{"gene":"SAMTOR","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":2017,"finding":"SAMTOR inhibits mTORC1 signaling by directly interacting with GATOR1 (the GAP for RagA/B). SAM binds directly to SAMTOR with a Kd of ~7 μM, disrupting the SAMTOR-GATOR1 complex. Methionine starvation reduces intracellular SAM below this Kd, promoting SAMTOR-GATOR1 association and thereby inhibiting mTORC1 in a SAMTOR-dependent manner.","method":"Co-immunoprecipitation, in vitro SAM-binding assay (radiolabeled SAM, scintillation counting), metabolomics, loss-of-function (SAMTOR knockdown/knockout) with mTORC1 signaling readouts, SAM-binding-deficient SAMTOR mutant rescue experiments","journal":"Science","confidence":"High","confidence_rationale":"Tier 1–2 — direct in vitro binding assay with Kd measurement, active-site mutagenesis, reciprocal Co-IP, and cellular epistasis; single rigorous paper with multiple orthogonal methods","pmids":["29123071"],"is_preprint":false},{"year":2022,"finding":"Crystal structures of Drosophila SAMTOR in apo and SAM-bound forms reveal an N-terminal helical domain and a C-terminal SAM-dependent methyltransferase (MTase) domain. SAM binds in the MTase domain, inducing a conformational change in the helical domain that acts as a molecular switch to modulate SAMTOR interaction with the GATOR1-KICSTOR complex. The GATOR1-KICSTOR-binding site is also located in the MTase domain.","method":"X-ray crystallography (apo and SAM-bound structures), mutagenesis of key residues validated by functional mTORC1 signaling assays","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 — crystal structures with functional mutagenesis validation; strong mechanistic insight into SAM-sensing conformational switch","pmids":["35776786"],"is_preprint":false},{"year":2026,"finding":"Cryo-EM structure of the KICSTOR-GATOR1-SAMTOR supercomplex reveals a ~60-nm crescent-shaped assembly. GATOR1 anchors to KICSTOR via an extensive interface; disruption of this interface impairs mTORC1 regulation. SAMTOR binds KICSTOR in a conformation incompatible with SAM binding, providing structural basis for how SAMTOR-KICSTOR association mediates methionine sensing. KICSTOR-GATOR1 forms a dimeric supercomplex that orients GATOR1 to favor the active GAP mode toward Rag GTPases while sterically restricting the inhibitory high-affinity Rag engagement mode.","method":"Cryo-EM structure determination, mutagenesis of KICSTOR-GATOR1 interface with mTORC1 functional assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — high-resolution cryo-EM structure of supercomplex with interface mutagenesis and functional validation","pmids":["41512879"],"is_preprint":false},{"year":2020,"finding":"MAT2A (methionine adenosyltransferase 2A) influences SAMTOR expression, and SAMTOR in turn activates mTORC1 and its downstream targets S6K1 and CAD, linking methionine/SAM levels to DNA synthesis via the SAMTOR/mTORC1/S6K1/CAD pathway during embryo implantation.","method":"siRNA knockdown of CBS and MAT2A in cell lines, transcriptome analysis, cell adhesion and proliferation assays, signaling pathway readouts (S6K1, CAD phosphorylation)","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 3 — genetic perturbation with signaling readouts in a single study; pathway placement supported but no direct SAMTOR binding assay","pmids":["33179842"],"is_preprint":false},{"year":2021,"finding":"SAMTOR overexpression in C2C12 muscle cells displaces mTORC1 from the lysosome, inhibiting mTORC1 signaling. Betaine increases SAM levels via the methionine cycle, disrupting the SAMTOR-GATOR1 complex and attenuating SAMTOR-mediated mTORC1 inhibition, thereby promoting lysosomal mTORC1 localization and activation.","method":"SAMTOR overexpression in C2C12 cells, immunofluorescence for mTORC1 lysosomal localization, UHPLC metabolomics for SAM quantification, mTORC1 signaling assays","journal":"Molecular nutrition & food research","confidence":"Medium","confidence_rationale":"Tier 2–3 — direct localization experiment with functional consequence, combined with metabolite measurement; single lab