcomplex, inducing conformational changes, while CASTOR1 engages Mios WD40 β-propellers. Binding of either sensor restricts the dynamic WDR24 β-propeller, a domain essential for nutrient-dependent mTORC1 activation. Amino acid binding triggers structural rearrangements in sensors that cause their dissociation from GATOR2.\",\n      \"method\": \"Cryo-electron microscopy, site-directed mutagenesis of binding interfaces, functional mTORC1 signaling assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structures with mutagenesis of interface residues validated functionally; replicated by contemporaneous Cell Reports structural study\",\n      \"pmids\": [\"40836086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structures of GATOR2 in three inhibitory states (CASTOR1-bound, Sestrin2-bound, dual-bound) confirmed that Sestrin2 interacts with the WDR24-Seh1L subcomplex while CASTOR1 engages Mios WD40 β-propellers. HDX-MS revealed dynamic motions in apo-GATOR2 and its sensor complexes.\",\n      \"method\": \"Cryo-electron microscopy, hydrogen-deuterium exchange mass spectrometry (HDX-MS)\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — independent cryo-EM structural study with HDX-MS, corroborating contemporaneous Nature structural paper\",\n      \"pmids\": [\"40742811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"D-serine produced by Mycobacterium tuberculosis interacts with WDR24 and inhibits mTORC1 activation in CD8+ T cells, decreasing T-bet expression and reducing IFN-γ production.\",\n      \"method\": \"Metabolomic, proteomic and genetic approaches; direct interaction assay between D-serine and WDR24; mTORC1 activity assays in CD8+ T cells\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction between D-serine and WDR24 with functional mTORC1 readout; single lab, abstract does not fully detail binding assay method\",\n      \"pmids\": [\"38806671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In mammalian HeLa cells, Wdr59 (another GATOR2 component) prevents the proteolytic destruction of GATOR2 proteins Mio and Wdr24. In Wdr59 knockout HeLa cells, reduced Wdr24 protein levels correlated with reduced TORC1 activity, which was restored along with Wdr24 levels upon proteasome inhibition.\",\n      \"method\": \"Wdr59 knockout HeLa cells, proteasome inhibition rescue, immunoblot for Wdr24 protein levels, mTORC1 activity assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with proteasome inhibitor rescue, multiple readouts; single lab\",\n      \"pmids\": [\"36577058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Radiation-induced AMPK activation phosphorylates WDR24, which promotes NPRL2 dissociation from the GATOR1 complex and facilitates NPRL2 nuclear translocation. Nuclear NPRL2 then inactivates E3 ubiquitin ligases HERC2 and RNF8 to enhance DNA repair. AMPK inhibition blocks this cascade, impairing DNA repair and radiosensitizing CRC cells.\",\n      \"method\": \"Co-immunoprecipitation, nuclear fractionation, AMPK inhibition, in vitro and in vivo radiosensitization assays\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway established by Co-IP and fractionation with functional rescue; single lab, single study\",\n      \"pmids\": [\"41584340\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"WDR24 is a core scaffold subunit of the GATOR2 complex (with MIOS, WDR59, SEH1L, SEC13) that forms a ~1.1 MDa cage-like structure at the lysosome; its WD40 β-propeller domain engages the leucine sensor Sestrin2 (and is restricted by sensor binding), mediates GATOR2 interactions with GATOR1 and mTORC2, and is subject to activating arginine methylation by PRMT1 and inhibitory phosphorylation at Ser155 by AMPK, thereby serving as a convergence point for amino acid and glucose signals that tune mTORC1 activity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"WDR24 is a core scaffold subunit of the GATOR2 complex that acts as a positive regulator of amino acid signaling to mTORC1 upstream of the Rag GTPases, where GATOR2 negatively regulates the GATOR1 GAP complex (DEPDC5/NPRL2/NPRL3) toward RagA/RagB [#0]. Within the ~1.1 MDa two-fold symmetric, cage-like GATOR2 architecture, WDR24 contributes