{"gene":"MON1A","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2007,"finding":"MON1A ortholog SAND-1 in C. elegans is essential for RAB-7 function at the transition from early to late endosomes; loss of SAND-1 causes delayed endocytic transport and failure to deliver cargo to lysosomes, while initial RAB-7 recruitment is not affected by SAND-1 loss at lysosomes.","method":"C. elegans genetics (RNAi, loss-of-function mutants), fluorescence microscopy of endocytic cargo trafficking","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean loss-of-function with defined cellular phenotype, replicated across multiple cargo tracers and tissues, foundational ortholog paper","pmids":["17203072"],"is_preprint":false},{"year":2007,"finding":"Mon1a controls vesicular trafficking of ferroportin (the major iron exporter) to the macrophage cell surface; a missense allele of Mon1a (C57BL/10J) reduces surface ferroportin levels, increasing macrophage iron content. Mon1a also affects trafficking of cell-surface and secreted molecules unrelated to iron metabolism, indicating a general role in the mammalian secretory apparatus.","method":"Quantitative trait locus analysis, congenic mouse lines, cell-based trafficking assays","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — QTL mapping combined with cell-based trafficking assays, replicated in congenic lines, multiple cargo molecules tested","pmids":["17632513"],"is_preprint":false},{"year":2010,"finding":"MON1A (and its paralog Mon1b) are required for phagosome maturation: phagosomes in Mon1a/b-depleted mammalian cells recruit RAB5 but fail to progress to the RAB7-positive stage. Mon1 interacts with GTP-bound Rab5, identifying Mon1 as a Rab5 effector. A Mon1-Ccz1 complex (but not either protein alone) binds Rab7 and can influence Rab7 activation, linking the Rab5-positive to Rab7-positive stage of phagosome maturation.","method":"C. elegans genetics, mammalian cell RNAi, Co-immunoprecipitation with GTP/GDP-locked Rab mutants, phagosome maturation assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with GTP-locked Rab mutants, parallel genetic and cell-biological validation in two organisms, multiple orthogonal methods","pmids":["20305638"],"is_preprint":false},{"year":2012,"finding":"Mon1a functions in anterograde trafficking through the secretory pathway including ER-to-Golgi and Golgi-to-plasma membrane steps. siRNA knockdown delays Golgi reassembly after Brefeldin A treatment and slows ER-to-Golgi transport of ts045VSVG-GFP (confirmed by EndoH sensitivity). Mon1a associates with dynein intermediate chain (by co-immunoprecipitation and mass spectrometry), and reductions in Mon1a or dynein both alter Golgi morphology.","method":"siRNA knockdown, Brefeldin A reformation assay, ts045VSVG-GFP trafficking assay with EndoH treatment, co-immunoprecipitation, mass spectrometry","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (trafficking assay + EndoH + Co-IP/MS), single lab but convergent results","pmids":["22665492"],"is_preprint":false},{"year":2013,"finding":"Drosophila Mon1 ortholog Dmon1 is required for recruitment of Rab7 to maturing endosomes; loss of Dmon1 causes enlarged maturing endosomes that lose Rab7 association and accumulate transmembrane cargo such as Notch, phenocopying Rab7 loss of function.","method":"Drosophila genetics (loss-of-function mutants), fluorescence microscopy, electron microscopy of endosomes","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean loss-of-function in metazoan model with EM validation and multiple cargo markers, consistent with C. elegans and mammalian data","pmids":["23418349"],"is_preprint":false},{"year":2020,"finding":"MON1A is a core component of the trimeric Mon1-Ccz1-C18orf8 (MCC) GEF complex for Rab7. MON1A/B-deficient cells lack Rab7 activation and show severe defects in late endosome morphology and endosomal LDL trafficking. Active Rab7 (dependent on MCC complex) interacts with the NPC1 cholesterol transporter to license lysosomal cholesterol export; this process is abolished in Mon1A/B-deficient cells and restored by constitutively active Rab7.","method":"Genome-wide CRISPR screen, CRISPR knockout, cholesterol reporter, Rab7 activation assays, co-immunoprecipitation with NPC1, rescue with constitutively active Rab7","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide CRISPR screen plus KO rescue, multiple orthogonal assays, NPC1 interaction validated by Co-IP","pmids":["33144569"],"is_preprint":false},{"year":2020,"finding":"NRBF2 interacts with the CCZ1-MON1A GEF complex and is required for maintaining its GEF activity toward RAB7; NRBF2 regulates CCZ1-MON1A interaction with PI3KC3/VPS34 and CCZ1-associated PI3KC3 kinase activity, which are required for CCZ1-MON1A GEF activity. Loss of NRBF2 impairs autophagosome maturation and APP-CTF degradation via reduced GTP-RAB7 levels on autophagosomes.","method":"Co-immunoprecipitation, GST-R7BD affinity-isolation (GTP-RAB7 pull-down), NRBF2 knockdown/knockout, autophagosome purification, PI3K activity assay","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP plus biochemical GEF activity assay plus autophagosome fractionation, single lab, multiple orthogonal methods","pmids":["32543313"],"is_preprint":false},{"year":2022,"finding":"The lysosomal V-ATPase a3 subunit interacts with the Mon1A-Ccz1 GEF complex; interaction is mediated by the amino-terminal half domain of a3 and the longin motifs of Mon1A and Ccz1. a3 recruits Mon1A-Ccz1 to secretory lysosomes in osteoclasts, which is required for Rab7 activation and subsequent outward trafficking of secretory lysosomes for bone resorption.","method":"Co-immunoprecipitation in HEK293T cells, Mon1A longin-domain mutants deficient in Rab7 interaction, immunofluorescence of endogenous Ccz1 in a3-deficient osteoclasts","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping