{"gene":"MAP7D3","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2004,"finding":"MAP7D3 (FLJ12649) was identified as a component of the human mitotic spindle by mass spectrometry analysis of purified spindles, and tagged MAP7D3 localized to the mitotic spindle in transfected cells.","method":"MS/MS proteomics of purified human mitotic spindles; fluorescence localization of tagged protein in transfected mitotic cells","journal":"Molecular & cellular proteomics : MCP","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment in cells, supported by proteomic identification; single study but two orthogonal methods","pmids":["15561729"],"is_preprint":false},{"year":2014,"finding":"The MAP7 domain (MD) of MAP7D3, together with its C-terminal tail (CT), binds to microtubules and promotes microtubule polymerization in vitro; MDCT binds reconstituted microtubules with an apparent Kd of ~3 µM, localizes along preassembled microtubules, competes with tau for the same binding site, and binds the C-terminal tail of tubulin.","method":"In vitro microtubule polymerization assays, sedimentation binding assays, competition experiments with tau, immunostaining of tagged protein on microtubules, binding to tubulin in HeLa cell extracts","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with quantified binding, mutagenesis-analogous domain dissection, multiple orthogonal methods in a single rigorous study","pmids":["24927501"],"is_preprint":false},{"year":2016,"finding":"MAP7D3 (Mdp3) forms a complex with DDA3 (PSRC1) and controls spindle microtubule dynamics at the minus end by inhibiting DDA3-mediated recruitment of the kinesin-13 depolymerase Kif2a to the spindle; depletion of MAP7D3 results in aberrant Kif2a activity, decreased spindle stability, unaligned chromosomes in metaphase, lagging chromosomes in anaphase, and chromosome bridges in telophase/cytokinesis.","method":"Co-immunoprecipitation (complex identification), siRNA knockdown with defined mitotic phenotypes, immunofluorescence of spindle localization and Kif2a recruitment","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal complex identification, loss-of-function with specific mechanistic phenotypes, multiple orthogonal methods; independently extends spindle localization finding from 2004","pmids":["27284004"],"is_preprint":false},{"year":2020,"finding":"Knockdown of Mtap7d3 in mouse spermatogonial stem cells (SSCs) inhibits SSC self-renewal in vitro, establishing a role for MAP7D3 in spermatogonial stem cell maintenance.","method":"siRNA knockdown in mouse SSCs with self-renewal assay readout","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean knockdown with defined cellular phenotype; single lab, single method","pmids":["32376790"],"is_preprint":false},{"year":2025,"finding":"Structural modeling and functional studies suggest that MAP7D3 binding to the kinesin-1 KHC coiled-coil region competes with intramolecular coiled-coil interactions that stabilize the autoinhibited kinesin-1 conformation, thereby activating kinesin-1 motor activity.","method":"8.0-Å cryo-EM structure of autoinhibited kinesin-1 heterotetramer; structural modeling of MAP7D3 interaction site; functional motility assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — cryo-EM structure plus functional studies, but MAP7D3-specific interaction is inferred from structural modeling rather than directly resolved; preprint, single study","pmids":["40791459"],"is_preprint":true},{"year":2023,"finding":"A frameshift mutation c.2174_2177del (p.Thr725MetfsTer2) in MAP7D3, causing loss of the C-terminal tail, was identified in two siblings with severe intellectual disability and autistic traits; 3D modeling predicts this truncation destabilizes the protein and may impair kinesin-1 binding to microtubules via an allosteric effect.","method":"Next-generation sequencing, segregation analysis, 3D protein modeling","journal":"Journal of molecular neuroscience : MN","confidence":"Low","confidence_rationale":"Tier 4 / Weak — structural prediction only for the mechanistic claim; no direct experimental validation of kinesin-1 binding disruption; single report","pmids":["37817054"],"is_preprint":false},{"year":2023,"finding":"Truncating variants in MAP7D3 in an infertile asthenozoospermic patient reduced MAP7D3 transcripts and protein in spermatozoa, and patient spermatozoa were unable to induce phosphorylation cascades associated with capacitation.","method":"Exome sequencing; RT-PCR and western blot of patient sperm; in vitro capacitation phosphorylation assays","journal":"iScience","confidence":"Low","confidence_rationale":"Tier 3 / Weak — patient-based loss-of-function with defined functional readout, but confounded by co-occurring IQCH variant; single case, mechanistic attribution to MAP7D3 alone is uncertain","pmids":["37520705"],"is_preprint":false}],"current_model":"MAP7D3 is a microtubule-associated protein that binds microtubules through both N-terminal coiled-coil motifs and a C-terminal MAP7 domain/C-tail region (binding the tubulin C-terminal tail, competing with tau), promotes microtubule polymerization and stability, localizes to the mitotic spindle where it forms a complex with DDA3 to inhibit Kif2a-mediated minus-end depolymerization and ensure proper chromosome segregation, supports spermatogonial stem cell self-renewal, and is proposed to activate kinesin-1 by disrupting its autoinhibited conformation through binding the KHC coiled-coil region."