{"gene":"MAP6","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":1996,"finding":"STOP (MAP6) is a 100.5-kDa microtubule-associated protein with two distinct repeat domains; it binds microtubules and Ca2+-calmodulin in vitro, and when expressed in cells reconstitutes microtubule cold stability, nocodazole resistance, and tubulin detyrosination, demonstrating its role as a microtubule stabilizer.","method":"cDNA cloning, in vitro binding assays, transfection of STOP cDNA into cells lacking cold-stable microtubules with phenotypic readouts","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of microtubule stabilization plus cellular expression with multiple functional readouts (cold stability, nocodazole resistance, detyrosination)","pmids":["8700896"],"is_preprint":false},{"year":1998,"finding":"The mouse STOP gene (Mtap6) is a single-copy gene on chromosome 7 composed of 4 exons spanning 67 kb, with transcription initiating at multiple sites in a TATA-less promoter region, encoding a 906-amino-acid protein with 91% identity to rat brain STOP.","method":"Genomic cloning, Southern blotting, chromosomal mapping, transcription start site mapping","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct genomic characterization using molecular cloning and mapping, single lab","pmids":["9501006"],"is_preprint":false},{"year":2003,"finding":"STOP proteins are calmodulin-binding, calmodulin-regulated microtubule-associated proteins encoded by a single mammalian gene; they exhibit cell-specific variability through mRNA splicing and alternative promoter use, and their microtubule-stabilizing activity is mediated by two classes of bifunctional calmodulin- and microtubule-binding motifs with distinct binding properties in vivo. STOP suppression in mice induces synaptic defects and neuroleptic-sensitive behavioral disorders.","method":"Biochemical characterization, domain analysis, STOP-knockout mouse phenotyping","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — synthesizes multiple orthogonal studies; domain characterization corroborated by KO mouse phenotype across labs","pmids":["14567673"],"is_preprint":false},{"year":2004,"finding":"Oligodendrocytes express a major STOP isoform of 89 kDa (O-STOP) that induces microtubule resistance to both cold and nocodazole, while astrocytes express STOP isoforms of 42, 48, and 60 kDa (A-STOP) that confer only cold stability (not nocodazole resistance), demonstrating cell-type-specific isoform expression and differential microtubule-stabilizing activity.","method":"Western blot, immunofluorescence, cold/nocodazole treatment assays in cultured oligodendrocytes and astrocytes","journal":"Journal of neuroscience research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional assays in primary cells, single lab, two orthogonal methods","pmids":["15389836"],"is_preprint":false},{"year":2006,"finding":"STOP/MAP6 is phosphorylated by CaMKII in vitro and in vivo on at least two independent sites; phosphorylated STOP does not bind or co-localize with microtubules but instead co-localizes with actin assemblies and synaptic protein clusters in differentiated neurons. STOP also binds actin in vitro, suggesting phosphorylation-driven translocation from microtubules to synaptic compartments.","method":"In vitro kinase assay, in vivo phosphorylation (metabolic labeling), immunofluorescence co-localization, in vitro actin-binding assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro kinase assay plus in vivo confirmation plus multiple co-localization readouts plus actin-binding assay in single study","pmids":["16651267"],"is_preprint":false},{"year":2012,"finding":"A MAP6-related protein in Trypanosoma brucei (TbSAXO) stabilizes microtubules via domains homologous to the Mn modules of MAP6; TbSAXO is an axonemal protein required for flagellum motility, defining a family of MAP6-related SAXO proteins present in ciliated/flagellated organisms.","method":"Heterologous expression, microtubule stabilization assay, RNAi knockdown in T. brucei with motility phenotyping, domain mapping","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reconstitution in heterologous system plus RNAi loss-of-function, single lab","pmids":["22355359"],"is_preprint":false},{"year":2013,"finding":"MAP6 identified as a novel interacting protein for TMEM106B by co-immunoprecipitation; MAP6 overexpression inhibits dendritic branching and increases retrograde lysosomal transport in dendrites, while MAP6 knockdown rescues the dendritic and lysosomal transport defects caused by TMEM106B knockdown, establishing a functional TMEM106B/MAP6 interaction that acts as a molecular brake on retrograde lysosomal transport.","method":"Co-immunoprecipitation, shRNA knockdown, overexpression, live-cell imaging of lysosomal transport, dendritic morphology quantification in primary neurons","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal functional rescue experiments