study","pmids":["34061446"],"is_preprint":false},{"year":2025,"finding":"SAMTOR directly interacts with phospho-AMPK (p-AMPK) and modulates cell fate under methionine-limited conditions in prostate cancer cells, establishing a mechanistic link between methionine sensing and AMPK-dependent metabolic stress signaling.","method":"Proteomic analysis, functional assays under methionine deprivation, co-interaction studies between SAMTOR and p-AMPK in PC3 cells","journal":"Biology","confidence":"Low","confidence_rationale":"Tier 3 — single lab, single study with limited mechanistic resolution of the SAMTOR-AMPK interaction","pmids":["40427696"],"is_preprint":false},{"year":2023,"finding":"Genetic knockdown of Drosophila SAMTOR (dSAMTOR) in vivo leads to upregulation of dTORC1 activity as measured by increased dp70S6K kinase activity in fly brain, confirming the inhibitory role of dSAMTOR on the dTORC1/dp70S6K signaling axis in a Drosophila model.","method":"GAL4/UAS-mediated tissue-specific RNAi knockdown of dSAMTOR, PamGene kinase activity profiling, survival and negative geotaxis behavioral assays","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — clean in vivo genetic KD with defined kinase activity readout (dp70S6K); ortholog validated as functionally consistent with mammalian SAMTOR","pmids":["37298625"],"is_preprint":false},{"year":2025,"finding":"A protocol using purified SAMTOR protein and radiolabeled SAM in scintillation binding assays was established and validated for quantitative determination of SAM-SAMTOR binding affinity (Kd), confirming direct physical binding and providing a generalizable method for nutrient-sensor Kd measurement.","method":"Protein purification, radioactive ligand binding assay, scintillation counting, mathematical Kd calculation","journal":"Methods in molecular biology","confidence":"Medium","confidence_rationale":"Tier 1 — direct in vitro binding assay with quantitative Kd; confirms and extends the original binding discovery with a reproducible protocol","pmids":["39992509"],"is_preprint":false}],"current_model":"SAMTOR is an intracellular SAM (S-adenosylmethionine) sensor that directly binds SAM (~7 μM Kd) through its methyltransferase-fold domain; when methionine/SAM levels are low, SAM dissociates from SAMTOR, allowing its N-terminal helical domain to adopt a conformation that promotes interaction with the KICSTOR-GATOR1 complex at the lysosome, thereby stimulating GATOR1's GAP activity toward RagA/B, inactivating Rag GTPases, and suppressing mTORC1 kinase activity and lysosomal localization; high SAM disrupts the SAMTOR-KICSTOR-GATOR1 supercomplex, releasing this inhibition and allowing mTORC1 activation."},"narrative":{"teleology":[{"year":2017,"claim":"Identification of SAMTOR as a direct SAM-binding protein that inhibits mTORC1 through GATOR1 interaction established the missing molecular link between methionine/SAM levels and Rag GTPase–dependent mTORC1 regulation.","evidence":"In vitro radiolabeled SAM binding (Kd ~7 µM), reciprocal co-IP, SAMTOR knockout/knockdown with mTORC1 readouts, and SAM-binding-deficient mutant rescue in human cells","pmids":["29123071"],"confidence":"High","gaps":["No structural information on how SAM binding alters SAMTOR conformation","Whether SAMTOR contacts KICSTOR or only GATOR1 was unresolved","The stoichiometry and architecture of the full signaling complex at the lysosome remained unknown"]},{"year":2020,"claim":"Placing MAT2A upstream of SAMTOR and connecting SAMTOR to S6K1/CAD phosphorylation extended the pathway from methionine metabolism through SAMTOR/mTORC1 to nucleotide synthesis during embryo implantation.","evidence":"siRNA knockdown of MAT2A and CBS with downstream SAMTOR expression and mTORC1/S6K1/CAD signaling readouts in cell lines","pmids":["33179842"],"confidence":"Medium","gaps":["No direct SAMTOR binding assay performed; pathway placement inferred from knockdown epistasis","In vivo relevance to implantation not tested with SAMTOR-specific perturbation"]},{"year":2021,"claim":"Demonstrating that SAMTOR overexpression displaces mTORC1 from the lysosome, and that betaine-driven SAM