{"gene":"MAP6","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2013,"finding":"MAP6 interacts with TMEM106B and controls dendritic trafficking of lysosomes; MAP6 overexpression inhibits dendritic branching and increases retrograde lysosomal transport in dendrites, while MAP6 knockdown rescues dendritic phenotypes caused by TMEM106B knockdown, indicating MAP6 acts as a molecular brake for retrograde lysosomal transport.","method":"Co-immunoprecipitation (MAP6–TMEM106B interaction), live imaging of lysosomal transport, shRNA knockdown and overexpression in primary neurons, dominant-negative Rab7-RILP rescue experiments","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — reciprocal functional interaction confirmed by multiple orthogonal methods (co-IP, live imaging, KD/OE with specific phenotypic readouts, epistasis rescue)","pmids":["24357581"],"is_preprint":false},{"year":2017,"finding":"MAP6 is dynamically palmitoylated; palmitoylation mediates shuttling of MAP6 between membranes and microtubules and is required for MAP6 retention in the proximal axon, where it stabilizes microtubules during neuronal polarization. ABHD17A-C depalmitoylating enzymes regulate this process.","method":"Live-cell imaging, FRAP, palmitoylation assays, overexpression/knockdown of ABHD17 enzymes in cultured neurons and in situ, axon/dendrite fractionation","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (palmitoylation biochemistry, live imaging, functional rescue) in a single rigorous study","pmids":["28521134"],"is_preprint":false},{"year":2020,"finding":"MAP6 localizes to the lumen of microtubules (intraluminal), induces neuronal microtubules to coil into a left-handed helix, and forms apertures in the microtubule lattice; MAP6 also promotes microtubule growth rather than merely preventing depolymerization.","method":"Cryo-electron microscopy/tomography, in vitro reconstitution with purified MAP6 and tubulin, fluorescence microscopy","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structural data combined with in vitro reconstitution revealing novel intraluminal localization and coiling mechanism","pmids":["32270043"],"is_preprint":false},{"year":2013,"finding":"MAP6 stabilizes microtubules via its Mn1 and Mn2 modules (MAP6(90-177)), which bind microtubules with 1:1 MAP6:tubulin heterodimer stoichiometry; each Mn module constitutes a full microtubule-binding domain. Ca²⁺-calmodulin competes with microtubules for MAP6 binding through overlapping residues, providing a mechanism for calmodulin-dependent regulation of microtubule stability.","method":"NMR spectroscopy, biochemical binding assays (in vitro), microtubule stabilization assays in cold/nocodazole conditions, calmodulin competition assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — NMR structural data with biochemical validation and mutagenesis-level domain dissection; calmodulin competition established by direct binding assay","pmids":["23831686"],"is_preprint":false},{"year":2012,"finding":"A MAP6-related protein (TbSAXO) in Trypanosoma brucei is an axonemal microtubule-stabilizing protein; its Mn-domain homologs mediate microtubule binding and stabilization, and TbSAXO is required for flagellum motility, identifying a conserved family of MAP6-related SAXO proteins in ciliated/flagellated organisms.","method":"Heterologous expression, in vitro microtubule stabilization assays, RNAi knockdown in T. brucei, immunolocalization","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — functional domain mapping with in vitro assays and RNAi phenotype, but in a protozoan ortholog","pmids":["22355359"],"is_preprint":false},{"year":2004,"finding":"Different cell types (neurons, oligodendrocytes, astrocytes, fibroblasts) express distinct isoforms of STOP/MAP6 (N-STOP, E-STOP, O-STOP, A-STOP, F-STOP) with differing microtubule-stabilizing capacities: neuronal and oligodendrocyte isoforms confer resistance to both cold and nocodazole, whereas astrocyte and fibroblast isoforms confer resistance only to cold.","method":"Western blot, immunofluorescence, in vitro microtubule stabilization assays (cold and nocodazole treatment) in cultured cell types","journal":"Journal of neuroscience research","confidence":"Medium","confidence_rationale":"Tier 2 — systematic comparison across cell types with functional microtubule stability assays; single lab but multiple cell types","pmids":["15389836"],"is_preprint":false},{"year":1998,"finding":"The mouse STOP gene (Mtap6) maps to