with live imaging and multiple genetic manipulations (KD + OE + dominant-negative Rab7-RILP) in single rigorous study","pmids":["24357581"],"is_preprint":false},{"year":2013,"finding":"A short MAP6 fragment encompassing its Mn1 and Mn2 modules (residues 90–177) recapitulates full-length MAP6-N microtubule-stabilizing activity with a 1:1 stoichiometry per tubulin heterodimer; NMR shows both Mn modules bind microtubules at a common interface; Ca2+-calmodulin competes with microtubules for MAP6 binding at the same amino-acid stretch, providing the structural basis for calmodulin regulation.","method":"Biochemical microtubule stabilization assays, NMR spectroscopy, Ca2+-calmodulin competition assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structural analysis combined with in vitro reconstitution and mutagenesis-equivalent domain dissection, single lab","pmids":["23831686"],"is_preprint":false},{"year":2014,"finding":"MAP6 KO mice display reduced neuronal Mn2+ axonal transport rate in vivo, with stronger defects in long-range and polysynaptic connections; chronic Epothilone D treatment restores axonal transport and alleviates behavioral defects, demonstrating that MAP6 is required for normal in vivo axonal transport.","method":"MEMRI (manganese-enhanced MRI) in vivo axonal transport measurement, pharmacological rescue with Epothilone D","journal":"NeuroImage","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo functional imaging with pharmacological rescue, single lab","pmids":["24704457"],"is_preprint":false},{"year":2017,"finding":"MAP6 undergoes dynamic palmitoylation that controls its subcellular localization: in unpolarized neurons MAP6 resides at the Golgi and in secretory vesicles; as neurons mature, palmitoylated MAP6 is translocated to the proximal axon where it binds and stabilizes microtubules. Depalmitoylation by ABHD17A-C enzymes shuttles MAP6 between membranes and microtubules and is required for MAP6 retention in axons and axon maturation.","method":"Live-cell imaging, palmitoylation assays, ABHD17 overexpression/knockdown, immunofluorescence fractionation in cultured neurons and in situ","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (live imaging, biochemical palmitoylation, genetic manipulation of writer/eraser enzymes) with functional consequences for axon development","pmids":["28521134"],"is_preprint":false},{"year":2020,"finding":"MAP6 localizes inside the lumen of microtubules (intraluminal localization) rather than exclusively on the outer surface; MAP6 induces neuronal microtubules to coil into a left-handed helix and forms apertures (holes) in the microtubule lattice, likely to relieve mechanical stress. MAP6 also promotes microtubule growth in addition to conferring cold stability.","method":"Cryo-electron microscopy/tomography, in vitro microtubule reconstitution with MAP6, quantitative imaging of microtubule dynamics","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structural imaging plus in vitro reconstitution with functional dynamics readout, single rigorous study","pmids":["32270043"],"is_preprint":false},{"year":2018,"finding":"MAP6 deletion in mice results in skeletal muscle dysfunction: reduced muscle force, altered microtubule network and sarcoplasmic reticulum organization, and reduced calcium release during contraction in cultured myotubes, demonstrating a role for MAP6 in organizing intracellular structures required for efficient muscle contraction.","method":"RT-PCR, western blot, in vivo electrostimulation force measurement, immunofluorescence, electron microscopy, Fluo-4 calcium imaging in KO vs. WT mice","journal":"Skeletal muscle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse phenotyping with multiple orthogonal structural and functional readouts, single lab","pmids":["30231928"],"is_preprint":false}],"current_model":"MAP6 (STOP) is a calmodulin-regulated microtubule-associated protein that stabilizes neuronal microtubules against cold and nocodazole via its Mn modules, which bind tubulin heterodimers (1:1 stoichiometry) at a surface competitively occupied by Ca2+-calmodulin; it localizes intraluminally in microtubules and induces helical coiling of the lattice; dynamic palmitoylation by ABHD17 depalmitoylases shuttles MAP6 between membranes and microtubules to control axonal targeting; CaMKII phosphorylation releases MAP6 from microtubules and redirects it to actin/synaptic compartments; MAP6 also interacts with TMEM106B to brake retrograde lysosomal transport in dendrites; and its loss disrupts axonal transport, synaptic plasticity, and skeletal muscle calcium release."