elevation reverses this, provided direct evidence that SAMTOR controls mTORC1 through lysosomal recruitment dynamics.","evidence":"SAMTOR overexpression in C2C12 cells with immunofluorescence for mTOR–lysosome colocalization and UHPLC SAM quantification","pmids":["34061446"],"confidence":"Medium","gaps":["Overexpression system; endogenous SAMTOR levels not manipulated","Betaine effects on SAM are indirect and could affect other pathways"]},{"year":2022,"claim":"Crystal structures of apo and SAM-bound Drosophila SAMTOR revealed how SAM occupancy in the MTase domain allosterically rearranges the N-terminal helical domain, providing the structural mechanism for the SAM-sensing conformational switch.","evidence":"X-ray crystallography of apo and SAM-bound dSAMTOR, with mutagenesis of key residues validated by mTORC1 signaling assays","pmids":["35776786"],"confidence":"High","gaps":["Structures were of the Drosophila ortholog; human SAMTOR structure not yet determined","The GATOR1/KICSTOR-binding interface was mapped to the MTase domain but not visualized in a complex structure"]},{"year":2023,"claim":"In vivo knockdown of Drosophila SAMTOR confirmed conservation of its inhibitory role on TORC1/S6K signaling, extending the mechanism beyond cultured mammalian cells.","evidence":"GAL4/UAS-driven tissue-specific RNAi in Drosophila brain with PamGene kinase activity profiling of dp70S6K","pmids":["37298625"],"confidence":"Medium","gaps":["Behavioral and survival phenotypes observed but mechanistic connection to SAM levels not directly tested in flies","Whether fly SAMTOR also requires KICSTOR for GATOR1 interaction was not examined"]},{"year":2026,"claim":"Cryo-EM of the full KICSTOR–GATOR1–SAMTOR supercomplex resolved the architectural basis for methionine sensing: SAMTOR binds KICSTOR in a SAM-incompatible conformation, and the dimeric supercomplex positions GATOR1 to favor its GAP-active mode toward Rag GTPases.","evidence":"Cryo-EM structure determination of the ~60-nm supercomplex, interface mutagenesis with mTORC1 functional assays","pmids":["41512879"],"confidence":"High","gaps":["Dynamic transition between SAM-bound (free) and apo (KICSTOR-engaged) states not captured in time-resolved experiments","Whether additional regulatory inputs modulate the supercomplex assembly is unknown","The structural basis for how GATOR1 GAP activity is catalytically stimulated by KICSTOR engagement has not been resolved at atomic detail"]},{"year":null,"claim":"Whether SAMTOR has additional mTORC1-independent signaling roles — such as the reported AMPK interaction — and how the SAMTOR-dependent SAM-sensing mechanism integrates with other amino acid sensing branches in vivo remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["The reported SAMTOR–phospho-AMPK interaction lacks mechanistic resolution and independent confirmation","No in vivo SAMTOR knockout phenotype in mammals has been reported","Whether SAMTOR SAM-binding Kd is tuned by post-translational modifications is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[0,1,2]},{"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":[2,4]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,2,4]}],"complexes":["KICSTOR-GATOR1-SAMTOR supercomplex"],"partners":["GATOR1","KICSTOR","DEPDC5","SZT2"],"other_free_text":[]},"mechanistic_narrative":"SAMTOR functions as an intracellular S-adenosylmethionine (SAM) sensor that couples methionine availability to mTORC1 signaling. SAMTOR possesses an inactive methyltransferase-fold domain that directly binds SAM with a Kd of ~7 µM; when intracellular SAM falls below this threshold during methionine starvation, SAM dissociates, triggering a conformational change in SAMTOR's N-terminal helical domain that promotes its association with the KICSTOR–GATOR1 complex at the lysosome, thereby stimulating GATOR1 GAP activity toward RagA/B GTPases and suppressing mTORC1 lysosomal recruitment and activation [PMID:29123071, PMID:35776786]. Cryo-EM of the KICSTOR–GATOR1–SAMTOR supercomplex reveals that SAMTOR binds KICSTOR in a conformation incompatible with SAM occupancy, and the dimeric supercomplex orients GATOR1 to favor its active GAP mode while sterically restricting inhibitory high-affinity Rag engagement [PMID:41512879]. This SAM-sensing mechanism is conserved in Drosophila, where SAMTOR knockdown elevates TORC1/S6K signaling in vivo [PMID:37298625]."