chromosome 7 E2-F1, is composed of 4 exons, encodes a 906-amino acid calmodulin-regulated microtubule-associated protein with 91% identity to rat brain STOP, and initiates transcription from multiple sites in a TATA-less promoter region.","method":"Genomic cloning, sequencing, chromosomal mapping, transcription start site mapping","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — direct genomic characterization establishing gene structure and chromosomal location","pmids":["9501006"],"is_preprint":false},{"year":2014,"finding":"MAP6 KO mice exhibit reduced neuronal Mn²⁺ transport in vivo, particularly in long-range and polysynaptic connections, indicating axonal transport defects; treatment with the microtubule-stabilizing drug Epothilone D rescues axonal transport in MAP6 KO mice and alleviates behavioral deficits.","method":"Manganese-enhanced MRI (MEMRI) in MAP6 KO vs. wild-type mice, pharmacological rescue with Epothilone D","journal":"NeuroImage","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo imaging with pharmacological rescue providing mechanistic link between MAP6 and axonal transport","pmids":["24704457"],"is_preprint":false},{"year":2018,"finding":"Deletion of MAP6 in mice causes skeletal muscle dysfunction including muscle weakness, alterations in microtubule network and sarcoplasmic reticulum organization, and reduced calcium release during contraction, establishing a role for MAP6 in skeletal muscle excitation-contraction coupling.","method":"MAP6 KO mouse line, in vivo force measurement, immunofluorescence, electron microscopy, Fluo-4 calcium imaging in myotubes","journal":"Skeletal muscle","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse with multiple orthogonal readouts (force, EM, calcium imaging) linking MAP6 to muscle function","pmids":["30231928"],"is_preprint":false},{"year":2012,"finding":"Reduced expression of STOP/MAP6 in heterozygous mice causes prominent deficits in social interaction and learning, and perinatal stress exacerbates behavioral phenotypes related to positive symptoms, demonstrating that MAP6 dosage has high penetrance on cognitive abilities.","method":"Behavioral testing battery in STOP heterozygous and KO mice with/without maternal deprivation; locomotor, amphetamine, and social interaction assays","journal":"Schizophrenia bulletin","confidence":"Medium","confidence_rationale":"Tier 2 — systematic behavioral phenotyping with genetic dosage manipulation showing dose-dependent cognitive effects","pmids":["23002183"],"is_preprint":false},{"year":2017,"finding":"MAP6-KO mice show structural brain abnormalities including reduced cerebellar and thalamic volumes and altered integrity/orientation of white matter tracts (anterior commissure, corpus callosum, corticospinal tract, fornix), establishing MAP6 as necessary for normal brain connectivity.","method":"High-resolution 3D MRI, diffusion tensor imaging (DTI), fiber tractography, optical imaging of cleared brains in MAP6-KO mice","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo structural neuroimaging with validated tractography in KO model","pmids":["28871106"],"is_preprint":false},{"year":2006,"finding":"STOP/MAP6 null and heterozygous mice show decreased mRNA expression of presynaptic proteins (synaptophysin, GAP-43, VGlut1) and postsynaptic spinophilin in hippocampus, cerebellum, and cortex, linking MAP6-dependent microtubule stability to synaptic protein expression.","method":"In situ hybridization histochemistry in STOP null, heterozygous, and wild-type mice","journal":"Journal of psychopharmacology (Oxford, England)","confidence":"Low","confidence_rationale":"Tier 3 — single method (ISH) measuring downstream mRNA changes without direct mechanistic dissection","pmids":["17050659"],"is_preprint":false}],"current_model":"MAP6 (STOP) is a calmodulin-regulated microtubule-associated protein that binds microtubules via its Mn modules (with 1:1 stoichiometry per tubulin heterodimer), localizes intraluminally to induce microtubule coiling and lattice apertures, and is dynamically palmitoylated to control its shuttling between membranes and microtubules for axon-specific retention; it interacts with TMEM106B to restrain retrograde lysosomal transport in dendrites, and its loss causes defects in axonal transport, synaptic protein expression, skeletal muscle calcium handling, and brain connectivity in mice."