},"narrative":{"mechanistic_narrative":"MAP6 (STOP) is a calmodulin-regulated microtubule-associated protein that stabilizes microtubules against cold and depolymerizing drugs, a function central to neuronal microtubule architecture and transport [PMID:8700896, PMID:14567673]. Stabilization is carried out by tandem Mn modules: a fragment spanning Mn1 and Mn2 (residues 90–177) recapitulates full activity, binding tubulin heterodimers 1:1 at a shared interface that is competitively occupied by Ca2+-calmodulin, providing the structural logic for calmodulin control [PMID:23831686]. MAP6 localizes within the microtubule lumen, drives the lattice into a left-handed helical coil with apertures, and promotes microtubule growth in addition to conferring cold stability [PMID:32270043]. Its compartmentalization is dynamically regulated: palmitoylation localizes MAP6 to the Golgi and secretory vesicles, and depalmitoylation by ABHD17A-C shuttles it onto axonal microtubules to support axon maturation [PMID:28521134], while CaMKII phosphorylation releases MAP6 from microtubules and redirects it to actin and synaptic compartments [PMID:16651267]. Through these activities MAP6 is required for normal in vivo axonal transport [PMID:24704457], brakes retrograde lysosomal transport in dendrites via interaction with TMEM106B [PMID:24357581], and organizes the microtubule and sarcoplasmic reticulum networks needed for skeletal muscle calcium release and contractile force [PMID:30231928]. Isoform diversity from a single gene produces cell-type-specific variants with distinct stabilizing properties in oligodendrocytes and astrocytes [PMID:15389836].","teleology":[{"year":1996,"claim":"Established MAP6/STOP as a bona fide microtubule stabilizer, answering whether a single protein could account for cold-stable neuronal microtubules.","evidence":"cDNA cloning with in vitro binding and cellular reconstitution of cold stability, nocodazole resistance, and detyrosination","pmids":["8700896"],"confidence":"High","gaps":["Did not resolve which protein domains mediate stabilization","Structural mechanism of lattice stabilization unknown"]},{"year":1998,"claim":"Defined the genomic organization of the single mammalian gene, framing how isoform diversity could arise.","evidence":"Genomic cloning, chromosomal mapping, and transcription start site mapping in mouse","pmids":["9501006"],"confidence":"Medium","gaps":["Did not characterize the spliced isoforms functionally","Promoter usage in different cell types not resolved"]},{"year":2003,"claim":"Connected MAP6 domain architecture to calmodulin regulation and to in vivo function, linking molecular activity to organismal phenotype.","evidence":"Domain analysis combined with STOP-knockout mouse phenotyping of synaptic and behavioral defects","pmids":["14567673"],"confidence":"High","gaps":["Molecular basis of calmodulin competition not yet structurally defined","Causal chain from microtubule defect to behavior unclear"]},{"year":2004,"claim":"Showed that distinct cell types express different MAP6 isoforms with different stabilizing capacities, explaining functional diversity from one gene.","evidence":"Western blot and cold/nocodazole assays in cultured oligodendrocytes and astrocytes","pmids":["15389836"],"confidence":"Medium","gaps":["Structural basis for differential nocodazole resistance not defined","Physiological role of glial isoforms not tested in vivo"]},{"year":2006,"claim":"Identified phosphorylation as a switch redirecting MAP6 from microtubules to actin/synaptic compartments, revealing regulated relocalization.","evidence":"In vitro and in vivo CaMKII phosphorylation, co-localization imaging, and actin-binding assay in neurons","pmids":["16651267"],"confidence":"High","gaps":["Functional consequence of synaptic relocalization not directly measured","Phosphatase reversing the switch not identified"]},{"year":2012,"claim":"Established an evolutionarily conserved family by showing Mn-module-homologous proteins stabilize axonemal microtubules in flagellated organisms.","evidence":"Heterologous expression and RNAi motility phenotyping of TbSAXO in T. brucei","pmids":["22355359"],"confidence":"Medium","gaps":["Direct relevance to mammalian MAP6 ciliary function not addressed","Ortholog comparison limited to domain homology"]},{"year":2013,"claim":"Provided the structural basis of stabilization and calmodulin control, showing the Mn modules bind tubulin 1:1 at a site competed by Ca2+-calmodulin.","evidence":"In vitro stabilization assays, NMR spectroscopy, and Ca2+-calmodulin competition with the Mn1-Mn2 fragment","pmids":["23831686"],"confidence":"High","gaps":["Atomic-resolution complex structure not obtained","Stoichiometry on full lattice in cells not confirmed"]},{"year":2013,"claim":"Defined a physical and functional MAP6 partner controlling dendritic organelle transport, expanding its role beyond microtubule stabilization.","evidence":"Co-IP plus reciprocal shRNA/overexpression rescue with live lysosomal imaging in primary neurons","pmids":["24357581"],"confidence":"High","gaps":["Mechanism by which the TMEM106B/MAP6 interaction brakes transport unresolved","Direct binding interface not mapped"]},{"year":2014,"claim":"Demonstrated that MAP6 is required for normal