},"prefetch_data":{"uniprot":{"accession":"Q1RMZ1","full_name":"S-adenosylmethionine sensor upstream of mTORC1","aliases":["Probable methyltransferase BMT2 homolog"],"length_aa":405,"mass_kda":46.3,"function":"S-adenosyl-L-methionine-binding protein that acts as an inhibitor of mTORC1 signaling via interaction with the GATOR1 and KICSTOR complexes (PubMed:29123071, PubMed:35776786). Acts as a sensor of S-adenosyl-L-methionine to signal methionine sufficiency to mTORC1: in presence of methionine, binds S-adenosyl-L-methionine, leading to disrupt interaction with the GATOR1 and KICSTOR complexes and promote mTORC1 signaling (PubMed:29123071, PubMed:35776786). Upon methionine starvation, S-adenosyl-L-methionine levels are reduced, thereby promoting the association with GATOR1 and KICSTOR, leading to inhibit mTORC1 signaling (PubMed:29123071, PubMed:35776786). Probably also acts as a S-adenosyl-L-methionine-dependent methyltransferase (Potential)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q1RMZ1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SAMTOR","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/SAMTOR","total_profiled":1310},"omim":[{"mim_id":"617855","title":"BASE METHYLTRANSFERASE OF 25S rRNA 2 HOMOLOG; BMT2","url":"https://www.omim.org/entry/617855"},{"mim_id":"617421","title":"INTEGRIN-ALPHA FG-GAP REPEAT-CONTAINING PROTEIN 2; ITFG2","url":"https://www.omim.org/entry/617421"},{"mim_id":"617420","title":"KICSTOR SUBUNIT 2; KICS2","url":"https://www.omim.org/entry/617420"},{"mim_id":"615620","title":"KAPTIN; KPTN","url":"https://www.omim.org/entry/615620"},{"mim_id":"615463","title":"SZT2 SUBUNIT OF KICSTOR COMPLEX; SZT2","url":"https://www.omim.org/entry/615463"}],"hpa":{"profiled":true,"resolved_as":"BMT2","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/BMT2"},"hgnc":{"alias_symbol":["DKFZp762M126","FLJ31818","SAMTOR"],"prev_symbol":["BMT2","C7orf60"]},"alphafold":{"accession":"Q1RMZ1","domains":[{"cath_id":"3.40.50.150","chopping":"96-117_162-346","consensus_level":"high","plddt":92.8375,"start":96,"end":346},{"cath_id":"1.10.287","chopping":"27-86","consensus_level":"medium","plddt":91.3198,"start":27,"end":86}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q1RMZ1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q1RMZ1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q1RMZ1-F1-predicted_aligned_error_v6.png","plddt_mean":79.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SAMTOR","jax_strain_url":"https://www.jax.org/strain/search?query=SAMTOR"},"sequence":{"accession":"Q1RMZ1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q1RMZ1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q1RMZ1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q1RMZ1"}},"corpus_meta":[{"pmid":"29123071","id":"PMC_29123071","title":"SAMTOR 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= 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2017,\n      \"finding\": \"SAMTOR inhibits mTORC1 signaling by directly interacting with GATOR1 (the GAP for RagA/B). SAM binds directly to SAMTOR with a Kd of ~7 μM, disrupting the SAMTOR-GATOR1 complex. Methionine starvation reduces intracellular SAM below this Kd, promoting SAMTOR-GATOR1 association and thereby inhibiting mTORC1 in a SAMTOR-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, in vitro SAM-binding assay (radiolabeled SAM, scintillation counting), metabolomics, loss-of-function (SAMTOR knockdown/knockout) with mTORC1 signaling readouts, SAM-binding-deficient SAMTOR mutant rescue experiments\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct in vitro binding assay with Kd measurement, active-site mutagenesis, reciprocal Co-IP, and cellular epistasis; single rigorous paper with multiple orthogonal methods\",\n      \"pmids\": [\"29123071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Crystal structures of Drosophila SAMTOR in apo and SAM-bound forms reveal an N-terminal helical domain and a C-terminal SAM-dependent methyltransferase (MTase) domain. SAM binds in the MTase domain, inducing a conformational change in the helical domain that acts as a molecular switch to modulate SAMTOR interaction with the GATOR1-KICSTOR complex. The GATOR1-KICSTOR-binding site is also located in the MTase domain.