and mutants, localization in knockout osteoclasts, single lab","pmids":["35589873"],"is_preprint":false},{"year":2022,"finding":"Overexpression of the CCZ1-MON1A GEF complex increases active (GTP-bound) RAB7 in autophagosome fractions, enhances autophagosome maturation, and promotes degradation of APP-CTFs, Aβ, and P-tau in an autophagy-dependent manner in AD cell and mouse models; conversely, knockdown of MON1A impairs autophagosome maturation.","method":"AAV-mediated stereotaxic brain injection for MON1A/CCZ1 overexpression or knockdown, GST-R7BD affinity-isolation from purified autophagosomes, immunoblotting, 3xTg AD mouse model","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo AAV gain/loss-of-function plus biochemical GTP-RAB7 measurement in purified autophagosomes, single lab","pmids":["35198070"],"is_preprint":false},{"year":2020,"finding":"The GOLD domain of FYCO1 interacts with the CCZ1-MON1A complex; this interaction was identified by AP-MS and validated by co-immunoprecipitation. FYCO1 interaction with CCZ1-MON1A is necessary for RAB7A activation and fusion of autophagosomal/endosomal vesicles with lysosomes.","method":"Affinity purification-mass spectrometry (spin-tip IMAC columns), co-immunoprecipitation validation, FYCO1 KO/KD functional assays","journal":"Analytical chemistry / Autophagy","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — AP-MS identification plus Co-IP validation, functional context from FYCO1 loss-of-function, findings from two separate papers converging on same interaction","pmids":["31992042","37418591"],"is_preprint":false},{"year":2014,"finding":"In C. elegans, the SAND-1/CCZ-1 complex acts as a GEF for RAB-7 to promote HOPS effector activity and late endosome-lysosome fusion. SAND-1 does not participate in gut granule (lysosome-related organelle) formation, indicating that CCZ-1 can partner with a different protein (GLO-3) to activate an alternate Rab (GLO-1) for LRO biogenesis.","method":"C. elegans genetics (loss-of-function mutants, epistasis), fluorescence microscopy of gut granule protein trafficking","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in C. elegans with clear pathway placement, single lab","pmids":["24501423"],"is_preprint":false},{"year":2023,"finding":"Mon1a is required for maintenance of Golgi architecture. Mon1a interacts with the F-BAR protein FCHO2 (identified by yeast two-hybrid and co-immunoprecipitation). siRNA-mediated depletion of Mon1a or FCHO2 causes Golgi fragmentation and abolishes exchange of resident membrane proteins between Golgi ministacks (shown by FRAP). Mon1a-silenced Golgi disruption is not cell cycle-dependent, unlike FCHO2-silenced disruption. Mon1a thus generates lateral links between Golgi ministacks to create Golgi ribbons.","method":"Yeast two-hybrid, co-immunoprecipitation, siRNA knockdown, fluorescence microscopy, FRAP analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus Co-IP plus FRAP, single lab, preprint not yet peer-reviewed","pmids":["37461455"],"is_preprint":true},{"year":2025,"finding":"MON1A variants were identified as causal for congenital diarrhea and enteropathy (CODEs) in human infants; functional characterization in cell and zebrafish models confirmed a role for MON1A in intestinal epithelial function.","method":"Exome/genome sequencing, cell models, zebrafish models with variant functional testing","journal":"The New England journal of medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human genetic discovery with cell and zebrafish model validation, novel disease association, single study","pmids":["40174224"],"is_preprint":false},{"year":2024,"finding":"GORASP2 controls RAB7A activity by modulating its GEF complex MON1A-CCZ1, thereby impacting RAB7A's interaction with the HOPS complex and autophagosome maturation.","method":"siRNA depletion of GORASP2, RAB7A activity assays, Co-IP, super-resolution microscopy","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and activity assays but mechanistic detail on MON1A-CCZ1 modulation by GORASP2 is secondary finding, single lab","pmids":["39056394"],"is_preprint":false},{"year":2025,"finding":"In C. elegans, ubiquitinated proteins on the endosomal limiting membrane prevent displacement of the Rab5 GEF RABX-5 by the Rab7 GEF SAND-1/CCZ-1, thus upstream ESCRT-0 activity and ubiquitinated cargo act as timers for the onset of Rab conversion mediated by SAND-1/CCZ-1.","method":"C. elegans genetics (loss-of-function, epistasis), fluorescence microscopy, Rab7 overexpression rescue","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple alleles and partial rescue, single lab, mechanistic placement of SAND-1/CCZ-1 downstream of ESCRT-0","pmids":["39910226"],"is_preprint":false}],"current_model":"MON1A forms a complex with CCZ1 (and a third subunit C18orf8/SAND1) that functions as a guanine nucleotide exchange factor (GEF) for RAB7; it acts as a RAB5 effector to couple early-to-late endosome Rab conversion, is required for phagosome and autophagosome maturation, controls NPC1-dependent lysosomal cholesterol export via active RAB7, and also participates in anterograde secretory trafficking (ER-to-Golgi and Golgi maintenance) through interactions with dynein intermediate chain and the F-BAR protein FCHO2."