},"narrative":{"teleology":[{"year":1998,"claim":"Establishing the gene structure of MAP6/STOP — including exon organization, calmodulin-binding capacity, and chromosomal locus — provided the foundation for subsequent mechanistic work on this microtubule-associated protein.","evidence":"Genomic cloning, sequencing, and transcription start site mapping of mouse Mtap6","pmids":["9501006"],"confidence":"Medium","gaps":["Promoter regulatory elements not functionally tested","Human gene structure not characterized in this study"]},{"year":2004,"claim":"Demonstration that distinct MAP6/STOP isoforms in different cell types confer different levels of microtubule stability (cold versus nocodazole resistance) established that MAP6 function is isoform- and cell-type-dependent.","evidence":"Western blot, immunofluorescence, and in vitro microtubule stabilization assays across neurons, oligodendrocytes, astrocytes, and fibroblasts","pmids":["15389836"],"confidence":"Medium","gaps":["Structural basis for differential stabilizing capacity of isoforms unknown","In vivo relevance of individual isoforms not tested"]},{"year":2012,"claim":"The finding that MAP6 Mn-domain homologs in Trypanosoma brucei (SAXO proteins) stabilize axonemal microtubules and are required for flagellum motility revealed that MAP6-family microtubule stabilization is an ancient, evolutionarily conserved function.","evidence":"Heterologous expression, in vitro MT stabilization, RNAi knockdown in T. brucei","pmids":["22355359"],"confidence":"Medium","gaps":["Structural conservation of Mn-module–tubulin interface not resolved","Direct functional complementation between mammalian MAP6 and SAXO not tested"]},{"year":2012,"claim":"Behavioral analysis of MAP6 heterozygous and KO mice revealed that MAP6 dosage has high penetrance on cognitive and social abilities, with perinatal stress exacerbating positive-symptom-like phenotypes — linking microtubule stabilization to complex behavior.","evidence":"Behavioral testing battery (locomotor, social interaction, amphetamine sensitivity) in heterozygous and KO mice with/without maternal deprivation","pmids":["23002183"],"confidence":"Medium","gaps":["Cellular mechanism linking MAP6 loss to behavioral deficits not dissected","Relevance to human psychiatric disease not established by direct genetic evidence"]},{"year":2013,"claim":"NMR-resolved domain dissection showed that MAP6 Mn modules each constitute complete microtubule-binding domains that bind at 1:1 stoichiometry per tubulin heterodimer, and that Ca²⁺-calmodulin competes for overlapping residues — providing the first molecular mechanism for calmodulin-dependent regulation of MAP6-mediated microtubule stability.","evidence":"NMR spectroscopy, biochemical binding and calmodulin competition assays, cold/nocodazole stabilization assays in vitro","pmids":["23831686"],"confidence":"High","gaps":["Atomic-resolution structure of Mn–tubulin complex not obtained","How calmodulin regulation is triggered in vivo (calcium dynamics) not addressed"]},{"year":2013,"claim":"Discovery that MAP6 physically interacts with TMEM106B and functions as a brake on retrograde lysosomal transport in dendrites revealed a non-structural role for MAP6 in organelle trafficking, with epistasis experiments showing MAP6 acts downstream of TMEM106B.","evidence":"Co-immunoprecipitation, live lysosomal imaging, shRNA knockdown/overexpression, and Rab7-RILP epistasis in primary neurons","pmids":["24357581"],"confidence":"High","gaps":["Direct binding domain on MAP6 for TMEM106B not mapped","Whether MAP6-TMEM106B interaction is palmitoylation-dependent unknown"]},{"year":2014,"claim":"Manganese-enhanced MRI in MAP6 KO mice demonstrated that MAP6 is required for normal axonal transport in vivo, particularly in long-range and polysynaptic pathways, and that the microtubule-stabilizing drug Epothilone D rescues these deficits — providing causal evidence that MAP6's transport role depends on microtubule integrity.","evidence":"MEMRI imaging and pharmacological rescue with Epothilone D in MAP6 KO vs. wild-type mice","pmids":["24704457"],"confidence":"Medium","gaps":["Molecular cargo affected by MAP6 loss not identified","Whether transport rescue also corrects behavioral deficits long-term unknown"]},{"year":2017,"claim":"Dynamic palmitoylation was identified as the switch controlling MAP6 partitioning between membranes and microtubules; ABHD17 depalmitoylases release MAP6 from membranes to enable its axon-specific microtubule binding during neuronal polarization.","evidence":"Palmitoylation assays, FRAP, live-cell