},"narrative":{"mechanistic_narrative":"MAP7D3 is a microtubule-associated protein that binds and stabilizes microtubules and contributes to mitotic spindle integrity and accurate chromosome segregation [PMID:15561729, PMID:27284004]. It engages microtubules through its MAP7 domain together with a C-terminal tail that contacts the tubulin C-terminal tail and competes with tau for the same binding site, promoting microtubule polymerization in vitro [PMID:24927501]. On the spindle, MAP7D3 forms a complex with DDA3 (PSRC1) and restrains DDA3-dependent recruitment of the kinesin-13 depolymerase Kif2a to spindle minus ends; loss of MAP7D3 produces aberrant Kif2a activity, reduced spindle stability, and segregation defects spanning unaligned, lagging, and bridged chromosomes [PMID:27284004]. Beyond mitosis, MAP7D3 supports spermatogonial stem cell self-renewal [PMID:32376790]. The available corpus does not establish the molecular detail of MAP7D3-dependent kinesin-1 activation beyond a structural-modeling inference that its binding to the KHC coiled-coil disrupts the autoinhibited motor conformation [PMID:40791459].","teleology":[{"year":2004,"claim":"Established MAP7D3 as a bona fide spindle-associated protein, placing an uncharacterized FLJ12649 product within the mitotic apparatus.","evidence":"MS/MS proteomics of purified human mitotic spindles plus localization of tagged protein in mitotic cells","pmids":["15561729"],"confidence":"Medium","gaps":["No molecular function or microtubule-binding mechanism defined","Spindle role not yet linked to a phenotype"]},{"year":2014,"claim":"Defined the biochemical basis of microtubule association, showing MAP7D3 binds microtubules via its MAP7 domain and C-terminal tail and promotes polymerization, competing with tau.","evidence":"In vitro reconstitution with quantified binding (Kd ~3 µM), sedimentation and tau-competition assays, tubulin C-tail binding","pmids":["24927501"],"confidence":"High","gaps":["Cellular consequence of tau competition not tested","Contribution of N-terminal regions to binding not resolved here"]},{"year":2016,"claim":"Connected MAP7D3's spindle localization to a mechanism for accurate segregation, showing it acts through a DDA3 complex to limit Kif2a-mediated minus-end depolymerization.","evidence":"Co-IP complex identification, siRNA knockdown with defined mitotic phenotypes, immunofluorescence of Kif2a recruitment","pmids":["27284004"],"confidence":"High","gaps":["Direct vs indirect inhibition of Kif2a recruitment not fully separated","Structural basis of MAP7D3–DDA3 interaction unknown"]},{"year":2020,"claim":"Extended MAP7D3 function beyond mitosis to tissue-specific stem cell biology by implicating it in spermatogonial stem cell self-renewal.","evidence":"siRNA knockdown in mouse spermatogonial stem cells with self-renewal assay readout","pmids":["32376790"],"confidence":"Medium","gaps":["Molecular pathway linking MAP7D3 to self-renewal not defined","Single method, single lab"]},{"year":2023,"claim":"Linked MAP7D3 loss-of-function to human phenotypes, associating truncating variants with intellectual disability/autistic traits and with impaired sperm capacitation.","evidence":"NGS/exome sequencing, segregation analysis, patient sperm RT-PCR/western blot, in vitro capacitation assays, 3D modeling","pmids":["37817054","37520705"],"confidence":"Low","gaps":["Mechanistic claims rest on structural prediction without experimental validation","Sperm phenotype confounded by co-occurring IQCH variant","Causality for neurodevelopmental phenotype not functionally proven"]},{"year":2025,"claim":"Proposed a kinesin-1 regulatory role, modeling MAP7D3 binding to the KHC coiled-coil as a means to relieve motor autoinhibition.","evidence":"8.0-Å cryo-EM of autoinhibited kinesin-1 heterotetramer, structural modeling of the MAP7D3 site, motility assays (preprint)","pmids":["40791459"],"confidence":"Medium","gaps":["MAP7D3 interaction inferred from modeling rather than directly resolved","Preprint, single study","Activation not shown for endogenous MAP7D3 in cells"]},{"year":null,"claim":"How MAP7D3's microtubule-stabilizing activity, spindle regulation, kinesin-1 activation, and tissue-specific roles are integrated into a single mechanistic program remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structure of MAP7D3 bound to microtubules or kinesin","Direct demonstration of kinesin-1 activation by MAP7D3 lacking","Mechanism connecting microtubule function to stem cell self-renewal unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1,2]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[2]}],"complexes":[],"partners":["PSRC1","KIF2A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IWC1","full_name":"MAP7 