WD40 \\u03b2-propeller dimers to an octagonal scaffold built from WDR24, MIOS, and WDR59 circularized through non-catalytic RING domains and \\u03b1-solenoids, with SEH1L and SEC13 stabilizing the assembly by \\u03b2-propeller blade donation [#1]. The WDR24 \\u03b2-propeller is the docking site for the leucine sensor Sestrin2, engaging it via the WDR24-SEH1L subcomplex; sensor binding restricts the dynamic WDR24 propeller that is essential for nutrient-dependent mTORC1 activation, and amino-acid-induced conformational changes drive sensor dissociation to relieve this restraint [#7, #8]. WDR24 is also the GATOR2 component required for the Sestrin2-GATOR2 interaction that couples to mTORC2 through WDR59 to activate AKT [#3], and lysosomal localization of GATOR2 imparted through WDR24 is sufficient for amino-acid-dependent mTORC1 signaling [#6]. The complex serves as a signal convergence point regulated by post-translational modification: PRMT1-mediated arginine methylation activates the WDR24/mTORC1 axis in response to amino acids [#5], whereas AMPK directly phosphorylates WDR24 at Ser155 upon glucose deprivation to disrupt GATOR2 integrity and suppress mTORC1, a regulatory event essential in vivo as phosphomimetic knock-in mice are embryonic-lethal [#4]. WDR24 protein stability within the complex depends on WDR59, which protects it from proteasomal degradation [#10]. Beyond mTORC1, WDR24 has a TORC1-independent role in lysosome acidification and autophagic flux [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established WDR24's foundational identity as a GATOR2 subunit and placed it in the amino-acid-sensing hierarchy upstream of mTORC1, defining the double-negative GATOR2\\u2192GATOR1\\u2192Rag logic.\",\n      \"evidence\": \"RNAi knockdown, reciprocal Co-IP, and epistasis with phospho-S6K1 mTORC1 readouts\",\n      \"pmids\": [\"23723238\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which GATOR2 represses GATOR1 not resolved\", \"Structural basis of subunit assembly unknown at this stage\", \"How amino acid signals are received not addressed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated that WDR24 is required for TORC1 activation in vivo while also carrying a TORC1-independent function in lysosome dynamics, separating its growth-signaling and organelle roles.\",\n      \"evidence\": \"Drosophila null allele characterization, genetic epistasis with GATOR1, and HeLa knockout cell lysosome/autophagy assays\",\n      \"pmids\": [\"27166823\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of the TORC1-independent lysosomal function unknown\", \"Direct effector of lysosome acidification not identified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified WDR24 as the obligate bridge linking the leucine sensor Sestrin2 to GATOR2 and, via WDR59, to mTORC2/AKT, extending GATOR2 signaling beyond mTORC1.\",\n      \"evidence\": \"Co-IP, siRNA knockdown, WDR24 deletion, and in vitro kinase/AKT activation assays\",\n      \"pmids\": [\"31915252\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural interface of Sestrin2-WDR24 not defined here\", \"Direct vs scaffold role of WDR24 in mTORC2 activation unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved the GATOR2 cage architecture, showing WDR24 contributes WD40 \\u03b2-propeller dimers that form the interaction platform for SESN2, CASTOR1, and GATOR1.\",\n      \"evidence\": \"Cryo-EM structure with biochemical reconstitution\",\n      \"pmids\": [\"35831510\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Static structure does not capture sensor-induced conformational dynamics\", \"Mechanism of GATOR1 regulation by GATOR2 still structurally unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed WDR24 protein abundance within GATOR2 is maintained by WDR59, which shields it from proteasomal turnover, linking complex assembly to subunit stability and TORC1 output.\",\n      \"evidence\": \"WDR59 knockout HeLa cells with proteasome-inhibitor rescue and WDR24 immunoblot\",\n      \"pmids\": [\"36577058\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase targeting WDR24 not identified\", \"Single lab, single cell system\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined AMPK as a direct glucose-sensitive negative regulator that phosphorylates WDR24 Ser155 to disassemble GATOR2 and suppress mTORC1, validated by knock-in mouse phenotypes.