},"narrative":{"mechanistic_narrative":"MON1A is the core subunit of a guanine nucleotide exchange factor (GEF) complex that drives the early-to-late endosome Rab conversion central to endolysosomal maturation [PMID:20305638, PMID:33144569]. It binds GTP-loaded RAB5 as a RAB5 effector and, in complex with CCZ1 (and the third subunit C18orf8/SAND1), activates RAB7 to advance endosomes and phagosomes from a RAB5-positive to a RAB7-positive stage [PMID:20305638, PMID:33144569]; orthologs in C. elegans (SAND-1) and Drosophila (Dmon1) establish that this RAB7-recruitment function is deeply conserved, with loss causing failure of endocytic cargo delivery to lysosomes and accumulation of transmembrane cargo such as Notch [PMID:17203072, PMID:23418349]. The MON1A-CCZ1 complex is recruited to and regulated at specific membranes by partners including the V-ATPase a3 subunit, FYCO1, NRBF2, and GORASP2, which couple RAB7 activation to autophagosome maturation, late endosome/lysosome fusion via HOPS, and secretory lysosome trafficking [PMID:32543313, PMID:35589873, PMID:31992042, PMID:37418591, PMID:39056394]. Active RAB7 generated by this complex licenses NPC1-dependent lysosomal cholesterol export and is required for autophagic degradation of substrates including APP-CTFs, Aβ, and P-tau [PMID:33144569, PMID:35198070]. Independently of its endosomal GEF role, MON1A participates in anterograde secretory trafficking and Golgi maintenance, acting through dynein intermediate chain and the F-BAR protein FCHO2 to support ER-to-Golgi transport and lateral linkage of Golgi ministacks into ribbons [PMID:22665492, PMID:37461455]. MON1A variants cause congenital diarrhea and enteropathy in humans [PMID:40174224].","teleology":[{"year":2007,"claim":"Established that the MON1A ortholog is required specifically at the early-to-late endosome transition, distinguishing its role from initial RAB7 recruitment.","evidence":"C. elegans loss-of-function genetics with fluorescent endocytic cargo tracers","pmids":["17203072"],"confidence":"High","gaps":["Did not define the biochemical activity of SAND-1","Mammalian relevance not yet shown","Partner proteins unidentified"]},{"year":2007,"claim":"Linked mammalian Mon1a to vesicular trafficking of cell-surface and secreted cargo, showing a missense allele reduces surface ferroportin and implicating a broad role in the secretory apparatus.","evidence":"QTL mapping, congenic mouse lines, cell-based trafficking assays","pmids":["17632513"],"confidence":"High","gaps":["Molecular mechanism connecting Mon1a to ferroportin trafficking unresolved","Relationship to endosomal Rab conversion not yet integrated"]},{"year":2010,"claim":"Defined MON1A as a RAB5 effector whose complex with CCZ1 binds and activates RAB7, providing the molecular basis for Rab conversion during phagosome maturation.","evidence":"Mammalian RNAi, reciprocal Co-IP with GTP/GDP-locked Rab mutants, phagosome maturation assays in two organisms","pmids":["20305638"],"confidence":"High","gaps":["Did not resolve the full subunit composition of the human complex","Structural basis of GEF catalysis not addressed"]},{"year":2012,"claim":"Revealed a distinct anterograde secretory role for Mon1a in ER-to-Golgi transport and Golgi reassembly, via association with dynein intermediate chain.","evidence":"siRNA knockdown, ts045VSVG-GFP/EndoH trafficking assay, Brefeldin A reformation, Co-IP/MS","pmids":["22665492"],"confidence":"High","gaps":["How a RAB7 GEF subunit also acts in anterograde secretion mechanistically unclear","Whether CCZ1 is involved in this function untested"]},{"year":2013,"claim":"Confirmed in Drosophila that Mon1 is required for RAB7 recruitment to maturing endosomes, with cargo accumulation phenocopying Rab7 loss.","evidence":"Drosophila loss-of-function genetics, fluorescence and electron microscopy","pmids":["23418349"],"confidence":"High","gaps":["Did not address regulatory inputs controlling timing of conversion"]},{"year":2020,"claim":"Resolved the human GEF as the trimeric MON1A-CCZ1-C18orf8 complex and showed active RAB7 it generates licenses NPC1-dependent lysosomal cholesterol export.","evidence":"Genome-wide CRISPR screen, KO and rescue with constitutively active Rab7, cholesterol reporter, NPC1 Co-IP","pmids":["33144569"],"confidence":"High","gaps":["Structural organization of the trimer not determined","Whether C18orf8 contributes catalytically or to recruitment unclear"]},{"year":2020,"claim":"Identified NRBF2 as a regulator that sustains CCZ1-MON1A GEF activity by linking it to PI3KC3/VPS34, connecting RAB7 activation to autophagosome maturation.","evidence":"Co-IP, GST-R7BD GTP-RAB7 pull-down, NRBF2 loss-of-function, autophagosome fractionation, PI3K activity assay","pmids":["32543313"],"confidence":"High","gaps":["How PI3KC3 activity feeds back on GEF catalysis mechanistically unresolved","Single lab"]},{"year":2020,"claim":"Showed FYCO1's GOLD domain binds CCZ1-MON1A and is required for RAB7A activation and autophagosomal/endosomal fusion with lysosomes.","evidence":"AP-MS, Co-IP validation, FYCO1 KO/KD functional assays","pmids":["31992042","37418591"],"confidence":"Medium","gaps":["Whether FYCO1 recruits or allosterically activates the complex unclear","Interaction interface not mapped"]},{"year":2022,"claim":"Demonstrated that the V-ATPase a3 subunit recruits Mon1A-Ccz1 to secretory lysosomes via longin-domain interactions, enabling RAB7-dependent bone resorption in osteoclasts.","evidence":"Co-IP with domain mapping, longin-domain mutants, immunofluorescence in a3-deficient osteoclasts","pmids":["35589873"],"confidence":"Medium","gaps":["Single lab","Direct demonstration of GEF activity at secretory lysosomes not shown"]},{"year":2022,"claim":"Established in vivo that boosting the CCZ1-MON1A complex raises autophagosomal GTP-RAB7 and promotes autophagic clearance of AD-associated substrates.","evidence":"AAV gain/loss-of-function in 3xTg AD mice, GST-R7BD pull-down from purified autophagosomes","pmids":["35198070"],"confidence":"Medium","gaps":["Single lab","Whether effect is direct on autophagy versus indirect endosomal contributions not fully separated"]},{"year":2014,"claim":"Placed SAND-1/CCZ-1 GEF activity upstream of HOPS-mediated late endosome-lysosome fusion and showed CCZ-1 can partner alternative subunits for distinct Rab pathways.","evidence":"C. elegans genetic epistasis, fluorescence