domain-containing protein 3","aliases":[],"length_aa":876,"mass_kda":98.4,"function":"Promotes the assembly and stability of microtubules","subcellular_location":"Cytoplasm, cytoskeleton, spindle","url":"https://www.uniprot.org/uniprotkb/Q8IWC1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MAP7D3","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CALM2","stoichiometry":0.2},{"gene":"CALM3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MAP7D3","total_profiled":1310},"omim":[{"mim_id":"621363","title":"MAP7 DOMAIN-CONTAINING PROTEIN 1; MAP7D1","url":"https://www.omim.org/entry/621363"},{"mim_id":"604108","title":"MICROTUBULE-ASSOCIATED PROTEIN 7; MAP7","url":"https://www.omim.org/entry/604108"},{"mim_id":"300930","title":"MAP7 DOMAIN-CONTAINING PROTEIN 3; MAP7D3","url":"https://www.omim.org/entry/300930"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Plasma membrane","reliability":"Uncertain"},{"location":"Centrosome","reliability":"Uncertain"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Primary cilium","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MAP7D3"},"hgnc":{"alias_symbol":["FLJ12649"],"prev_symbol":[]},"alphafold":{"accession":"Q8IWC1","domains":[{"cath_id":"1.20.5","chopping":"65-157","consensus_level":"medium","plddt":91.6265,"start":65,"end":157}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IWC1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IWC1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IWC1-F1-predicted_aligned_error_v6.png","plddt_mean":55.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MAP7D3","jax_strain_url":"https://www.jax.org/strain/search?query=MAP7D3"},"sequence":{"accession":"Q8IWC1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IWC1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IWC1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IWC1"}},"corpus_meta":[{"pmid":"15561729","id":"PMC_15561729","title":"Proteome analysis of the human mitotic spindle.","date":"2004","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/15561729","citation_count":224,"is_preprint":false},{"pmid":"24927501","id":"PMC_24927501","title":"C-terminal region of MAP7 domain containing protein 3 (MAP7D3) promotes microtubule polymerization by binding at the C-terminal tail of tubulin.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24927501","citation_count":25,"is_preprint":false},{"pmid":"32376790","id":"PMC_32376790","title":"Human X chromosome exome sequencing identifies BCORL1 as contributor to spermatogenesis.","date":"2020","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32376790","citation_count":21,"is_preprint":false},{"pmid":"27284004","id":"PMC_27284004","title":"DDA3 and Mdp3 modulate Kif2a recruitment onto the mitotic spindle to control minus-end spindle dynamics.","date":"2016","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/27284004","citation_count":16,"is_preprint":false},{"pmid":"27409453","id":"PMC_27409453","title":"Muscle hypertrophy as the presenting sign in a patient with a complete FHL1 deletion.","date":"2016","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27409453","citation_count":8,"is_preprint":false},{"pmid":"36259570","id":"PMC_36259570","title":"Identification of risk genes in Chinese nonobstructive azoospermia patients based on whole-exome sequencing.","date":"2023","source":"Asian journal of andrology","url":"https://pubmed.ncbi.nlm.nih.gov/36259570","citation_count":6,"is_preprint":false},{"pmid":"37817054","id":"PMC_37817054","title":"A Novel Mutation in the MAP7D3 Gene in Two Siblings with Severe Intellectual Disability and Autistic Traits: Concurrent Assessment of BDNF Functional Polymorphism, X-Inactivation and Oxidative Stress to Explain Disease Severity.","date":"2023","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/37817054","citation_count":4,"is_preprint":false},{"pmid":"37520705","id":"PMC_37520705","title":"Identification of IQCH as a calmodulin-associated protein required for sperm motility in humans.","date":"2023","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/37520705","citation_count":4,"is_preprint":false},{"pmid":"40791459","id":"PMC_40791459","title":"Structural Basis of Kinesin-1 Autoinhibition and Its Control of Microtubule-Based Motility.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40791459","citation_count":3,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6655,"output_tokens":1801,"usd":0.02349,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8636,"output_tokens":2202,"usd":0.049115,"stage2_stop_reason":"end_turn"},"total_usd":0.072605,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"MAP7D3 (FLJ12649) was identified as a component of the human mitotic spindle by mass spectrometry analysis of purified spindles, and tagged MAP7D3 localized to the mitotic spindle in transfected cells.