\",\n      \"method\": \"X-ray crystallography (apo and SAM-bound structures), mutagenesis of key residues validated by functional mTORC1 signaling assays\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structures with functional mutagenesis validation; strong mechanistic insight into SAM-sensing conformational switch\",\n      \"pmids\": [\"35776786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Cryo-EM structure of the KICSTOR-GATOR1-SAMTOR supercomplex reveals a ~60-nm crescent-shaped assembly. GATOR1 anchors to KICSTOR via an extensive interface; disruption of this interface impairs mTORC1 regulation. SAMTOR binds KICSTOR in a conformation incompatible with SAM binding, providing structural basis for how SAMTOR-KICSTOR association mediates methionine sensing. KICSTOR-GATOR1 forms a dimeric supercomplex that orients GATOR1 to favor the active GAP mode toward Rag GTPases while sterically restricting the inhibitory high-affinity Rag engagement mode.\",\n      \"method\": \"Cryo-EM structure determination, mutagenesis of KICSTOR-GATOR1 interface with mTORC1 functional assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution cryo-EM structure of supercomplex with interface mutagenesis and functional validation\",\n      \"pmids\": [\"41512879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MAT2A (methionine adenosyltransferase 2A) influences SAMTOR expression, and SAMTOR in turn activates mTORC1 and its downstream targets S6K1 and CAD, linking methionine/SAM levels to DNA synthesis via the SAMTOR/mTORC1/S6K1/CAD pathway during embryo implantation.\",\n      \"method\": \"siRNA knockdown of CBS and MAT2A in cell lines, transcriptome analysis, cell adhesion and proliferation assays, signaling pathway readouts (S6K1, CAD phosphorylation)\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — genetic perturbation with signaling readouts in a single study; pathway placement supported but no direct SAMTOR binding assay\",\n      \"pmids\": [\"33179842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SAMTOR overexpression in C2C12 muscle cells displaces mTORC1 from the lysosome, inhibiting mTORC1 signaling. Betaine increases SAM levels via the methionine cycle, disrupting the SAMTOR-GATOR1 complex and attenuating SAMTOR-mediated mTORC1 inhibition, thereby promoting lysosomal mTORC1 localization and activation.\",\n      \"method\": \"SAMTOR overexpression in C2C12 cells, immunofluorescence for mTORC1 lysosomal localization, UHPLC metabolomics for SAM quantification, mTORC1 signaling assays\",\n      \"journal\": \"Molecular nutrition & food research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — direct localization experiment with functional consequence, combined with metabolite measurement; single lab study\",\n      \"pmids\": [\"34061446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SAMTOR directly interacts with phospho-AMPK (p-AMPK) and modulates cell fate under methionine-limited conditions in prostate cancer cells, establishing a mechanistic link between methionine sensing and AMPK-dependent metabolic stress signaling.\",\n      \"method\": \"Proteomic analysis, functional assays under methionine deprivation, co-interaction studies between SAMTOR and p-AMPK in PC3 cells\",\n      \"journal\": \"Biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single study with limited mechanistic resolution of the SAMTOR-AMPK interaction\",\n      \"pmids\": [\"40427696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Genetic knockdown of Drosophila SAMTOR (dSAMTOR) in vivo leads to upregulation of dTORC1 activity as measured by increased dp70S6K kinase activity in fly brain, confirming the inhibitory role of dSAMTOR on the dTORC1/dp70S6K signaling axis in a Drosophila model.