microscopy of gut granule trafficking","pmids":["24501423"],"confidence":"Medium","gaps":["Mammalian equivalent of CCZ1 partner-switching not characterized","Single lab"]},{"year":2023,"claim":"Proposed a secretory-pathway role in which Mon1a interacts with FCHO2 to laterally link Golgi ministacks into ribbons.","evidence":"Yeast two-hybrid, Co-IP, siRNA knockdown, FRAP (preprint)","pmids":["37461455"],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","Relationship of this Golgi function to RAB7 GEF activity unresolved"]},{"year":2024,"claim":"Identified GORASP2 as a modulator of MON1A-CCZ1 that tunes RAB7A activity, HOPS interaction, and autophagosome maturation.","evidence":"siRNA depletion, RAB7A activity assays, Co-IP, super-resolution microscopy","pmids":["39056394"],"confidence":"Medium","gaps":["MON1A-CCZ1 modulation is a secondary finding","Mechanism of GORASP2 action on the GEF unclear","Single lab"]},{"year":2025,"claim":"Connected MON1A to human disease, showing variants cause congenital diarrhea and enteropathy with a confirmed role in intestinal epithelial function.","evidence":"Exome/genome sequencing, cell and zebrafish variant functional testing","pmids":["40174224"],"confidence":"Medium","gaps":["Single study","Mechanism linking specific variants to epithelial dysfunction not detailed"]},{"year":2025,"claim":"Showed that ubiquitinated endosomal cargo and ESCRT-0 act as a timer controlling when SAND-1/CCZ-1 displaces the RAB5 GEF to initiate conversion.","evidence":"C. elegans genetic epistasis, fluorescence microscopy, Rab7 overexpression rescue","pmids":["39910226"],"confidence":"Medium","gaps":["Molecular mechanism of GEF displacement not resolved","Mammalian conservation untested"]},{"year":null,"claim":"How MON1A reconciles its conserved RAB7 GEF function with its distinct roles in anterograde ER-to-Golgi/Golgi-ribbon maintenance, and the structural basis of complex assembly and catalysis, remain open.","evidence":"No structural or mechanistic reconciliation present in the corpus","pmids":[],"confidence":"Medium","gaps":["No structure of the human MON1A-CCZ1-C18orf8 complex in the corpus","Whether anterograde and endosomal functions use the same protein pool unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,5,6]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,7]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,4,5]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[5,7]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[3,11]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,2,5]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[6,8]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[3,11]}],"complexes":["MON1A-CCZ1-C18orf8 (MCC) RAB7 GEF complex"],"partners":["CCZ1","C18ORF8","RAB7","RAB5","NPC1","FYCO1","NRBF2","FCHO2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q86VX9","full_name":"Vacuolar fusion protein MON1 homolog A","aliases":[],"length_aa":652,"mass_kda":72.9,"function":"Plays an important role in membrane trafficking through the secretory apparatus. Not involved in endocytic trafficking to lysosomes (By similarity). Acts in concert with CCZ1, as a guanine exchange factor (GEF) for RAB7, promotes the exchange of GDP to GTP, converting it from an inactive GDP-bound form into an active GTP-bound form (PubMed:23084991)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q86VX9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MON1A","classification":"Not Classified","n_dependent_lines":8,"n_total_lines":383,"dependency_fraction":0.020887728459530026},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MON1A","total_profiled":1310},"omim":[{"mim_id":"620660","title":"CCZ1 HOMOLOG, VACUOLAR PROTEIN TRAFFICKING- AND BIOGENESIS-ASSOCIATED PROTEIN; CCZ1","url":"https://www.omim.org/entry/620660"},{"mim_id":"611464","title":"MON1 HOMOLOG A, SECRETORY TRAFFICKING-ASSOCIATED; MON1A","url":"https://www.omim.org/entry/611464"},{"mim_id":"608954","title":"MON1 HOMOLOG B, SECRETORY TRAFFICKING-ASSOCIATED; MON1B","url":"https://www.omim.org/entry/608954"},{"mim_id":"601126","title":"TATA ELEMENT MODULATORY FACTOR 1; TMF1","url":"https://www.omim.org/entry/601126"},{"mim_id":"214700","title":"DIARRHEA 1, SECRETORY CHLORIDE, CONGENITAL; DIAR1","url":"https://www.omim.org/entry/214700"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MON1A"},"hgnc":{"alias_symbol":["MGC13272","SAND1"],"prev_symbol":[]},"alphafold":{"accession":"Q86VX9","domains":[{"cath_id":"3.30.450.70","chopping":"252-374","consensus_level":"high","plddt":93.7794,"start":252,"end":374},{"cath_id":"3.30.450.30","chopping":"391-529","consensus_level":"high","plddt":94.7392,"start":391,"end":529},{"cath_id":"3.40.1840.10","chopping":"535-645","consensus_level":"high","plddt":93.7948,"start":535,"end":645}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86VX9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86VX9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86VX9-F1-predicted_aligned_error_v6.png","plddt_mean":72.