\",\n      \"method\": \"MS/MS proteomics of purified human mitotic spindles; fluorescence localization of tagged protein in transfected mitotic cells\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment in cells, supported by proteomic identification; single study but two orthogonal methods\",\n      \"pmids\": [\"15561729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The MAP7 domain (MD) of MAP7D3, together with its C-terminal tail (CT), binds to microtubules and promotes microtubule polymerization in vitro; MDCT binds reconstituted microtubules with an apparent Kd of ~3 µM, localizes along preassembled microtubules, competes with tau for the same binding site, and binds the C-terminal tail of tubulin.\",\n      \"method\": \"In vitro microtubule polymerization assays, sedimentation binding assays, competition experiments with tau, immunostaining of tagged protein on microtubules, binding to tubulin in HeLa cell extracts\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with quantified binding, mutagenesis-analogous domain dissection, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"24927501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MAP7D3 (Mdp3) forms a complex with DDA3 (PSRC1) and controls spindle microtubule dynamics at the minus end by inhibiting DDA3-mediated recruitment of the kinesin-13 depolymerase Kif2a to the spindle; depletion of MAP7D3 results in aberrant Kif2a activity, decreased spindle stability, unaligned chromosomes in metaphase, lagging chromosomes in anaphase, and chromosome bridges in telophase/cytokinesis.\",\n      \"method\": \"Co-immunoprecipitation (complex identification), siRNA knockdown with defined mitotic phenotypes, immunofluorescence of spindle localization and Kif2a recruitment\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal complex identification, loss-of-function with specific mechanistic phenotypes, multiple orthogonal methods; independently extends spindle localization finding from 2004\",\n      \"pmids\": [\"27284004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Knockdown of Mtap7d3 in mouse spermatogonial stem cells (SSCs) inhibits SSC self-renewal in vitro, establishing a role for MAP7D3 in spermatogonial stem cell maintenance.\",\n      \"method\": \"siRNA knockdown in mouse SSCs with self-renewal assay readout\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockdown with defined cellular phenotype; single lab, single method\",\n      \"pmids\": [\"32376790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Structural modeling and functional studies suggest that MAP7D3 binding to the kinesin-1 KHC coiled-coil region competes with intramolecular coiled-coil interactions that stabilize the autoinhibited kinesin-1 conformation, thereby activating kinesin-1 motor activity.\",\n      \"method\": \"8.0-Å cryo-EM structure of autoinhibited kinesin-1 heterotetramer; structural modeling of MAP7D3 interaction site; functional motility assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — cryo-EM structure plus functional studies, but MAP7D3-specific interaction is inferred from structural modeling rather than directly resolved; preprint, single study\",\n      \"pmids\": [\"40791459\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A frameshift mutation c.2174_2177del (p.Thr725MetfsTer2) in MAP7D3, causing loss of the C-terminal tail, was identified in two siblings with severe intellectual disability and autistic traits; 3D modeling predicts this truncation destabilizes the protein and may impair kinesin-1 binding to microtubules via an allosteric effect.\",\n      \"method\": \"Next-generation sequencing, segregation analysis, 3D protein modeling\",\n      \"journal\": \"Journal of molecular neuroscience : MN\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — structural prediction only for the mechanistic claim; no direct experimental validation of kinesin-1 binding disruption; single report\",\n      \"pmids\": [\"37817054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Truncating variants in MAP7D3 in an infertile asthenozoospermic patient reduced MAP7D3 transcripts and protein in spermatozoa, and patient spermatozoa were unable to induce phosphorylation cascades associated with capacitation.\",\n      \"method\": \"Exome sequencing; RT-PCR and western blot of patient sperm; in vitro capacitation phosphorylation assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — patient-based loss-of-function with defined functional readout, but confounded by co-occurring IQCH variant; single case, mechanistic attribution to MAP7D3 alone is uncertain\",\n      \"pmids\": [\"37520705\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAP7D3 is a microtubule-associated protein that binds microtubules through both N-terminal coiled-coil motifs and a C-terminal MAP7 domain/C-tail region (binding the tubulin C-terminal tail, competing with tau), promotes microtubule polymerization and stability, localizes to the mitotic spindle where it forms a complex with DDA3 to inhibit Kif2a-mediated minus-end depolymerization and ensure proper chromosome segregation, supports spermatogonial stem cell self-renewal, and is proposed to activate kinesin-1 by disrupting its autoinhibited conformation through binding the KHC coiled-coil region.