{"gene":"MYCBPAP","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2002,"finding":"MYCBPAP (AMAP-1) was identified as a novel AMY-1-binding protein via yeast two-hybrid screening of a human testis cDNA library. MYCBPAP co-localizes with AMY-1 in human 293T and HeLa cells, and is specifically expressed in the testis post-meiotically, suggesting a role in spermatogenesis.","method":"Yeast two-hybrid screening, co-immunoprecipitation/co-localization in human cell lines","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, two orthogonal methods (two-hybrid + co-localization), but no functional readout beyond expression pattern","pmids":["12151104"],"is_preprint":false},{"year":2021,"finding":"MYCBPAP (human ortholog of Chlamydomonas FAP147) is a component of the C2a projection of the ciliary central apparatus. In fap70-1 Chlamydomonas mutants lacking the C2a projection, FAP147 is absent from axonemes, and FAP147 co-immunoprecipitates with HA-tagged FAP70, indicating it is part of the FAP70/FAP65/FAP147 C2a projection complex.","method":"Cryo-electron microscopy, mass spectrometry of mutant axonemes, co-immunoprecipitation with HA-tagged FAP70","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — cryo-EM structural localization, MS-based protein absence in mutant, and reciprocal Co-IP in a single rigorous study","pmids":["33988244"],"is_preprint":false},{"year":2024,"finding":"MYCBPAP is required for centrosome-nuclear envelope docking and sperm tail biogenesis in mice. Mycbpap-knockout mice are male-infertile with disrupted centrosome docking and abnormal flagellar biogenesis. Interactome analyses revealed MYCBPAP binds central apparatus proteins CFAP65 and CFAP70 (C2a projection components) and centrosome-associated protein CCP110.","method":"Knockout mouse model, transgenic rescue, interactome/co-IP mass spectrometry","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO with defined fertility/structural phenotype, transgenic rescue, and interactome by MS in a single rigorous study","pmids":["39092789"],"is_preprint":false},{"year":2024,"finding":"Homozygous loss-of-function variants in MYCBPAP cause asthenoteratozoospermia in humans. In Mycbpap-knockout mice, deletion leads to disrupted acrosome biogenesis, abnormally elongated manchette, reduced sperm motility, and abnormal sperm morphology. Endogenous co-immunoprecipitation/MS identified MYCBPAP interactions with central apparatus proteins CFAP65 and CFAP70, and the ribosome elimination-related protein ARMC3.","method":"Whole-exome sequencing (human), knockout mouse model, proteomic analysis of testes, endogenous co-IP/mass spectrometry","journal":"Science China. Life sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — human genetic evidence replicated in two cohorts, KO mouse with multiple orthogonal phenotypic readouts, and endogenous interactome by MS","pmids":["39704931"],"is_preprint":false},{"year":2024,"finding":"MYCBPAP shuttled by bone marrow mesenchymal stem cell-derived exosomes facilitates synaptic remodeling after ischemic stroke. Knockdown of MYCBPAP inhibited the protective effects of BMSC exosomes on rat neuronal cells and exacerbated synaptic damage in spontaneously hypertensive rats with ischemic stroke.","method":"Exosome internalization assay, MYCBPAP knockdown with loss-of-function phenotype (CCK-8, LDH, immunofluorescence, immunohistochemistry, Western blot)","journal":"Journal of chemical neuroanatomy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single loss-of-function approach without defined molecular mechanism for synaptic remodeling; no direct mechanistic pathway placement","pmids":["37423468"],"is_preprint":false},{"year":2020,"finding":"MYCBPAP protein localizes to motile cilia, as determined by new localization experiments on ciliated cells as part of a transcriptional signature study of motile cilia-associated genes.","method":"mRNA and protein localization in motile ciliated cells (direct localization experiment)","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — localization only, no functional consequence described for MYCBPAP specifically; part of a multi-gene study","pmids":["32616903"],"is_preprint":false},{"year":2026,"finding":"The MYCBPAP domain (residues 129–639) of FAP147 (MYCBPAP) binds to the C-terminus (residues 47–92) of FAP174 within the Chlamydomonas C2a projection. Molecular dynamics simulations identified stable interfacial contacts, and individual alanine substitutions of key FAP174 residues retained the interaction, indicating the interaction depends on a broad interface rather than discrete residues.","method":"In vitro overlay