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MON1A","jax_strain_url":"https://www.jax.org/strain/search?query=MON1A"},"sequence":{"accession":"Q86VX9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86VX9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86VX9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86VX9"}},"corpus_meta":[{"pmid":"20305638","id":"PMC_20305638","title":"Identification 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8).","date":"2023","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/37418591","citation_count":17,"is_preprint":false},{"pmid":"16042554","id":"PMC_16042554","title":"A role of SAND-family proteins in endocytosis.","date":"2005","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/16042554","citation_count":17,"is_preprint":false},{"pmid":"34323678","id":"PMC_34323678","title":"Sphingomonas sabuli sp. nov., a carotenoid-producing bacterium isolated from beach sand.","date":"2021","source":"International journal of systematic and evolutionary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/34323678","citation_count":16,"is_preprint":false},{"pmid":"35589873","id":"PMC_35589873","title":"The lysosomal V-ATPase a3 subunit is involved in localization of Mon1-Ccz1, the GEF for Rab7, to secretory lysosomes in osteoclasts.","date":"2022","source":"Scientific 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Genetic Architecture of Congenital Diarrhea and Enteropathy.","date":"2025","source":"The New England journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40174224","citation_count":10,"is_preprint":false},{"pmid":"22665492","id":"PMC_22665492","title":"Mon1a protein acts in trafficking through the secretory apparatus.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22665492","citation_count":8,"is_preprint":false},{"pmid":"26940354","id":"PMC_26940354","title":"A fresh look at the function of Rabaptin5 on endosomes.","date":"2016","source":"Small GTPases","url":"https://pubmed.ncbi.nlm.nih.gov/26940354","citation_count":8,"is_preprint":false},{"pmid":"34139218","id":"PMC_34139218","title":"Extending the Horizon of Homology Detection with Coevolution-based Structure Prediction.","date":"2021","source":"Journal of molecular 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International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/24121729","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17445,"output_tokens":4016,"usd":0.056287,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11751,"output_tokens":4434,"usd":0.084803,"stage2_stop_reason":"end_turn"},"total_usd":0.14109,"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\": 2007,\n      \"finding\": \"MON1A ortholog SAND-1 in C. elegans is essential for RAB-7 function at the transition from early to late endosomes; loss of SAND-1 causes delayed endocytic transport and failure to deliver cargo to lysosomes, while initial RAB-7 recruitment is not affected by SAND-1 loss at lysosomes.\",\n      \"method\": \"C. elegans genetics (RNAi, loss-of-function mutants), fluorescence microscopy of endocytic cargo trafficking\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean loss-of-function with defined cellular phenotype, replicated across multiple cargo tracers and tissues, foundational ortholog paper\",\n      \"pmids\": [\"17203072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Mon1a controls vesicular trafficking of ferroportin (the major iron exporter) to the macrophage cell surface; a missense allele of Mon1a (C57BL/10J) reduces surface ferroportin levels, increasing macrophage iron content. Mon1a also affects trafficking of cell-surface and secreted molecules unrelated to iron metabolism, indicating a general role in the mammalian secretory apparatus.\",\n      \"method\": \"Quantitative trait locus analysis, congenic mouse lines, cell-based trafficking assays\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — QTL mapping combined with cell-based trafficking assays, replicated in congenic lines, multiple cargo molecules tested\",\n      \"pmids\": [\"17632513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MON1A (and its paralog Mon1b) are required for phagosome maturation: phagosomes in Mon1a/b-depleted mammalian cells recruit RAB5 but fail to progress to the RAB7-positive stage. Mon1 interacts with GTP-bound Rab5, identifying Mon1 as a Rab5 effector. A Mon1-Ccz1 complex (but not either protein alone) binds Rab7 and can influence Rab7 activation, linking the Rab5-positive to Rab7-positive stage of phagosome maturation.\",\n      \"method\": \"C. elegans genetics, mammalian cell RNAi, Co-immunoprecipitation with GTP/GDP-locked Rab mutants, phagosome maturation assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with GTP-locked Rab mutants, parallel genetic and cell-biological validation in two organisms, multiple orthogonal methods\",\n      \"pmids\": [\"20305638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Mon1a functions in anterograde trafficking through the secretory pathway including ER-to-Golgi and Golgi-to-plasma membrane steps. siRNA knockdown delays Golgi reassembly after Brefeldin A treatment and slows ER-to-Golgi transport of ts045VSVG-GFP (confirmed by EndoH sensitivity). Mon1a associates with dynein intermediate chain (by co-immunoprecipitation and mass spectrometry), and reductions in Mon1a or dynein both alter Golgi morphology.\",\n      \"method\": \"siRNA knockdown, Brefeldin A reformation assay, ts045VSVG-GFP trafficking assay with EndoH treatment, co-immunoprecipitation, mass spectrometry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (trafficking assay + EndoH + Co-IP/MS), single lab but convergent results\",\n      \"pmids\": [\"22665492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Drosophila Mon1 ortholog Dmon1 is required for recruitment of Rab7 to maturing endosomes; loss of Dmon1 causes enlarged maturing endosomes that lose Rab7 association and accumulate transmembrane cargo such as Notch, phenocopying Rab7 loss of function.\",\n      \"method\": \"Drosophila genetics (loss-of-function mutants), fluorescence microscopy, electron microscopy of endosomes\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean loss-of-function in metazoan model with EM validation and multiple cargo markers, consistent with C. elegans and mammalian data\",\n      \"pmids\": [\"23418349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MON1A is a core component of the trimeric Mon1-Ccz1-C18orf8 (MCC) GEF complex for Rab7. MON1A/B-deficient cells lack Rab7 activation and show severe defects in late endosome morphology and endosomal LDL trafficking. Active Rab7 (dependent on MCC complex) interacts with the NPC1 cholesterol transporter to license lysosomal cholesterol export; this process is abolished in Mon1A/B-deficient cells and restored by constitutively active Rab7.