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MAP7D3 is a microtubule-associated protein that binds and stabilizes microtubules and contributes to mitotic spindle integrity and accurate chromosome segregation [#0, #2]. It engages microtubules through its MAP7 domain together with a C-terminal tail that contacts the tubulin C-terminal tail and competes with tau for the same binding site, promoting microtubule polymerization in vitro [#1]. On the spindle, MAP7D3 forms a complex with DDA3 (PSRC1) and restrains DDA3-dependent recruitment of the kinesin-13 depolymerase Kif2a to spindle minus ends; loss of MAP7D3 produces aberrant Kif2a activity, reduced spindle stability, and segregation defects spanning unaligned, lagging, and bridged chromosomes [#2]. Beyond mitosis, MAP7D3 supports spermatogonial stem cell self-renewal [#3]. The available corpus does not establish the molecular detail of MAP7D3-dependent kinesin-1 activation beyond a structural-modeling inference that its binding to the KHC coiled-coil disrupts the autoinhibited motor conformation [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established MAP7D3 as a bona fide spindle-associated protein, placing an uncharacterized FLJ12649 product within the mitotic apparatus.\",\n      \"evidence\": \"MS/MS proteomics of purified human mitotic spindles plus localization of tagged protein in mitotic cells\",\n      \"pmids\": [\"15561729\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular function or microtubule-binding mechanism defined\", \"Spindle role not yet linked to a phenotype\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the biochemical basis of microtubule association, showing MAP7D3 binds microtubules via its MAP7 domain and C-terminal tail and promotes polymerization, competing with tau.\",\n      \"evidence\": \"In vitro reconstitution with quantified binding (Kd ~3 µM), sedimentation and tau-competition assays, tubulin C-tail binding\",\n      \"pmids\": [\"24927501\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular consequence of tau competition not tested\", \"Contribution of N-terminal regions to binding not resolved here\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected MAP7D3's spindle localization to a mechanism for accurate segregation, showing it acts through a DDA3 complex to limit Kif2a-mediated minus-end depolymerization.\",\n      \"evidence\": \"Co-IP complex identification, siRNA knockdown with defined mitotic phenotypes, immunofluorescence of Kif2a recruitment\",\n      \"pmids\": [\"27284004\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect inhibition of Kif2a recruitment not fully separated\", \"Structural basis of MAP7D3–DDA3 interaction unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended MAP7D3 function beyond mitosis to tissue-specific stem cell biology by implicating it in spermatogonial stem cell self-renewal.\",\n      \"evidence\": \"siRNA knockdown in mouse spermatogonial stem cells with self-renewal assay readout\",\n      \"pmids\": [\"32376790\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular pathway linking MAP7D3 to self-renewal not defined\", \"Single method, single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked MAP7D3 loss-of-function to human phenotypes, associating truncating variants with intellectual disability/autistic traits and with impaired sperm capacitation.\",\n      \"evidence\": \"NGS/exome sequencing, segregation analysis, patient sperm RT-PCR/western blot, in vitro capacitation assays, 3D modeling\",\n      \"pmids\": [\"37817054\", \"37520705\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Mechanistic claims rest on structural prediction without experimental validation\", \"Sperm phenotype confounded by co-occurring IQCH variant\", \"Causality for neurodevelopmental phenotype not functionally proven\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Proposed a kinesin-1 regulatory role, modeling MAP7D3 binding to the KHC coiled-coil as a means to relieve motor autoinhibition.\",\n      \"evidence\": \"8.0-Å cryo-EM of autoinhibited kinesin-1 heterotetramer, structural modeling of the MAP7D3 site, motility assays (preprint)\",\n      \"pmids\": [\"40791459\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"MAP7D3 interaction inferred from modeling rather than directly resolved\", \"Preprint, single study\", \"Activation not shown for endogenous MAP7D3 in cells\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MAP7D3's microtubule-stabilizing activity, spindle regulation, kinesin-1 activation, and tissue-specific roles are integrated into a single mechanistic program remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of MAP7D3 bound to microtubules or kinesin\", \"Direct demonstration of kinesin-1 activation by MAP7D3 lacking\", \"Mechanism connecting microtubule function to stem cell self-renewal unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005819\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PSRC1\", \"KIF2A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":5,"faith_total":5,"faith_pct":100.0}}