\",\n      \"method\": \"GAL4/UAS-mediated tissue-specific RNAi knockdown of dSAMTOR, PamGene kinase activity profiling, survival and negative geotaxis behavioral assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean in vivo genetic KD with defined kinase activity readout (dp70S6K); ortholog validated as functionally consistent with mammalian SAMTOR\",\n      \"pmids\": [\"37298625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A protocol using purified SAMTOR protein and radiolabeled SAM in scintillation binding assays was established and validated for quantitative determination of SAM-SAMTOR binding affinity (Kd), confirming direct physical binding and providing a generalizable method for nutrient-sensor Kd measurement.\",\n      \"method\": \"Protein purification, radioactive ligand binding assay, scintillation counting, mathematical Kd calculation\",\n      \"journal\": \"Methods in molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro binding assay with quantitative Kd; confirms and extends the original binding discovery with a reproducible protocol\",\n      \"pmids\": [\"39992509\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SAMTOR is an intracellular SAM (S-adenosylmethionine) sensor that directly binds SAM (~7 μM Kd) through its methyltransferase-fold domain; when methionine/SAM levels are low, SAM dissociates from SAMTOR, allowing its N-terminal helical domain to adopt a conformation that promotes interaction with the KICSTOR-GATOR1 complex at the lysosome, thereby stimulating GATOR1's GAP activity toward RagA/B, inactivating Rag GTPases, and suppressing mTORC1 kinase activity and lysosomal localization; high SAM disrupts the SAMTOR-KICSTOR-GATOR1 supercomplex, releasing this inhibition and allowing mTORC1 activation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SAMTOR functions as an intracellular S-adenosylmethionine (SAM) sensor that couples methionine availability to mTORC1 signaling. SAMTOR possesses an inactive methyltransferase-fold domain that directly binds SAM with a Kd of ~7 µM; when intracellular SAM falls below this threshold during methionine starvation, SAM dissociates, triggering a conformational change in SAMTOR's N-terminal helical domain that promotes its association with the KICSTOR–GATOR1 complex at the lysosome, thereby stimulating GATOR1 GAP activity toward RagA/B GTPases and suppressing mTORC1 lysosomal recruitment and activation [PMID:29123071, PMID:35776786]. Cryo-EM of the KICSTOR–GATOR1–SAMTOR supercomplex reveals that SAMTOR binds KICSTOR in a conformation incompatible with SAM occupancy, and the dimeric supercomplex orients GATOR1 to favor its active GAP mode while sterically restricting inhibitory high-affinity Rag engagement [PMID:41512879]. This SAM-sensing mechanism is conserved in Drosophila, where SAMTOR knockdown elevates TORC1/S6K signaling in vivo [PMID:37298625].\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"Identification of SAMTOR as a direct SAM-binding protein that inhibits mTORC1 through GATOR1 interaction established the missing molecular link between methionine/SAM levels and Rag GTPase–dependent mTORC1 regulation.\",\n      \"evidence\": \"In vitro radiolabeled SAM binding (Kd ~7 µM), reciprocal co-IP, SAMTOR knockout/knockdown with mTORC1 readouts, and SAM-binding-deficient mutant rescue in human cells\",\n      \"pmids\": [\"29123071\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural information on how SAM binding alters SAMTOR conformation\",\n        \"Whether SAMTOR contacts KICSTOR or only GATOR1 was unresolved\",\n        \"The stoichiometry and architecture of the full signaling complex at the lysosome remained unknown\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placing MAT2A upstream of SAMTOR and connecting SAMTOR to S6K1/CAD phosphorylation extended the pathway from methionine metabolism through SAMTOR/mTORC1 to nucleotide synthesis during embryo implantation.