\",\n      \"method\": \"Genome-wide CRISPR screen, CRISPR knockout, cholesterol reporter, Rab7 activation assays, co-immunoprecipitation with NPC1, rescue with constitutively active Rab7\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide CRISPR screen plus KO rescue, multiple orthogonal assays, NPC1 interaction validated by Co-IP\",\n      \"pmids\": [\"33144569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NRBF2 interacts with the CCZ1-MON1A GEF complex and is required for maintaining its GEF activity toward RAB7; NRBF2 regulates CCZ1-MON1A interaction with PI3KC3/VPS34 and CCZ1-associated PI3KC3 kinase activity, which are required for CCZ1-MON1A GEF activity. Loss of NRBF2 impairs autophagosome maturation and APP-CTF degradation via reduced GTP-RAB7 levels on autophagosomes.\",\n      \"method\": \"Co-immunoprecipitation, GST-R7BD affinity-isolation (GTP-RAB7 pull-down), NRBF2 knockdown/knockout, autophagosome purification, PI3K activity assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus biochemical GEF activity assay plus autophagosome fractionation, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"32543313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The lysosomal V-ATPase a3 subunit interacts with the Mon1A-Ccz1 GEF complex; interaction is mediated by the amino-terminal half domain of a3 and the longin motifs of Mon1A and Ccz1. a3 recruits Mon1A-Ccz1 to secretory lysosomes in osteoclasts, which is required for Rab7 activation and subsequent outward trafficking of secretory lysosomes for bone resorption.\",\n      \"method\": \"Co-immunoprecipitation in HEK293T cells, Mon1A longin-domain mutants deficient in Rab7 interaction, immunofluorescence of endogenous Ccz1 in a3-deficient osteoclasts\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping and mutants, localization in knockout osteoclasts, single lab\",\n      \"pmids\": [\"35589873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Overexpression of the CCZ1-MON1A GEF complex increases active (GTP-bound) RAB7 in autophagosome fractions, enhances autophagosome maturation, and promotes degradation of APP-CTFs, Aβ, and P-tau in an autophagy-dependent manner in AD cell and mouse models; conversely, knockdown of MON1A impairs autophagosome maturation.\",\n      \"method\": \"AAV-mediated stereotaxic brain injection for MON1A/CCZ1 overexpression or knockdown, GST-R7BD affinity-isolation from purified autophagosomes, immunoblotting, 3xTg AD mouse model\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo AAV gain/loss-of-function plus biochemical GTP-RAB7 measurement in purified autophagosomes, single lab\",\n      \"pmids\": [\"35198070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The GOLD domain of FYCO1 interacts with the CCZ1-MON1A complex; this interaction was identified by AP-MS and validated by co-immunoprecipitation. FYCO1 interaction with CCZ1-MON1A is necessary for RAB7A activation and fusion of autophagosomal/endosomal vesicles with lysosomes.\",\n      \"method\": \"Affinity purification-mass spectrometry (spin-tip IMAC columns), co-immunoprecipitation validation, FYCO1 KO/KD functional assays\",\n      \"journal\": \"Analytical chemistry / Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — AP-MS identification plus Co-IP validation, functional context from FYCO1 loss-of-function, findings from two separate papers converging on same interaction\",\n      \"pmids\": [\"31992042\", \"37418591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In C. elegans, the SAND-1/CCZ-1 complex acts as a GEF for RAB-7 to promote HOPS effector activity and late endosome-lysosome fusion. SAND-1 does not participate in gut granule (lysosome-related organelle) formation, indicating that CCZ-1 can partner with a different protein (GLO-3) to activate an alternate Rab (GLO-1) for LRO biogenesis.\",\n      \"method\": \"C. elegans genetics (loss-of-function mutants, epistasis), fluorescence microscopy of gut granule protein trafficking\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in C. elegans with clear pathway placement, single lab\",\n      \"pmids\": [\"24501423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Mon1a is required for maintenance of Golgi architecture. Mon1a interacts with the F-BAR protein FCHO2 (identified by yeast two-hybrid and co-immunoprecipitation). siRNA-mediated depletion of Mon1a or FCHO2 causes Golgi fragmentation and abolishes exchange of resident membrane proteins between Golgi ministacks (shown by FRAP). Mon1a-silenced Golgi disruption is not cell cycle-dependent, unlike FCHO2-silenced disruption. Mon1a thus generates lateral links between Golgi ministacks to create Golgi ribbons.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, siRNA knockdown, fluorescence microscopy, FRAP analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus Co-IP plus FRAP, single lab, preprint not yet peer-reviewed\",\n      \"pmids\": [\"37461455\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MON1A variants were identified as causal for congenital diarrhea and enteropathy (CODEs) in human infants; functional characterization in cell and zebrafish models confirmed a role for MON1A in intestinal epithelial function.\",\n      \"method\": \"Exome/genome sequencing, cell models, zebrafish models with variant functional testing\",\n      \"journal\": \"The New England journal of medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human genetic discovery with cell and zebrafish model validation, novel disease association, single study\",\n      \"pmids\": [\"40174224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GORASP2 controls RAB7A activity by modulating its GEF complex MON1A-CCZ1, thereby impacting RAB7A's interaction with the HOPS complex and autophagosome maturation.