assay, in silico docking (CABS-Dock), molecular dynamics simulation, alanine mutagenesis of FAP174","journal":"Cytoskeleton (Hoboken, N.J.)","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — domain mapping by overlay assay with mutagenesis validation, supported by MD simulations, single lab","pmids":["41724729"],"is_preprint":false}],"current_model":"MYCBPAP is a conserved central apparatus (C2a projection) protein in motile cilia that binds CFAP65/FAP65, CFAP70/FAP70, and FAP174/MYCBP-1 to form the C2a scaffold; in mammals it is essential for centrosome–nuclear envelope docking, acrosome biogenesis, and sperm tail assembly, with loss-of-function causing male infertility in mice and humans (asthenoteratozoospermia), and it was originally identified as a testis-specific binding partner of the c-Myc-associated protein AMY-1."},"narrative":{"mechanistic_narrative":"MYCBPAP is a conserved structural component of the C2a projection of the central apparatus in motile cilia and flagella, where it functions within a scaffold complex with the central-apparatus proteins CFAP65/FAP65, CFAP70/FAP70, and FAP174/MYCBP-1 [PMID:33988244, PMID:39092789, PMID:41724729]. Its incorporation into the axoneme is dependent on the C2a projection: in fap70 Chlamydomonas mutants lacking C2a, the MYCBPAP ortholog FAP147 is absent, and it co-immunoprecipitates with FAP70, placing it physically within the FAP70/FAP65/FAP147 complex [PMID:33988244]. The MYCBPAP domain (residues 129–639) binds the C-terminus of FAP174 through a broad interfacial contact rather than discrete residues [PMID:41724729]. In mammals MYCBPAP is essential for male germ cell differentiation, mediating centrosome–nuclear envelope docking, acrosome biogenesis, manchette organization, and sperm tail assembly; knockout mice are infertile with disrupted centrosome docking and abnormal flagellar biogenesis, and its interactome includes CFAP65, CFAP70, the centrosome-associated protein CCP110, and the ribosome elimination-related protein ARMC3 [PMID:39092789, PMID:39704931]. Homozygous loss-of-function variants in MYCBPAP cause asthenoteratozoospermia in humans [PMID:39704931]. It was originally identified as a testis-specific, post-meiotically expressed binding partner of the c-Myc-associated protein AMY-1 [PMID:12151104].","teleology":[{"year":2002,"claim":"Establishing the first molecular handle on MYCBPAP, it was identified as a testis-specific binding partner of the c-Myc-associated protein AMY-1, hinting at a role in spermatogenesis.","evidence":"Yeast two-hybrid screen of human testis cDNA with co-localization in 293T/HeLa cells","pmids":["12151104"],"confidence":"Medium","gaps":["No functional readout beyond expression pattern and binding","Cellular role of the AMY-1 interaction undefined","Connection to cilia/flagella not yet made"]},{"year":2020,"claim":"Localization of MYCBPAP protein to motile cilia connected the testis-expressed protein to the ciliary apparatus.","evidence":"mRNA/protein localization in motile ciliated cells within a multi-gene transcriptional signature study","pmids":["32616903"],"confidence":"Low","gaps":["Localization only, no functional consequence for MYCBPAP","Sub-axonemal position not resolved","No interacting partners identified"]},{"year":2021,"claim":"Structural and biochemical work placed MYCBPAP/FAP147 as a defined component of the C2a projection of the central apparatus within a FAP70/FAP65/FAP147 complex, defining where the protein sits in the axoneme.","evidence":"Cryo-EM, mass spectrometry of fap70-1 mutant axonemes, and reciprocal Co-IP with HA-FAP70 in Chlamydomonas","pmids":["33988244"],"confidence":"High","gaps":["Stoichiometry and assembly order of the C2a complex unresolved","Mammalian role not addressed","Direct binding interfaces among subunits not mapped"]},{"year":2024,"claim":"Mouse knockout and human genetics established MYCBPAP as essential for male fertility, linking its loss to defective centrosome-nuclear envelope docking, acrosome/manchette defects, and sperm tail biogenesis, and tying it to asthenoteratozoospermia.","evidence":"Knockout mice with transgenic rescue, testis proteomics, whole-exome sequencing of human patients, and endogenous co-IP/MS identifying CFAP65, CFAP70, CCP110, and ARMC3","pmids":["39092789","39704931"],"confidence":"High","gaps":["Mechanism by which MYCBPAP enables centrosome docking unknown","Functional significance of CCP110 and ARMC3 interactions not dissected","How a central-apparatus protein contributes to acrosome/manchette biology unexplained"]},{"year":2026,"claim":"Domain mapping resolved the molecular basis of MYCBPAP's place