axonal transport in vivo and that microtubule-targeting drugs can rescue the defect.","evidence":"Manganese-enhanced MRI of axonal transport in MAP6 KO mice with Epothilone D rescue","pmids":["24704457"],"confidence":"Medium","gaps":["Cargo-specific transport effects not resolved","Link to the molecular stabilization mechanism inferred not shown directly"]},{"year":2017,"claim":"Revealed palmitoylation-controlled trafficking that shuttles MAP6 between membranes and axonal microtubules during maturation.","evidence":"Live imaging, palmitoylation assays, and ABHD17A-C writer/eraser manipulation in cultured neurons","pmids":["28521134"],"confidence":"High","gaps":["Palmitoyltransferase adding the modification not identified","Coordination with phosphorylation switch not addressed"]},{"year":2018,"claim":"Extended MAP6 function to skeletal muscle, showing it organizes microtubule and SR networks needed for calcium release and force.","evidence":"KO mouse force measurement, EM, and Fluo-4 calcium imaging in myotubes","pmids":["30231928"],"confidence":"Medium","gaps":["Muscle-relevant MAP6 isoform not defined","Mechanism linking microtubule organization to SR calcium release unresolved"]},{"year":2020,"claim":"Established the structural mode of action, showing MAP6 acts from inside the microtubule lumen to coil the lattice and promote growth.","evidence":"Cryo-EM/tomography and in vitro reconstitution of microtubule dynamics with MAP6","pmids":["32270043"],"confidence":"High","gaps":["How intraluminal access is achieved in vivo unclear","Relationship of lattice coiling to cold stability mechanistically open"]},{"year":null,"claim":"How the palmitoylation, phosphorylation, and calmodulin-competition inputs are integrated to spatially and temporally direct MAP6 between microtubules, actin, membranes, and partner complexes remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No unified model coupling the three regulatory switches","In vivo dynamics of MAP6 redistribution not measured","Cross-talk with TMEM106B-dependent transport not integrated with stabilization role"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,7,10]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,2,10]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,7,10]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[9]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[9]}],"pathway":[],"complexes":[],"partners":["CALM1","TMEM106B","ABHD17A","CAMK2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96JE9","full_name":"Microtubule-associated protein 6","aliases":["Stable tubule-only polypeptide","STOP"],"length_aa":813,"mass_kda":86.5,"function":"Involved in microtubule stabilization in many cell types, including neuronal cells (By similarity). Specifically has microtubule cold stabilizing activity (By similarity). Involved in dendrite morphogenesis and maintenance by regulating lysosomal trafficking via its interaction with TMEM106B (PubMed:24357581). Regulates KIF5A-mediated axonal cargo transport (By similarity). Regulates axonal growth during neuron polarization (By similarity)","subcellular_location":"Cytoplasm, cytoskeleton; Golgi apparatus; Cell projection, axon; Cell projection, dendrite; Cytoplasmic vesicle, secretory vesicle membrane","url":"https://www.uniprot.org/uniprotkb/Q96JE9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MAP6","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MAP6","total_profiled":1310},"omim":[{"mim_id":"616292","title":"STABILIZER OF AXONEMAL MICROTUBULES 1; SAXO1","url":"https://www.omim.org/entry/616292"},{"mim_id":"610593","title":"MAP6 DOMAIN-CONTAINING PROTEIN 1; MAP6D1","url":"https://www.omim.org/entry/610593"},{"mim_id":"601783","title":"MICROTUBULE-ASSOCIATED PROTEIN 6; MAP6","url":"https://www.omim.org/entry/601783"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":83.1},{"tissue":"choroid plexus","ntpm":86.5},{"tissue":"pituitary gland","ntpm":73.9},{"tissue":"retina","ntpm":89.1}],"url":"https://www.proteinatlas.org/search/MAP6"},"hgnc":{"alias_symbol":["KIAA1878","STOP","FLJ41346","MAP6-N"],"prev_symbol":[]},"alphafold":{"accession":"Q96JE9","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96JE9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96JE9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96JE9-F1-predicted_aligned_error_v6.png","plddt_mean":47.