\",\n      \"method\": \"siRNA depletion of GORASP2, RAB7A activity assays, Co-IP, super-resolution microscopy\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and activity assays but mechanistic detail on MON1A-CCZ1 modulation by GORASP2 is secondary finding, single lab\",\n      \"pmids\": [\"39056394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In C. elegans, ubiquitinated proteins on the endosomal limiting membrane prevent displacement of the Rab5 GEF RABX-5 by the Rab7 GEF SAND-1/CCZ-1, thus upstream ESCRT-0 activity and ubiquitinated cargo act as timers for the onset of Rab conversion mediated by SAND-1/CCZ-1.\",\n      \"method\": \"C. elegans genetics (loss-of-function, epistasis), fluorescence microscopy, Rab7 overexpression rescue\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple alleles and partial rescue, single lab, mechanistic placement of SAND-1/CCZ-1 downstream of ESCRT-0\",\n      \"pmids\": [\"39910226\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MON1A forms a complex with CCZ1 (and a third subunit C18orf8/SAND1) that functions as a guanine nucleotide exchange factor (GEF) for RAB7; it acts as a RAB5 effector to couple early-to-late endosome Rab conversion, is required for phagosome and autophagosome maturation, controls NPC1-dependent lysosomal cholesterol export via active RAB7, and also participates in anterograde secretory trafficking (ER-to-Golgi and Golgi maintenance) through interactions with dynein intermediate chain and the F-BAR protein FCHO2.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MON1A is the core subunit of a guanine nucleotide exchange factor (GEF) complex that drives the early-to-late endosome Rab conversion central to endolysosomal maturation [#2, #5]. It binds GTP-loaded RAB5 as a RAB5 effector and, in complex with CCZ1 (and the third subunit C18orf8/SAND1), activates RAB7 to advance endosomes and phagosomes from a RAB5-positive to a RAB7-positive stage [#2, #5]; orthologs in C. elegans (SAND-1) and Drosophila (Dmon1) establish that this RAB7-recruitment function is deeply conserved, with loss causing failure of endocytic cargo delivery to lysosomes and accumulation of transmembrane cargo such as Notch [#0, #4]. The MON1A-CCZ1 complex is recruited to and regulated at specific membranes by partners including the V-ATPase a3 subunit, FYCO1, NRBF2, and GORASP2, which couple RAB7 activation to autophagosome maturation, late endosome/lysosome fusion via HOPS, and secretory lysosome trafficking [#6, #7, #9, #13]. Active RAB7 generated by this complex licenses NPC1-dependent lysosomal cholesterol export and is required for autophagic degradation of substrates including APP-CTFs, A\\u03b2, and P-tau [#5, #8]. Independently of its endosomal GEF role, MON1A participates in anterograde secretory trafficking and Golgi maintenance, acting through dynein intermediate chain and the F-BAR protein FCHO2 to support ER-to-Golgi transport and lateral linkage of Golgi ministacks into ribbons [#3, #11]. MON1A variants cause congenital diarrhea and enteropathy in humans [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established that the MON1A ortholog is required specifically at the early-to-late endosome transition, distinguishing its role from initial RAB7 recruitment.\",\n      \"evidence\": \"C. elegans loss-of-function genetics with fluorescent endocytic cargo tracers\",\n      \"pmids\": [\"17203072\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the biochemical activity of SAND-1\", \"Mammalian relevance not yet shown\", \"Partner proteins unidentified\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Linked mammalian Mon1a to vesicular trafficking of cell-surface and secreted cargo, showing a missense allele reduces surface ferroportin and implicating a broad role in the secretory apparatus.\",\n      \"evidence\": \"QTL mapping, congenic mouse lines, cell-based trafficking assays\",\n      \"pmids\": [\"17632513\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism connecting Mon1a to ferroportin trafficking unresolved\", \"Relationship to endosomal Rab conversion not yet integrated\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined MON1A as a RAB5 effector whose complex with CCZ1 binds and activates RAB7, providing the molecular basis for Rab conversion during phagosome maturation.\",\n      \"evidence\": \"Mammalian RNAi, reciprocal Co-IP with GTP/GDP-locked Rab mutants, phagosome maturation assays in two organisms\",\n      \"pmids\": [\"20305638\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the full subunit composition of the human complex\", \"Structural basis of GEF catalysis not addressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Revealed a distinct anterograde secretory role for Mon1a in ER-to-Golgi transport and Golgi reassembly, via association with dynein intermediate chain.\",\n      \"evidence\": \"siRNA knockdown, ts045VSVG-GFP/EndoH trafficking assay, Brefeldin A reformation, Co-IP/MS\",\n      \"pmids\": [\"22665492\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a RAB7 GEF subunit also acts in anterograde secretion mechanistically unclear\", \"Whether CCZ1 is involved in this function untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Confirmed in Drosophila that Mon1 is required for RAB7 recruitment to maturing endosomes, with cargo accumulation phenocopying Rab7 loss.\",\n      \"evidence\": \"Drosophila loss-of-function genetics, fluorescence and electron microscopy\",\n      \"pmids\": [\"23418349\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address regulatory inputs controlling timing of conversion\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved the human GEF as the trimeric MON1A-CCZ1-C18orf8 complex and showed active RAB7 it generates licenses NPC1-dependent lysosomal cholesterol export.