in the C2a complex, showing its central domain engages FAP174 through a broad interface.","evidence":"In vitro overlay assay, CABS-Dock docking, molecular dynamics, and alanine mutagenesis of FAP174 in Chlamydomonas","pmids":["41724729"],"confidence":"Medium","gaps":["Interaction not validated in a reconstituted full complex","Functional consequence of disrupting the interface in vivo untested","Single-lab in vitro/in silico characterization"]},{"year":2024,"claim":"A separate finding implicated MYCBPAP in exosome-mediated synaptic remodeling after ischemic stroke, raising the possibility of a non-ciliary role.","evidence":"BMSC-derived exosome internalization assays and MYCBPAP knockdown loss-of-function in rat neurons and stroke model","pmids":["37423468"],"confidence":"Low","gaps":["Single loss-of-function approach without a defined molecular mechanism","No pathway placement linking MYCBPAP to synaptic remodeling","Relationship to its ciliary/flagellar function unclear"]},{"year":null,"claim":"How MYCBPAP mechanistically couples its central-apparatus scaffolding role to centrosome-nuclear envelope docking and acrosome/manchette assembly in spermatids remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No mechanistic link between C2a scaffolding and centrosome docking","Roles of CCP110 and ARMC3 interactions undefined","Whether the AMY-1 interaction has functional relevance in spermatogenesis unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,2,6]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,6]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[1,5]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[1,2]}],"complexes":["C2a projection (central apparatus)"],"partners":["CFAP70","CFAP65","FAP174","CCP110","ARMC3","AMY-1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8TBZ2","full_name":"MYCBP-associated protein","aliases":["AMAM-1","AMY-1-binding protein 1","AMAP-1"],"length_aa":984,"mass_kda":111.9,"function":"Plays a crucial role in centrosome-nuclear envelope docking during spermiogenesis, a key step for anchoring the centrosome to the nucleus that is essential for proper sperm flagellum biogenesis. Also required for acrosome biogenesis, manchette organization, and spermatid head morphogenesis, contributing to the complete and functional assembly of the sperm flagellum","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q8TBZ2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MYCBPAP","classification":"Not Classified","n_dependent_lines":39,"n_total_lines":1208,"dependency_fraction":0.03228476821192053},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MYCBPAP","total_profiled":1310},"omim":[{"mim_id":"609835","title":"MYCBP-ASSOCIATED PROTEIN; MYCBPAP","url":"https://www.omim.org/entry/609835"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"testis","ntpm":61.7}],"url":"https://www.proteinatlas.org/search/MYCBPAP"},"hgnc":{"alias_symbol":["AMAP-1","DKFZp434N1415"],"prev_symbol":[]},"alphafold":{"accession":"Q8TBZ2","domains":[{"cath_id":"-","chopping":"232-260_268-354","consensus_level":"high","plddt":73.6184,"start":232,"end":354},{"cath_id":"2.60.40.10","chopping":"362-375_402-470_480-541","consensus_level":"high","plddt":81.6298,"start":362,"end":541}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TBZ2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TBZ2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TBZ2-F1-predicted_aligned_error_v6.png","plddt_mean":59.72},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MYCBPAP","jax_strain_url":"https://www.jax.org/strain/search?query=MYCBPAP"},"sequence":{"accession":"Q8TBZ2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8TBZ2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8TBZ2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TBZ2"}},"corpus_meta":[{"pmid":"32616903","id":"PMC_32616903","title":"The transcriptional signature associated with human motile cilia.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32616903","citation_count":46,"is_preprint":false},{"pmid":"33988244","id":"PMC_33988244","title":"Chlamydomonas FAP70 is a component of the previously uncharacterized ciliary central apparatus projection C2a.","date":"2021","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/33988244","citation_count":18,"is_preprint":false},{"pmid":"12151104","id":"PMC_12151104","title":"AMAP-1, a novel testis-specific AMY-1-binding protein, is differentially expressed during the course of spermatogenesis.","date":"2002","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/12151104","citation_count":12,"is_preprint":false},{"pmid":"37423468","id":"PMC_37423468","title":"Exosome-shuttled