imaging, ABHD17 overexpression/knockdown in cultured neurons","pmids":["28521134"],"confidence":"High","gaps":["Which palmitoyl transferase(s) initially palmitoylate MAP6 not identified","Whether palmitoylation also regulates MAP6 in non-neuronal cells unknown"]},{"year":2017,"claim":"High-resolution MRI and DTI of MAP6-KO brains established that MAP6 is essential for normal brain connectivity, with reduced cerebellar/thalamic volumes and disrupted major white matter tracts.","evidence":"3D MRI, diffusion tensor imaging, fiber tractography, and optical imaging of cleared MAP6-KO mouse brains","pmids":["28871106"],"confidence":"Medium","gaps":["Whether connectivity defects are developmental or degenerative not resolved","Cell-type-specific contributions not dissected"]},{"year":2018,"claim":"MAP6 deletion was shown to cause skeletal muscle weakness with disorganized sarcoplasmic reticulum and reduced calcium release, extending MAP6's physiological role beyond the nervous system to excitation-contraction coupling.","evidence":"MAP6 KO mouse, in vivo force measurements, electron microscopy, Fluo-4 calcium imaging in myotubes","pmids":["30231928"],"confidence":"Medium","gaps":["Whether muscle phenotype is due to microtubule instability or a non-MT function of MAP6 not distinguished","MAP6 isoform responsible for muscle function not identified"]},{"year":2020,"claim":"Cryo-EM/ET revealed that MAP6 occupies the microtubule lumen — an unprecedented localization — where it induces left-handed helical coiling and lattice apertures, and promotes microtubule growth rather than merely preventing depolymerization, fundamentally revising the model of how MAP6 stabilizes microtubules.","evidence":"Cryo-electron microscopy/tomography with in vitro reconstituted MAP6–tubulin assemblies, fluorescence microscopy","pmids":["32270043"],"confidence":"High","gaps":["Intraluminal binding site on tubulin not resolved at atomic resolution","How MAP6 enters the lumen is unknown","Whether intraluminal localization occurs in vivo confirmed only indirectly"]},{"year":null,"claim":"Key open questions include: how MAP6 enters the microtubule lumen, the atomic structure of the Mn–tubulin interface, whether palmitoylation governs the MAP6–TMEM106B interaction, and the molecular identity of cargoes whose transport depends on MAP6.","evidence":"","pmids":[],"confidence":"Low","gaps":["Mechanism of luminal entry unknown","No high-resolution co-structure of Mn domain bound to tubulin","Relationship between palmitoylation state and TMEM106B interaction untested","Specific transport cargoes disrupted in MAP6 KO not identified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[2,3,4,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,3]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[2,3,5]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,7]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[7,10,9]}],"complexes":[],"partners":["TMEM106B","ABHD17A","ABHD17B","ABHD17C","CALM1"],"other_free_text":[]},"mechanistic_narrative":"MAP6 (also known as STOP) is a calmodulin-regulated microtubule-associated protein that stabilizes microtubules in neurons, muscle, and other cell types, and coordinates intracellular transport and organelle positioning. Its Mn modules bind tubulin heterodimers at 1:1 stoichiometry, and Ca²⁺-calmodulin competes for the same binding surface to dynamically regulate microtubule stabilization [PMID:23831686]; structurally, MAP6 localizes to the microtubule lumen, where it induces left-handed helical coiling and lattice apertures and promotes microtubule growth [PMID:32270043]. Dynamic palmitoylation, regulated by ABHD17 depalmitoylases, shuttles MAP6 between membranes and microtubules and is required for its axon-specific retention during neuronal polarization [PMID:28521134]. MAP6 also interacts with TMEM106B to restrain retrograde lysosomal transport in dendrites [PMID:24357581], and its loss in mice produces defective axonal transport, impaired brain connectivity, reduced synaptic protein expression, skeletal muscle weakness with altered calcium handling, and dose-dependent cognitive and social deficits [PMID:24704457, PMID:28871106, PMID:30231928, PMID:23002183]."