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MAP6","jax_strain_url":"https://www.jax.org/strain/search?query=MAP6"},"sequence":{"accession":"Q96JE9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96JE9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96JE9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96JE9"}},"corpus_meta":[{"pmid":"22608085","id":"PMC_22608085","title":"Comprehensive analysis of mRNA methylation reveals enrichment in 3' UTRs and near stop codons.","date":"2012","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/22608085","citation_count":3389,"is_preprint":false},{"pmid":"7489507","id":"PMC_7489507","title":"When cells stop making sense: effects of nonsense codons on RNA metabolism in vertebrate cells.","date":"1995","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/7489507","citation_count":496,"is_preprint":false},{"pmid":"18403413","id":"PMC_18403413","title":"Controlling morpholino experiments: don't stop making antisense.","date":"2008","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/18403413","citation_count":472,"is_preprint":false},{"pmid":"10697411","id":"PMC_10697411","title":"Topoisomerase II as a target for anticancer drugs: when enzymes stop being nice.","date":"2000","source":"Progress in nucleic acid research and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/10697411","citation_count":299,"is_preprint":false},{"pmid":"28581493","id":"PMC_28581493","title":"CRISPR-STOP: gene silencing through base-editing-induced nonsense mutations.","date":"2017","source":"Nature methods","url":"https://pubmed.ncbi.nlm.nih.gov/28581493","citation_count":277,"is_preprint":false},{"pmid":"24773318","id":"PMC_24773318","title":"Therapeutics based on stop codon readthrough.","date":"2014","source":"Annual review of genomics and human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24773318","citation_count":237,"is_preprint":false},{"pmid":"25650800","id":"PMC_25650800","title":"Transcription termination and the control of the transcriptome: why, where and how to stop.","date":"2015","source":"Nature reviews. 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it binds microtubules and Ca2+-calmodulin in vitro, and when expressed in cells reconstitutes microtubule cold stability, nocodazole resistance, and tubulin detyrosination, demonstrating its role as a microtubule stabilizer.\",\n      \"method\": \"cDNA cloning, in vitro binding assays, transfection of STOP cDNA into cells lacking cold-stable microtubules with phenotypic readouts\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of microtubule stabilization plus cellular expression with multiple functional readouts (cold stability, nocodazole resistance, detyrosination)\",\n      \"pmids\": [\"8700896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The mouse STOP gene (Mtap6) is a single-copy gene on chromosome 7 composed of 4 exons spanning 67 kb, with transcription initiating at multiple sites in a TATA-less promoter region, encoding a 906-amino-acid protein with 91% identity to rat brain STOP.\",\n      \"method\": \"Genomic cloning, Southern blotting, chromosomal mapping, transcription start site mapping\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct genomic characterization using molecular cloning and mapping, single lab\",\n      \"pmids\": [\"9501006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"STOP proteins are calmodulin-binding, calmodulin-regulated microtubule-associated proteins encoded by a single mammalian gene; they exhibit cell-specific variability through mRNA splicing and alternative promoter use, and their microtubule-stabilizing activity is mediated by two classes of bifunctional calmodulin- and microtubule-binding motifs with distinct binding properties in vivo. STOP suppression in mice induces synaptic defects and neuroleptic-sensitive behavioral disorders.\",\n      \"method\": \"Biochemical characterization, domain analysis, STOP-knockout mouse phenotyping\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — synthesizes multiple orthogonal studies; domain characterization corroborated by KO mouse phenotype across labs\",\n      \"pmids\": [\"14567673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Oligodendrocytes express a major STOP isoform of 89 kDa (O-STOP) that induces microtubule resistance to both cold and nocodazole, while astrocytes express STOP isoforms of 42, 48, and 60 kDa (A-STOP) that confer only cold stability (not nocodazole resistance), demonstrating cell-type-specific isoform expression and differential microtubule-stabilizing activity.\",\n      \"method\": \"Western blot, immunofluorescence, cold/nocodazole treatment assays in cultured oligodendrocytes and astrocytes\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional assays in primary cells, single lab, two orthogonal methods\",\n      \"pmids\": [\"15389836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"STOP/MAP6 is phosphorylated by CaMKII in vitro and in vivo on at least two independent sites; phosphorylated STOP does not bind or co-localize with microtubules but instead co-localizes with actin assemblies and synaptic protein clusters in differentiated neurons. STOP also binds actin in vitro, suggesting phosphorylation-driven translocation from microtubules to synaptic compartments.