MYCBPAP from bone marrow mesenchymal stem cells regulates synaptic remodeling and ameliorates ischemic stroke in rats.","date":"2023","source":"Journal of chemical neuroanatomy","url":"https://pubmed.ncbi.nlm.nih.gov/37423468","citation_count":8,"is_preprint":false},{"pmid":"39092789","id":"PMC_39092789","title":"MYCBPAP is a central apparatus protein required for centrosome-nuclear envelope docking and sperm tail biogenesis in mice.","date":"2024","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/39092789","citation_count":3,"is_preprint":false},{"pmid":"39704931","id":"PMC_39704931","title":"Homozygous deleterious variants in MYCBPAP induce asthenoteratozoospermia involving abnormal acrosome biogenesis, manchette structure and sperm tail assembly in humans and mice.","date":"2024","source":"Science China. Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39704931","citation_count":2,"is_preprint":false},{"pmid":"40979936","id":"PMC_40979936","title":"Identification of Specific LncRNA Markers in Severe Tuberculosis for Early Diagnosis.","date":"2025","source":"Infection and drug resistance","url":"https://pubmed.ncbi.nlm.nih.gov/40979936","citation_count":1,"is_preprint":false},{"pmid":"41504506","id":"PMC_41504506","title":"Genetic correlations among diaphragmatic, femoral, inguinal, ventral, and umbilical hernias and identification of their candidate genes.","date":"2026","source":"International journal of surgery (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/41504506","citation_count":1,"is_preprint":false},{"pmid":"41724729","id":"PMC_41724729","title":"Domain-Level Interaction of FAP174 (MYCBP-1) and FAP147 (MYCBPAP) Proteins of the C2a Projection of Chlamydomonas Cilia.","date":"2026","source":"Cytoskeleton (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/41724729","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6834,"output_tokens":1861,"usd":0.024209,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8726,"output_tokens":2763,"usd":0.056352,"stage2_stop_reason":"end_turn"},"total_usd":0.080561,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"MYCBPAP (AMAP-1) was identified as a novel AMY-1-binding protein via yeast two-hybrid screening of a human testis cDNA library. MYCBPAP co-localizes with AMY-1 in human 293T and HeLa cells, and is specifically expressed in the testis post-meiotically, suggesting a role in spermatogenesis.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation/co-localization in human cell lines\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, two orthogonal methods (two-hybrid + co-localization), but no functional readout beyond expression pattern\",\n      \"pmids\": [\"12151104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MYCBPAP (human ortholog of Chlamydomonas FAP147) is a component of the C2a projection of the ciliary central apparatus. In fap70-1 Chlamydomonas mutants lacking the C2a projection, FAP147 is absent from axonemes, and FAP147 co-immunoprecipitates with HA-tagged FAP70, indicating it is part of the FAP70/FAP65/FAP147 C2a projection complex.\",\n      \"method\": \"Cryo-electron microscopy, mass spectrometry of mutant axonemes, co-immunoprecipitation with HA-tagged FAP70\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — cryo-EM structural localization, MS-based protein absence in mutant, and reciprocal Co-IP in a single rigorous study\",\n      \"pmids\": [\"33988244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MYCBPAP is required for centrosome-nuclear envelope docking and sperm tail biogenesis in mice. Mycbpap-knockout mice are male-infertile with disrupted centrosome docking and abnormal flagellar biogenesis. Interactome analyses revealed MYCBPAP binds central apparatus proteins CFAP65 and CFAP70 (C2a projection components) and centrosome-associated protein CCP110.\",\n      \"method\": \"Knockout mouse model, transgenic rescue, interactome/co-IP mass spectrometry\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO with defined fertility/structural phenotype, transgenic rescue, and interactome by MS in a single rigorous study\",\n      \"pmids\": [\"39092789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Homozygous loss-of-function variants in MYCBPAP cause asthenoteratozoospermia in humans. In Mycbpap-knockout mice, deletion leads to disrupted acrosome biogenesis, abnormally elongated manchette, reduced sperm motility, and abnormal sperm morphology. Endogenous co-immunoprecipitation/MS identified MYCBPAP interactions with central apparatus proteins CFAP65 and CFAP70, and the ribosome elimination-related protein ARMC3.