},"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":3345,"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":494,"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":"10391242","id":"PMC_10391242","title":"A stop-codon mutation in the BRI gene associated with familial British dementia.","date":"1999","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/10391242","citation_count":386,"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":272,"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":236,"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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ABHD17A-C depalmitoylating enzymes regulate this process.\",\n      \"method\": \"Live-cell imaging, FRAP, palmitoylation assays, overexpression/knockdown of ABHD17 enzymes in cultured neurons and in situ, axon/dendrite fractionation\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (palmitoylation biochemistry, live imaging, functional rescue) in a single rigorous study\",\n      \"pmids\": [\"28521134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MAP6 localizes to the lumen of microtubules (intraluminal), induces neuronal microtubules to coil into a left-handed helix, and forms apertures in the microtubule lattice; MAP6 also promotes microtubule growth rather than merely preventing depolymerization.\",\n      \"method\": \"Cryo-electron microscopy/tomography, in vitro reconstitution with purified MAP6 and tubulin, fluorescence microscopy\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structural data combined with in vitro reconstitution revealing novel intraluminal localization and coiling mechanism\",\n      \"pmids\": [\"32270043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MAP6 stabilizes microtubules via its Mn1 and Mn2 modules (MAP6(90-177)), which bind microtubules with 1:1 MAP6:tubulin heterodimer stoichiometry; each Mn module constitutes a full microtubule-binding domain. Ca²⁺-calmodulin competes with microtubules for MAP6 binding through overlapping residues, providing a mechanism for calmodulin-dependent regulation of microtubule stability.\",\n      \"method\": \"NMR spectroscopy, biochemical binding assays (in vitro), microtubule stabilization assays in cold/nocodazole conditions, calmodulin competition assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structural data with biochemical validation and mutagenesis-level domain dissection; calmodulin competition established by direct binding assay\",\n      \"pmids\": [\"23831686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"A MAP6-related protein (TbSAXO) in Trypanosoma brucei is an axonemal microtubule-stabilizing protein; its Mn-domain homologs mediate microtubule binding and stabilization, and TbSAXO is required for flagellum motility, identifying a conserved family of MAP6-related SAXO proteins in ciliated/flagellated organisms.\",\n      \"method\": \"Heterologous expression, in vitro microtubule stabilization assays, RNAi knockdown in T. brucei, immunolocalization\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional domain mapping with in vitro assays and RNAi phenotype, but in a protozoan ortholog\",\n      \"pmids\": [\"22355359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Different cell types (neurons, oligodendrocytes, astrocytes, fibroblasts) express distinct isoforms of STOP/MAP6 (N-STOP, E-STOP, O-STOP, A-STOP, F-STOP) with differing microtubule-stabilizing capacities: neuronal and oligodendrocyte isoforms confer resistance to both cold and nocodazole, whereas astrocyte and fibroblast isoforms confer resistance only to cold.\",\n      \"method\": \"Western blot, immunofluorescence, in vitro microtubule stabilization assays (cold and nocodazole treatment) in cultured cell types\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — systematic comparison across cell types with functional microtubule stability assays; single lab but multiple cell types\",\n      \"pmids\": [\"15389836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The mouse STOP gene (Mtap6) maps to chromosome 7 E2-F1, is composed of 4 exons, encodes a 906-amino acid calmodulin-regulated microtubule-associated protein with 91% identity to rat brain STOP, and initiates transcription from multiple sites in a TATA-less promoter region.\",\n      \"method\": \"Genomic cloning, sequencing, chromosomal mapping, transcription start site mapping\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct genomic characterization establishing gene structure and chromosomal location\",\n      \"pmids\": [\"9501006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MAP6 KO mice exhibit reduced neuronal Mn²⁺ transport in vivo, particularly in long-range and polysynaptic connections, indicating axonal transport defects; treatment with the microtubule-stabilizing drug Epothilone D rescues axonal transport in MAP6 KO mice and alleviates behavioral deficits.