\",\n      \"method\": \"In vitro kinase assay, in vivo phosphorylation (metabolic labeling), immunofluorescence co-localization, in vitro actin-binding assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro kinase assay plus in vivo confirmation plus multiple co-localization readouts plus actin-binding assay in single study\",\n      \"pmids\": [\"16651267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"A MAP6-related protein in Trypanosoma brucei (TbSAXO) stabilizes microtubules via domains homologous to the Mn modules of MAP6; TbSAXO is an axonemal protein required for flagellum motility, defining a family of MAP6-related SAXO proteins present in ciliated/flagellated organisms.\",\n      \"method\": \"Heterologous expression, microtubule stabilization assay, RNAi knockdown in T. brucei with motility phenotyping, domain mapping\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reconstitution in heterologous system plus RNAi loss-of-function, single lab\",\n      \"pmids\": [\"22355359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MAP6 identified as a novel interacting protein for TMEM106B by co-immunoprecipitation; MAP6 overexpression inhibits dendritic branching and increases retrograde lysosomal transport in dendrites, while MAP6 knockdown rescues the dendritic and lysosomal transport defects caused by TMEM106B knockdown, establishing a functional TMEM106B/MAP6 interaction that acts as a molecular brake on retrograde lysosomal transport.\",\n      \"method\": \"Co-immunoprecipitation, shRNA knockdown, overexpression, live-cell imaging of lysosomal transport, dendritic morphology quantification in primary neurons\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal functional rescue experiments with live imaging and multiple genetic manipulations (KD + OE + dominant-negative Rab7-RILP) in single rigorous study\",\n      \"pmids\": [\"24357581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A short MAP6 fragment encompassing its Mn1 and Mn2 modules (residues 90–177) recapitulates full-length MAP6-N microtubule-stabilizing activity with a 1:1 stoichiometry per tubulin heterodimer; NMR shows both Mn modules bind microtubules at a common interface; Ca2+-calmodulin competes with microtubules for MAP6 binding at the same amino-acid stretch, providing the structural basis for calmodulin regulation.\",\n      \"method\": \"Biochemical microtubule stabilization assays, NMR spectroscopy, Ca2+-calmodulin competition assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structural analysis combined with in vitro reconstitution and mutagenesis-equivalent domain dissection, single lab\",\n      \"pmids\": [\"23831686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MAP6 KO mice display reduced neuronal Mn2+ axonal transport rate in vivo, with stronger defects in long-range and polysynaptic connections; chronic Epothilone D treatment restores axonal transport and alleviates behavioral defects, demonstrating that MAP6 is required for normal in vivo axonal transport.\",\n      \"method\": \"MEMRI (manganese-enhanced MRI) in vivo axonal transport measurement, pharmacological rescue with Epothilone D\",\n      \"journal\": \"NeuroImage\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo functional imaging with pharmacological rescue, single lab\",\n      \"pmids\": [\"24704457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MAP6 undergoes dynamic palmitoylation that controls its subcellular localization: in unpolarized neurons MAP6 resides at the Golgi and in secretory vesicles; as neurons mature, palmitoylated MAP6 is translocated to the proximal axon where it binds and stabilizes microtubules. Depalmitoylation by ABHD17A-C enzymes shuttles MAP6 between membranes and microtubules and is required for MAP6 retention in axons and axon maturation.\",\n      \"method\": \"Live-cell imaging, palmitoylation assays, ABHD17 overexpression/knockdown, immunofluorescence fractionation in cultured neurons and in situ\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (live imaging, biochemical palmitoylation, genetic manipulation of writer/eraser enzymes) with functional consequences for axon development\",\n      \"pmids\": [\"28521134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MAP6 localizes inside the lumen of microtubules (intraluminal localization) rather than exclusively on the outer surface; MAP6 induces neuronal microtubules to coil into a left-handed helix and forms apertures (holes) in the microtubule lattice, likely to relieve mechanical stress. MAP6 also promotes microtubule growth in addition to conferring cold stability.\",\n      \"method\": \"Cryo-electron microscopy/tomography, in vitro microtubule reconstitution with MAP6, quantitative imaging of microtubule dynamics\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structural imaging plus in vitro reconstitution with functional dynamics readout, single rigorous study\",\n      \"pmids\": [\"32270043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MAP6 deletion in mice results in skeletal muscle dysfunction: reduced muscle force, altered microtubule network and sarcoplasmic reticulum organization, and reduced calcium release during contraction in cultured myotubes, demonstrating a role for MAP6 in organizing intracellular structures required for efficient muscle contraction.