\",\n      \"method\": \"Whole-exome sequencing (human), knockout mouse model, proteomic analysis of testes, endogenous co-IP/mass spectrometry\",\n      \"journal\": \"Science China. Life sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human genetic evidence replicated in two cohorts, KO mouse with multiple orthogonal phenotypic readouts, and endogenous interactome by MS\",\n      \"pmids\": [\"39704931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MYCBPAP shuttled by bone marrow mesenchymal stem cell-derived exosomes facilitates synaptic remodeling after ischemic stroke. Knockdown of MYCBPAP inhibited the protective effects of BMSC exosomes on rat neuronal cells and exacerbated synaptic damage in spontaneously hypertensive rats with ischemic stroke.\",\n      \"method\": \"Exosome internalization assay, MYCBPAP knockdown with loss-of-function phenotype (CCK-8, LDH, immunofluorescence, immunohistochemistry, Western blot)\",\n      \"journal\": \"Journal of chemical neuroanatomy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single loss-of-function approach without defined molecular mechanism for synaptic remodeling; no direct mechanistic pathway placement\",\n      \"pmids\": [\"37423468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MYCBPAP protein localizes to motile cilia, as determined by new localization experiments on ciliated cells as part of a transcriptional signature study of motile cilia-associated genes.\",\n      \"method\": \"mRNA and protein localization in motile ciliated cells (direct localization experiment)\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — localization only, no functional consequence described for MYCBPAP specifically; part of a multi-gene study\",\n      \"pmids\": [\"32616903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"The MYCBPAP domain (residues 129–639) of FAP147 (MYCBPAP) binds to the C-terminus (residues 47–92) of FAP174 within the Chlamydomonas C2a projection. Molecular dynamics simulations identified stable interfacial contacts, and individual alanine substitutions of key FAP174 residues retained the interaction, indicating the interaction depends on a broad interface rather than discrete residues.\",\n      \"method\": \"In vitro overlay assay, in silico docking (CABS-Dock), molecular dynamics simulation, alanine mutagenesis of FAP174\",\n      \"journal\": \"Cytoskeleton (Hoboken, N.J.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — domain mapping by overlay assay with mutagenesis validation, supported by MD simulations, single lab\",\n      \"pmids\": [\"41724729\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MYCBPAP is a conserved central apparatus (C2a projection) protein in motile cilia that binds CFAP65/FAP65, CFAP70/FAP70, and FAP174/MYCBP-1 to form the C2a scaffold; in mammals it is essential for centrosome–nuclear envelope docking, acrosome biogenesis, and sperm tail assembly, with loss-of-function causing male infertility in mice and humans (asthenoteratozoospermia), and it was originally identified as a testis-specific binding partner of the c-Myc-associated protein AMY-1.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MYCBPAP is a conserved structural component of the C2a projection of the central apparatus in motile cilia and flagella, where it functions within a scaffold complex with the central-apparatus proteins CFAP65/FAP65, CFAP70/FAP70, and FAP174/MYCBP-1 [#1, #2, #6]. Its incorporation into the axoneme is dependent on the C2a projection: in fap70 Chlamydomonas mutants lacking C2a, the MYCBPAP ortholog FAP147 is absent, and it co-immunoprecipitates with FAP70, placing it physically within the FAP70/FAP65/FAP147 complex [#1]. The MYCBPAP domain (residues 129\\u2013639) binds the C-terminus of FAP174 through a broad interfacial contact rather than discrete residues [#6]. In mammals MYCBPAP is essential for male germ cell differentiation, mediating centrosome\\u2013nuclear envelope docking, acrosome biogenesis, manchette organization, and sperm tail assembly; knockout mice are infertile with disrupted centrosome docking and abnormal flagellar biogenesis, and its interactome includes CFAP65, CFAP70, the centrosome-associated protein CCP110, and the ribosome elimination-related protein ARMC3 [#2, #3]. Homozygous loss-of-function variants in MYCBPAP cause asthenoteratozoospermia in humans [#3]. It was originally identified as a testis-specific, post-meiotically expressed binding partner of the c-Myc-associated protein AMY-1 [#0].