\",\n      \"method\": \"Manganese-enhanced MRI (MEMRI) in MAP6 KO vs. wild-type mice, pharmacological rescue with Epothilone D\",\n      \"journal\": \"NeuroImage\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo imaging with pharmacological rescue providing mechanistic link between MAP6 and axonal transport\",\n      \"pmids\": [\"24704457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Deletion of MAP6 in mice causes skeletal muscle dysfunction including muscle weakness, alterations in microtubule network and sarcoplasmic reticulum organization, and reduced calcium release during contraction, establishing a role for MAP6 in skeletal muscle excitation-contraction coupling.\",\n      \"method\": \"MAP6 KO mouse line, in vivo force measurement, immunofluorescence, electron microscopy, Fluo-4 calcium imaging in myotubes\",\n      \"journal\": \"Skeletal muscle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with multiple orthogonal readouts (force, EM, calcium imaging) linking MAP6 to muscle function\",\n      \"pmids\": [\"30231928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Reduced expression of STOP/MAP6 in heterozygous mice causes prominent deficits in social interaction and learning, and perinatal stress exacerbates behavioral phenotypes related to positive symptoms, demonstrating that MAP6 dosage has high penetrance on cognitive abilities.\",\n      \"method\": \"Behavioral testing battery in STOP heterozygous and KO mice with/without maternal deprivation; locomotor, amphetamine, and social interaction assays\",\n      \"journal\": \"Schizophrenia bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — systematic behavioral phenotyping with genetic dosage manipulation showing dose-dependent cognitive effects\",\n      \"pmids\": [\"23002183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MAP6-KO mice show structural brain abnormalities including reduced cerebellar and thalamic volumes and altered integrity/orientation of white matter tracts (anterior commissure, corpus callosum, corticospinal tract, fornix), establishing MAP6 as necessary for normal brain connectivity.\",\n      \"method\": \"High-resolution 3D MRI, diffusion tensor imaging (DTI), fiber tractography, optical imaging of cleared brains in MAP6-KO mice\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo structural neuroimaging with validated tractography in KO model\",\n      \"pmids\": [\"28871106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"STOP/MAP6 null and heterozygous mice show decreased mRNA expression of presynaptic proteins (synaptophysin, GAP-43, VGlut1) and postsynaptic spinophilin in hippocampus, cerebellum, and cortex, linking MAP6-dependent microtubule stability to synaptic protein expression.\",\n      \"method\": \"In situ hybridization histochemistry in STOP null, heterozygous, and wild-type mice\",\n      \"journal\": \"Journal of psychopharmacology (Oxford, England)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single method (ISH) measuring downstream mRNA changes without direct mechanistic dissection\",\n      \"pmids\": [\"17050659\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAP6 (STOP) is a calmodulin-regulated microtubule-associated protein that binds microtubules via its Mn modules (with 1:1 stoichiometry per tubulin heterodimer), localizes intraluminally to induce microtubule coiling and lattice apertures, and is dynamically palmitoylated to control its shuttling between membranes and microtubules for axon-specific retention; it interacts with TMEM106B to restrain retrograde lysosomal transport in dendrites, and its loss causes defects in axonal transport, synaptic protein expression, skeletal muscle calcium handling, and brain connectivity in mice.