\",\n      \"evidence\": \"Genome-wide CRISPR screen, KO and rescue with constitutively active Rab7, cholesterol reporter, NPC1 Co-IP\",\n      \"pmids\": [\"33144569\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural organization of the trimer not determined\", \"Whether C18orf8 contributes catalytically or to recruitment unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified NRBF2 as a regulator that sustains CCZ1-MON1A GEF activity by linking it to PI3KC3/VPS34, connecting RAB7 activation to autophagosome maturation.\",\n      \"evidence\": \"Co-IP, GST-R7BD GTP-RAB7 pull-down, NRBF2 loss-of-function, autophagosome fractionation, PI3K activity assay\",\n      \"pmids\": [\"32543313\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PI3KC3 activity feeds back on GEF catalysis mechanistically unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed FYCO1's GOLD domain binds CCZ1-MON1A and is required for RAB7A activation and autophagosomal/endosomal fusion with lysosomes.\",\n      \"evidence\": \"AP-MS, Co-IP validation, FYCO1 KO/KD functional assays\",\n      \"pmids\": [\"31992042\", \"37418591\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether FYCO1 recruits or allosterically activates the complex unclear\", \"Interaction interface not mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated that the V-ATPase a3 subunit recruits Mon1A-Ccz1 to secretory lysosomes via longin-domain interactions, enabling RAB7-dependent bone resorption in osteoclasts.\",\n      \"evidence\": \"Co-IP with domain mapping, longin-domain mutants, immunofluorescence in a3-deficient osteoclasts\",\n      \"pmids\": [\"35589873\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct demonstration of GEF activity at secretory lysosomes not shown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established in vivo that boosting the CCZ1-MON1A complex raises autophagosomal GTP-RAB7 and promotes autophagic clearance of AD-associated substrates.\",\n      \"evidence\": \"AAV gain/loss-of-function in 3xTg AD mice, GST-R7BD pull-down from purified autophagosomes\",\n      \"pmids\": [\"35198070\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Whether effect is direct on autophagy versus indirect endosomal contributions not fully separated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placed SAND-1/CCZ-1 GEF activity upstream of HOPS-mediated late endosome-lysosome fusion and showed CCZ-1 can partner alternative subunits for distinct Rab pathways.\",\n      \"evidence\": \"C. elegans genetic epistasis, fluorescence microscopy of gut granule trafficking\",\n      \"pmids\": [\"24501423\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mammalian equivalent of CCZ1 partner-switching not characterized\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Proposed a secretory-pathway role in which Mon1a interacts with FCHO2 to laterally link Golgi ministacks into ribbons.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, siRNA knockdown, FRAP (preprint)\",\n      \"pmids\": [\"37461455\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"Relationship of this Golgi function to RAB7 GEF activity unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified GORASP2 as a modulator of MON1A-CCZ1 that tunes RAB7A activity, HOPS interaction, and autophagosome maturation.\",\n      \"evidence\": \"siRNA depletion, RAB7A activity assays, Co-IP, super-resolution microscopy\",\n      \"pmids\": [\"39056394\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"MON1A-CCZ1 modulation is a secondary finding\", \"Mechanism of GORASP2 action on the GEF unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected MON1A to human disease, showing variants cause congenital diarrhea and enteropathy with a confirmed role in intestinal epithelial function.\",\n      \"evidence\": \"Exome/genome sequencing, cell and zebrafish variant functional testing\",\n      \"pmids\": [\"40174224\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study\", \"Mechanism linking specific variants to epithelial dysfunction not detailed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed that ubiquitinated endosomal cargo and ESCRT-0 act as a timer controlling when SAND-1/CCZ-1 displaces the RAB5 GEF to initiate conversion.\",\n      \"evidence\": \"C. elegans genetic epistasis, fluorescence microscopy, Rab7 overexpression rescue\",\n      \"pmids\": [\"39910226\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of GEF displacement not resolved\", \"Mammalian conservation untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MON1A reconciles its conserved RAB7 GEF function with its distinct roles in anterograde ER-to-Golgi/Golgi-ribbon maintenance, and the structural basis of complex assembly and catalysis, remain open.\",\n      \"evidence\": \"No structural or mechanistic reconciliation present in the corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of the human MON1A-CCZ1-C18orf8 complex in the corpus\", \"Whether anterograde and endosomal functions use the same protein pool unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 5, 6]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 4, 5]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [5, 7]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [3, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 2, 5]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [6, 8]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [3, 11]}\n    ],\n    \"complexes\": [\"MON1A-CCZ1-C18orf8 (MCC) RAB7 GEF complex\"],\n    \"partners\": [\"CCZ1\", \"C18orf8\", \"RAB7\", \"RAB5\", \"NPC1\", \"FYCO1\", \"NRBF2\", \"FCHO2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}