\",\n      \"method\": \"RT-PCR, western blot, in vivo electrostimulation force measurement, immunofluorescence, electron microscopy, Fluo-4 calcium imaging in KO vs. WT mice\",\n      \"journal\": \"Skeletal muscle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse phenotyping with multiple orthogonal structural and functional readouts, single lab\",\n      \"pmids\": [\"30231928\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAP6 (STOP) is a calmodulin-regulated microtubule-associated protein that stabilizes neuronal microtubules against cold and nocodazole via its Mn modules, which bind tubulin heterodimers (1:1 stoichiometry) at a surface competitively occupied by Ca2+-calmodulin; it localizes intraluminally in microtubules and induces helical coiling of the lattice; dynamic palmitoylation by ABHD17 depalmitoylases shuttles MAP6 between membranes and microtubules to control axonal targeting; CaMKII phosphorylation releases MAP6 from microtubules and redirects it to actin/synaptic compartments; MAP6 also interacts with TMEM106B to brake retrograde lysosomal transport in dendrites; and its loss disrupts axonal transport, synaptic plasticity, and skeletal muscle calcium release.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MAP6 (STOP) is a calmodulin-regulated microtubule-associated protein that stabilizes microtubules against cold and depolymerizing drugs, a function central to neuronal microtubule architecture and transport [#0, #2]. Stabilization is carried out by tandem Mn modules: a fragment spanning Mn1 and Mn2 (residues 90–177) recapitulates full activity, binding tubulin heterodimers 1:1 at a shared interface that is competitively occupied by Ca2+-calmodulin, providing the structural logic for calmodulin control [#7]. MAP6 localizes within the microtubule lumen, drives the lattice into a left-handed helical coil with apertures, and promotes microtubule growth in addition to conferring cold stability [#10]. Its compartmentalization is dynamically regulated: palmitoylation localizes MAP6 to the Golgi and secretory vesicles, and depalmitoylation by ABHD17A-C shuttles it onto axonal microtubules to support axon maturation [#9], while CaMKII phosphorylation releases MAP6 from microtubules and redirects it to actin and synaptic compartments [#4]. Through these activities MAP6 is required for normal in vivo axonal transport [#8], brakes retrograde lysosomal transport in dendrites via interaction with TMEM106B [#6], and organizes the microtubule and sarcoplasmic reticulum networks needed for skeletal muscle calcium release and contractile force [#11]. Isoform diversity from a single gene produces cell-type-specific variants with distinct stabilizing properties in oligodendrocytes and astrocytes [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established MAP6/STOP as a bona fide microtubule stabilizer, answering whether a single protein could account for cold-stable neuronal microtubules.\",\n      \"evidence\": \"cDNA cloning with in vitro binding and cellular reconstitution of cold stability, nocodazole resistance, and detyrosination\",\n      \"pmids\": [\"8700896\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which protein domains mediate stabilization\", \"Structural mechanism of lattice stabilization unknown\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Defined the genomic organization of the single mammalian gene, framing how isoform diversity could arise.\",\n      \"evidence\": \"Genomic cloning, chromosomal mapping, and transcription start site mapping in mouse\",\n      \"pmids\": [\"9501006\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not characterize the spliced isoforms functionally\", \"Promoter usage in different cell types not resolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Connected MAP6 domain architecture to calmodulin regulation and to in vivo function, linking molecular activity to organismal phenotype.\",\n      \"evidence\": \"Domain analysis combined with STOP-knockout mouse phenotyping of synaptic and behavioral defects\",\n      \"pmids\": [\"14567673\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of calmodulin competition not yet structurally defined\", \"Causal chain from microtubule defect to behavior unclear\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed that distinct cell types express different MAP6 isoforms with different stabilizing capacities, explaining functional diversity from one gene.\",\n      \"evidence\": \"Western blot and cold/nocodazole assays in cultured oligodendrocytes and astrocytes\",\n      \"pmids\": [\"15389836\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis for differential nocodazole resistance not defined\", \"Physiological role of glial isoforms not tested in vivo\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified phosphorylation as a switch redirecting MAP6 from microtubules to actin/synaptic compartments, revealing regulated relocalization.