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MAP6 (also known as STOP) is a calmodulin-regulated microtubule-associated protein that stabilizes microtubules in neurons, muscle, and other cell types, and coordinates intracellular transport and organelle positioning. Its Mn modules bind tubulin heterodimers at 1:1 stoichiometry, and Ca²⁺-calmodulin competes for the same binding surface to dynamically regulate microtubule stabilization [PMID:23831686]; structurally, MAP6 localizes to the microtubule lumen, where it induces left-handed helical coiling and lattice apertures and promotes microtubule growth [PMID:32270043]. Dynamic palmitoylation, regulated by ABHD17 depalmitoylases, shuttles MAP6 between membranes and microtubules and is required for its axon-specific retention during neuronal polarization [PMID:28521134]. MAP6 also interacts with TMEM106B to restrain retrograde lysosomal transport in dendrites [PMID:24357581], and its loss in mice produces defective axonal transport, impaired brain connectivity, reduced synaptic protein expression, skeletal muscle weakness with altered calcium handling, and dose-dependent cognitive and social deficits [PMID:24704457, PMID:28871106, PMID:30231928, PMID:23002183].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Establishing the gene structure of MAP6/STOP — including exon organization, calmodulin-binding capacity, and chromosomal locus — provided the foundation for subsequent mechanistic work on this microtubule-associated protein.\",\n      \"evidence\": \"Genomic cloning, sequencing, and transcription start site mapping of mouse Mtap6\",\n      \"pmids\": [\"9501006\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Promoter regulatory elements not functionally tested\", \"Human gene structure not characterized in this study\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstration that distinct MAP6/STOP isoforms in different cell types confer different levels of microtubule stability (cold versus nocodazole resistance) established that MAP6 function is isoform- and cell-type-dependent.\",\n      \"evidence\": \"Western blot, immunofluorescence, and in vitro microtubule stabilization assays across neurons, oligodendrocytes, astrocytes, and fibroblasts\",\n      \"pmids\": [\"15389836\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis for differential stabilizing capacity of isoforms unknown\", \"In vivo relevance of individual isoforms not tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"The finding that MAP6 Mn-domain homologs in Trypanosoma brucei (SAXO proteins) stabilize axonemal microtubules and are required for flagellum motility revealed that MAP6-family microtubule stabilization is an ancient, evolutionarily conserved function.\",\n      \"evidence\": \"Heterologous expression, in vitro MT stabilization, RNAi knockdown in T. brucei\",\n      \"pmids\": [\"22355359\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural conservation of Mn-module–tubulin interface not resolved\", \"Direct functional complementation between mammalian MAP6 and SAXO not tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Behavioral analysis of MAP6 heterozygous and KO mice revealed that MAP6 dosage has high penetrance on cognitive and social abilities, with perinatal stress exacerbating positive-symptom-like phenotypes — linking microtubule stabilization to complex behavior.\",\n      \"evidence\": \"Behavioral testing battery (locomotor, social interaction, amphetamine sensitivity) in heterozygous and KO mice with/without maternal deprivation\",\n      \"pmids\": [\"23002183\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular mechanism linking MAP6 loss to behavioral deficits not dissected\", \"Relevance to human psychiatric disease not established by direct genetic evidence\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"NMR-resolved domain dissection showed that MAP6 Mn modules each constitute complete microtubule-binding domains that bind at 1:1 stoichiometry per tubulin heterodimer, and that Ca²⁺-calmodulin competes for overlapping residues — providing the first molecular mechanism for calmodulin-dependent regulation of MAP6-mediated microtubule stability.\",\n      \"evidence\": \"NMR spectroscopy, biochemical binding and calmodulin competition assays, cold/nocodazole stabilization assays in vitro\",\n      \"pmids\": [\"23831686\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution structure of Mn–tubulin complex not obtained\", \"How calmodulin regulation is triggered in vivo (calcium dynamics) not addressed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery that MAP6 physically interacts with TMEM106B and functions as a brake on retrograde lysosomal transport in dendrites revealed a non-structural role for MAP6 in organelle trafficking, with epistasis experiments showing MAP6 acts downstream of TMEM106B.