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Establishing the first molecular handle on MYCBPAP, it was identified as a testis-specific binding partner of the c-Myc-associated protein AMY-1, hinting at a role in spermatogenesis.\",\n      \"evidence\": \"Yeast two-hybrid screen of human testis cDNA with co-localization in 293T/HeLa cells\",\n      \"pmids\": [\"12151104\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"No functional readout beyond expression pattern and binding\",\n        \"Cellular role of the AMY-1 interaction undefined\",\n        \"Connection to cilia/flagella not yet made\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Localization of MYCBPAP protein to motile cilia connected the testis-expressed protein to the ciliary apparatus.\",\n      \"evidence\": \"mRNA/protein localization in motile ciliated cells within a multi-gene transcriptional signature study\",\n      \"pmids\": [\"32616903\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Localization only, no functional consequence for MYCBPAP\",\n        \"Sub-axonemal position not resolved\",\n        \"No interacting partners identified\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Structural and biochemical work placed MYCBPAP/FAP147 as a defined component of the C2a projection of the central apparatus within a FAP70/FAP65/FAP147 complex, defining where the protein sits in the axoneme.\",\n      \"evidence\": \"Cryo-EM, mass spectrometry of fap70-1 mutant axonemes, and reciprocal Co-IP with HA-FAP70 in Chlamydomonas\",\n      \"pmids\": [\"33988244\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Stoichiometry and assembly order of the C2a complex unresolved\",\n        \"Mammalian role not addressed\",\n        \"Direct binding interfaces among subunits not mapped\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Mouse knockout and human genetics established MYCBPAP as essential for male fertility, linking its loss to defective centrosome-nuclear envelope docking, acrosome/manchette defects, and sperm tail biogenesis, and tying it to asthenoteratozoospermia.\",\n      \"evidence\": \"Knockout mice with transgenic rescue, testis proteomics, whole-exome sequencing of human patients, and endogenous co-IP/MS identifying CFAP65, CFAP70, CCP110, and ARMC3\",\n      \"pmids\": [\"39092789\", \"39704931\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Mechanism by which MYCBPAP enables centrosome docking unknown\",\n        \"Functional significance of CCP110 and ARMC3 interactions not dissected\",\n        \"How a central-apparatus protein contributes to acrosome/manchette biology unexplained\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Domain mapping resolved the molecular basis of MYCBPAP's place in the C2a complex, showing its central domain engages FAP174 through a broad interface.\",\n      \"evidence\": \"In vitro overlay assay, CABS-Dock docking, molecular dynamics, and alanine mutagenesis of FAP174 in Chlamydomonas\",\n      \"pmids\": [\"41724729\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Interaction not validated in a reconstituted full complex\",\n        \"Functional consequence of disrupting the interface in vivo untested\",\n        \"Single-lab in vitro/in silico characterization\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A separate finding implicated MYCBPAP in exosome-mediated synaptic remodeling after ischemic stroke, raising the possibility of a non-ciliary role.\",\n      \"evidence\": \"BMSC-derived exosome internalization assays and MYCBPAP knockdown loss-of-function in rat neurons and stroke model\",\n      \"pmids\": [\"37423468\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Single loss-of-function approach without a defined molecular mechanism\",\n        \"No pathway placement linking MYCBPAP to synaptic remodeling\",\n        \"Relationship to its ciliary/flagellar function unclear\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MYCBPAP mechanistically couples its central-apparatus scaffolding role to centrosome-nuclear envelope docking and acrosome/manchette assembly in spermatids remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"No mechanistic link between C2a scaffolding and centrosome docking\",\n        \"Roles of CCP110 and ARMC3 interactions undefined\",\n        \"Whether the AMY-1 interaction has functional relevance in spermatogenesis unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 2, 6]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [\n      \"C2a projection (central apparatus)\"\n    ],\n    \"partners\": [\n      \"CFAP70\",\n      \"CFAP65\",\n      \"FAP174\",\n      \"CCP110\",\n      \"ARMC3\",\n      \"AMY-1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}