\",\n      \"evidence\": \"In vitro kinase assay with site-specific mutagenesis and S155D/S155A knock-in mice with mTORC1 and fasting phenotypes\",\n      \"pmids\": [\"36732624\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural consequence of Ser155 phosphorylation on the cage not visualized\", \"How disassembly is reversed upon glucose restoration unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified arginine methylation of WDR24 by PRMT1, driven by a CDK5-PRMT1 amino-acid-responsive axis, as an activating modification promoting mTORC1 and tumor growth.\",\n      \"evidence\": \"Co-IP, arginine methylation assays, subcellular fractionation, knockdown, and HCC xenograft models\",\n      \"pmids\": [\"36995937\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific WDR24 methylation site not mapped\", \"Mechanistic link between methylation and complex activation undefined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established that lysosomal recruitment of GATOR2, mediated through WDR24, is the rate-limiting step for amino-acid-dependent mTORC1, with ILF3 as the tether.\",\n      \"evidence\": \"Genome-wide CRISPR screen and lysosome-targeting WDR24 construct rescue with pS6 FACS\",\n      \"pmids\": [\"37037994\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct WDR24-ILF3 contact not structurally defined\", \"Regulation of the tethering step by nutrients unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed WDR24 as a target of pathogen-derived metabolite signaling, where M. tuberculosis D-serine binds WDR24 to suppress mTORC1 in CD8+ T cells and dampen IFN-\\u03b3.\",\n      \"evidence\": \"Metabolomic/proteomic/genetic approaches with direct D-serine\\u2013WDR24 interaction assay and mTORC1 readouts in CD8+ T cells\",\n      \"pmids\": [\"38806671\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding site of D-serine on WDR24 not mapped\", \"Structural mechanism of inhibition unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Cryo-EM and HDX-MS of sensor-bound GATOR2 pinpointed the WDR24-SEH1L subcomplex as the Sestrin2 interface and showed sensor binding restricts the dynamic WDR24 \\u03b2-propeller required for activation.\",\n      \"evidence\": \"Cryo-EM structures in apo and inhibitory states, interface mutagenesis, and HDX-MS with functional mTORC1 assays\",\n      \"pmids\": [\"40836086\", \"40742811\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coupling of WDR24 propeller dynamics to downstream GATOR1 regulation not fully resolved\", \"Active (sensor-free) signaling conformation not captured\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended WDR24 signaling into the DNA damage response, showing radiation-induced AMPK phosphorylation of WDR24 drives NPRL2 release and nuclear translocation to enhance DNA repair.\",\n      \"evidence\": \"Co-IP, nuclear fractionation, AMPK inhibition, and radiosensitization assays in CRC cells in vitro and in vivo\",\n      \"pmids\": [\"41584340\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphorylation site mediating this effect not specified\", \"Direct WDR24 contribution vs upstream GATOR2 disassembly not separated\", \"Single study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple WDR24 post-translational and metabolite inputs (Ser155 phosphorylation, PRMT1 methylation, D-serine binding) are structurally integrated on the GATOR2 cage to set a graded mTORC1 output remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of a modified WDR24 within GATOR2\", \"Quantitative hierarchy among amino acid, glucose, and metabolite signals undefined\", \"Mechanism converting WDR24 propeller dynamics into GATOR1 inhibition unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [7, 9]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [4, 7]}\n    ],\n    \"complexes\": [\"GATOR2\"],\n    \"partners\": [\"MIOS\", \"WDR59\", \"SEH1L\", \"SEC13\", \"SESN2\", \"PRMT1\", \"ILF3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}