\",\n      \"evidence\": \"Co-immunoprecipitation, live lysosomal imaging, shRNA knockdown/overexpression, and Rab7-RILP epistasis in primary neurons\",\n      \"pmids\": [\"24357581\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding domain on MAP6 for TMEM106B not mapped\", \"Whether MAP6-TMEM106B interaction is palmitoylation-dependent unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Manganese-enhanced MRI in MAP6 KO mice demonstrated that MAP6 is required for normal axonal transport in vivo, particularly in long-range and polysynaptic pathways, and that the microtubule-stabilizing drug Epothilone D rescues these deficits — providing causal evidence that MAP6's transport role depends on microtubule integrity.\",\n      \"evidence\": \"MEMRI imaging and pharmacological rescue with Epothilone D in MAP6 KO vs. wild-type mice\",\n      \"pmids\": [\"24704457\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular cargo affected by MAP6 loss not identified\", \"Whether transport rescue also corrects behavioral deficits long-term unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Dynamic palmitoylation was identified as the switch controlling MAP6 partitioning between membranes and microtubules; ABHD17 depalmitoylases release MAP6 from membranes to enable its axon-specific microtubule binding during neuronal polarization.\",\n      \"evidence\": \"Palmitoylation assays, FRAP, live-cell imaging, ABHD17 overexpression/knockdown in cultured neurons\",\n      \"pmids\": [\"28521134\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which palmitoyl transferase(s) initially palmitoylate MAP6 not identified\", \"Whether palmitoylation also regulates MAP6 in non-neuronal cells unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"High-resolution MRI and DTI of MAP6-KO brains established that MAP6 is essential for normal brain connectivity, with reduced cerebellar/thalamic volumes and disrupted major white matter tracts.\",\n      \"evidence\": \"3D MRI, diffusion tensor imaging, fiber tractography, and optical imaging of cleared MAP6-KO mouse brains\",\n      \"pmids\": [\"28871106\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether connectivity defects are developmental or degenerative not resolved\", \"Cell-type-specific contributions not dissected\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"MAP6 deletion was shown to cause skeletal muscle weakness with disorganized sarcoplasmic reticulum and reduced calcium release, extending MAP6's physiological role beyond the nervous system to excitation-contraction coupling.\",\n      \"evidence\": \"MAP6 KO mouse, in vivo force measurements, electron microscopy, Fluo-4 calcium imaging in myotubes\",\n      \"pmids\": [\"30231928\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether muscle phenotype is due to microtubule instability or a non-MT function of MAP6 not distinguished\", \"MAP6 isoform responsible for muscle function not identified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Cryo-EM/ET revealed that MAP6 occupies the microtubule lumen — an unprecedented localization — where it induces left-handed helical coiling and lattice apertures, and promotes microtubule growth rather than merely preventing depolymerization, fundamentally revising the model of how MAP6 stabilizes microtubules.\",\n      \"evidence\": \"Cryo-electron microscopy/tomography with in vitro reconstituted MAP6–tubulin assemblies, fluorescence microscopy\",\n      \"pmids\": [\"32270043\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Intraluminal binding site on tubulin not resolved at atomic resolution\", \"How MAP6 enters the lumen is unknown\", \"Whether intraluminal localization occurs in vivo confirmed only indirectly\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include: how MAP6 enters the microtubule lumen, the atomic structure of the Mn–tubulin interface, whether palmitoylation governs the MAP6–TMEM106B interaction, and the molecular identity of cargoes whose transport depends on MAP6.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Mechanism of luminal entry unknown\", \"No high-resolution co-structure of Mn domain bound to tubulin\", \"Relationship between palmitoylation state and TMEM106B interaction untested\", \"Specific transport cargoes disrupted in MAP6 KO not identified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2, 3, 4, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2, 3, 5]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [7, 10, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"TMEM106B\",\n      \"ABHD17A\",\n      \"ABHD17B\",\n      \"ABHD17C\",\n      \"CALM1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}