\",\n      \"evidence\": \"siRNA knockdown of MAT2A and CBS with downstream SAMTOR expression and mTORC1/S6K1/CAD signaling readouts in cell lines\",\n      \"pmids\": [\"33179842\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct SAMTOR binding assay performed; pathway placement inferred from knockdown epistasis\",\n        \"In vivo relevance to implantation not tested with SAMTOR-specific perturbation\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrating that SAMTOR overexpression displaces mTORC1 from the lysosome, and that betaine-driven SAM elevation reverses this, provided direct evidence that SAMTOR controls mTORC1 through lysosomal recruitment dynamics.\",\n      \"evidence\": \"SAMTOR overexpression in C2C12 cells with immunofluorescence for mTOR–lysosome colocalization and UHPLC SAM quantification\",\n      \"pmids\": [\"34061446\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Overexpression system; endogenous SAMTOR levels not manipulated\",\n        \"Betaine effects on SAM are indirect and could affect other pathways\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Crystal structures of apo and SAM-bound Drosophila SAMTOR revealed how SAM occupancy in the MTase domain allosterically rearranges the N-terminal helical domain, providing the structural mechanism for the SAM-sensing conformational switch.\",\n      \"evidence\": \"X-ray crystallography of apo and SAM-bound dSAMTOR, with mutagenesis of key residues validated by mTORC1 signaling assays\",\n      \"pmids\": [\"35776786\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structures were of the Drosophila ortholog; human SAMTOR structure not yet determined\",\n        \"The GATOR1/KICSTOR-binding interface was mapped to the MTase domain but not visualized in a complex structure\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"In vivo knockdown of Drosophila SAMTOR confirmed conservation of its inhibitory role on TORC1/S6K signaling, extending the mechanism beyond cultured mammalian cells.\",\n      \"evidence\": \"GAL4/UAS-driven tissue-specific RNAi in Drosophila brain with PamGene kinase activity profiling of dp70S6K\",\n      \"pmids\": [\"37298625\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Behavioral and survival phenotypes observed but mechanistic connection to SAM levels not directly tested in flies\",\n        \"Whether fly SAMTOR also requires KICSTOR for GATOR1 interaction was not examined\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Cryo-EM of the full KICSTOR–GATOR1–SAMTOR supercomplex resolved the architectural basis for methionine sensing: SAMTOR binds KICSTOR in a SAM-incompatible conformation, and the dimeric supercomplex positions GATOR1 to favor its GAP-active mode toward Rag GTPases.\",\n      \"evidence\": \"Cryo-EM structure determination of the ~60-nm supercomplex, interface mutagenesis with mTORC1 functional assays\",\n      \"pmids\": [\"41512879\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Dynamic transition between SAM-bound (free) and apo (KICSTOR-engaged) states not captured in time-resolved experiments\",\n        \"Whether additional regulatory inputs modulate the supercomplex assembly is unknown\",\n        \"The structural basis for how GATOR1 GAP activity is catalytically stimulated by KICSTOR engagement has not been resolved at atomic detail\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether SAMTOR has additional mTORC1-independent signaling roles — such as the reported AMPK interaction — and how the SAMTOR-dependent SAM-sensing mechanism integrates with other amino acid sensing branches in vivo remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"The reported SAMTOR–phospho-AMPK interaction lacks mechanistic resolution and independent confirmation\",\n        \"No in vivo SAMTOR knockout phenotype in mammals has been reported\",\n        \"Whether SAMTOR SAM-binding Kd is tuned by post-translational modifications is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 2, 4]}\n    ],\n    \"complexes\": [\n      \"KICSTOR-GATOR1-SAMTOR supercomplex\"\n    ],\n    \"partners\": [\n      \"GATOR1\",\n      \"KICSTOR\",\n      \"DEPDC5\",\n      \"SZT2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}