\",\n      \"evidence\": \"In vitro and in vivo CaMKII phosphorylation, co-localization imaging, and actin-binding assay in neurons\",\n      \"pmids\": [\"16651267\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of synaptic relocalization not directly measured\", \"Phosphatase reversing the switch not identified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established an evolutionarily conserved family by showing Mn-module-homologous proteins stabilize axonemal microtubules in flagellated organisms.\",\n      \"evidence\": \"Heterologous expression and RNAi motility phenotyping of TbSAXO in T. brucei\",\n      \"pmids\": [\"22355359\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct relevance to mammalian MAP6 ciliary function not addressed\", \"Ortholog comparison limited to domain homology\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Provided the structural basis of stabilization and calmodulin control, showing the Mn modules bind tubulin 1:1 at a site competed by Ca2+-calmodulin.\",\n      \"evidence\": \"In vitro stabilization assays, NMR spectroscopy, and Ca2+-calmodulin competition with the Mn1-Mn2 fragment\",\n      \"pmids\": [\"23831686\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution complex structure not obtained\", \"Stoichiometry on full lattice in cells not confirmed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined a physical and functional MAP6 partner controlling dendritic organelle transport, expanding its role beyond microtubule stabilization.\",\n      \"evidence\": \"Co-IP plus reciprocal shRNA/overexpression rescue with live lysosomal imaging in primary neurons\",\n      \"pmids\": [\"24357581\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which the TMEM106B/MAP6 interaction brakes transport unresolved\", \"Direct binding interface not mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated that MAP6 is required for normal axonal transport in vivo and that microtubule-targeting drugs can rescue the defect.\",\n      \"evidence\": \"Manganese-enhanced MRI of axonal transport in MAP6 KO mice with Epothilone D rescue\",\n      \"pmids\": [\"24704457\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cargo-specific transport effects not resolved\", \"Link to the molecular stabilization mechanism inferred not shown directly\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed palmitoylation-controlled trafficking that shuttles MAP6 between membranes and axonal microtubules during maturation.\",\n      \"evidence\": \"Live imaging, palmitoylation assays, and ABHD17A-C writer/eraser manipulation in cultured neurons\",\n      \"pmids\": [\"28521134\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Palmitoyltransferase adding the modification not identified\", \"Coordination with phosphorylation switch not addressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended MAP6 function to skeletal muscle, showing it organizes microtubule and SR networks needed for calcium release and force.\",\n      \"evidence\": \"KO mouse force measurement, EM, and Fluo-4 calcium imaging in myotubes\",\n      \"pmids\": [\"30231928\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Muscle-relevant MAP6 isoform not defined\", \"Mechanism linking microtubule organization to SR calcium release unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established the structural mode of action, showing MAP6 acts from inside the microtubule lumen to coil the lattice and promote growth.\",\n      \"evidence\": \"Cryo-EM/tomography and in vitro reconstitution of microtubule dynamics with MAP6\",\n      \"pmids\": [\"32270043\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How intraluminal access is achieved in vivo unclear\", \"Relationship of lattice coiling to cold stability mechanistically open\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the palmitoylation, phosphorylation, and calmodulin-competition inputs are integrated to spatially and temporally direct MAP6 between microtubules, actin, membranes, and partner complexes remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unified model coupling the three regulatory switches\", \"In vivo dynamics of MAP6 redistribution not measured\", \"Cross-talk with TMEM106B-dependent transport not integrated with stabilization role\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 7, 10]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 2, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 7, 10]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": []}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CALM1\",\n      \"TMEM106B\",\n      \"ABHD17A\",\n      \"CAMK2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}