{"gene":"MOAP1","run_date":"2026-04-28T18:30:28","timeline":{"discoveries":[{"year":2000,"finding":"MOAP-1 (MAP-1, Modulator of Apoptosis) was identified as a Bax-associating protein containing a BH3-like motif. It homodimerizes and associates with proapoptotic Bax and prosurvival Bcl-2/Bcl-XL in vitro and in vivo. The BH3-like domain is required for Bax association and apoptosis induction but not for Bcl-XL binding. Bax binding requires all three BH domains (BH1, BH2, BH3) of Bax.","method":"Yeast two-hybrid screen, Co-IP, in vitro binding assays, mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — yeast two-hybrid discovery + reciprocal Co-IP + mutagenesis of both MOAP-1 and Bax domains, multiple orthogonal methods","pmids":["11060313"],"is_preprint":false},{"year":2005,"finding":"MOAP-1 is a mitochondria-enriched protein that associates with Bax only upon apoptotic induction, coinciding with cytochrome c release. siRNA-mediated knockdown of MOAP-1 selectively inhibits Bax-mediated apoptosis, blocks Bax conformational change and translocation, and impairs recombinant Bax- or tBid-mediated cytochrome c release from isolated mitochondria. MOAP-1-deficient cells show aggressive anchorage-independent growth similar to Bax-deficient cells.","method":"siRNA knockdown, subcellular fractionation, isolated mitochondria cytochrome c release assay, anchorage-independent growth assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods including in vitro reconstitution with isolated mitochondria, siRNA KD with defined phenotypic readouts","pmids":["16199525"],"is_preprint":false},{"year":2005,"finding":"RASSF1A is required for death receptor (TNFα/TRAIL)-induced Bax conformational change and apoptosis. TNFα or TRAIL stimulation recruits RASSF1A and MOAP-1 to receptor complexes and promotes RASSF1A/MOAP-1 complex formation. RASSF1A binding to MOAP-1 relieves an intramolecular inhibitory interaction in MOAP-1, enabling MOAP-1 to associate with Bax and trigger Bax conformational change, mitochondrial membrane insertion, and cytochrome c release.","method":"Co-IP, shRNA knockdown, Bax conformational change assay, cytochrome c release assay","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, shRNA knockdown of both RASSF1A and MOAP-1 with defined apoptotic phenotypes, replicated pathway placement","pmids":["15949439"],"is_preprint":false},{"year":2005,"finding":"RASSF1A and MOAP-1 interact directly, and this interaction is enhanced by activated K-Ras. RASSF1A activates Bax via MOAP-1, and activated K-Ras, RASSF1A, and MOAP-1 synergize to induce Bax activation and cell death. A tumor-derived RASSF1A point mutant defective for MOAP-1 interaction fails to activate Bax.","method":"Co-IP, pulldown, shRNA knockdown, Bax activation assay, mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — direct interaction confirmed by Co-IP/pulldown + mutagenesis + functional epistasis, corroborated by independent lab (Baksh et al., same year)","pmids":["16344548"],"is_preprint":false},{"year":2007,"finding":"MOAP-1 is a short-lived protein (t1/2 ~25 min) constitutively degraded by the ubiquitin-proteasome system. Apoptotic stimuli rapidly upregulate MOAP-1 by inhibiting its polyubiquitination. Elevated MOAP-1 promotes recombinant Bax-mediated cytochrome c release from isolated mitochondria, and in vitro-translated MOAP-1 can restore Bax-mediated cytochrome c release in mitochondria depleted of short-lived proteins.","method":"Cycloheximide chase, ubiquitination assay, isolated mitochondria cytochrome c release assay, in vitro translation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro reconstitution with isolated mitochondria + biochemical ubiquitination assay, multiple orthogonal approaches","pmids":["17535899"],"is_preprint":false},{"year":2008,"finding":"TRIM39 was identified as a MOAP-1-binding protein that stabilizes MOAP-1 by inhibiting its polyubiquitination. TRIM39 overexpression extends MOAP-1 half-life, elevates MOAP-1 in mitochondria, and promotes cytochrome c release from isolated mitochondria stimulated by recombinant Bax. TRIM39 knockdown reduces sensitivity to etoposide-induced apoptosis.","method":"Co-IP, ubiquitination assay, cycloheximide chase, isolated mitochondria cytochrome c release assay, siRNA knockdown","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, ubiquitination assay, in vitro mitochondria reconstitution, multiple orthogonal methods","pmids":["19100260"],"is_preprint":false},{"year":2012,"finding":"MOAP-1 is a substrate of the APC/C(Cdh1) ubiquitin ligase. TRIM39, a RING domain E3 ligase, directly inhibits APC/C(Cdh1)-mediated ubiquitylation of MOAP-1 (not just competing for substrate), thereby stabilizing MOAP-1. Cdh1 siRNA knockdown stabilizes MOAP-1 and enhances etoposide-induced Bax activation and apoptosis.","method":"In vitro ubiquitylation assay, siRNA knockdown of Cdh1, Co-IP, Bax activation assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro ubiquitylation assay identifying APC/C(Cdh1) as E3 ligase + siRNA epistasis + functional apoptosis readout","pmids":["22529100"],"is_preprint":false},{"year":2012,"finding":"miR-1228 targets MOAP-1 mRNA, reduces MOAP-1 protein expression, and delays stress-induced apoptosis. Rescue experiments showed that miR-1228 inhibition of apoptosis is attenuated by repressing MOAP-1 expression, establishing MOAP-1 as a direct target.","method":"miRNA overexpression, siRNA, apoptosis assays","journal":"Apoptosis : an international journal on programmed cell death","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, miRNA-target interaction demonstrated by rescue experiment but limited mechanistic depth","pmids":["22434376"],"is_preprint":false},{"year":2016,"finding":"UBR5, a HECT family E3 ubiquitin ligase, physically interacts with MOAP-1, ubiquitylates MOAP-1 in vitro, and destabilizes MOAP-1 in cultured cells. Dyrk2 kinase cooperates with UBR5 in mediating MOAP-1 ubiquitylation. UBR5 knockdown increases MOAP-1 levels, enhances Bax activation, and sensitizes cisplatin-resistant ovarian cancer cells to apoptosis.","method":"Co-IP, in vitro ubiquitylation assay, siRNA knockdown, Bax activation assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro ubiquitylation reconstitution + Co-IP + siRNA functional rescue, multiple orthogonal methods","pmids":["27721409"],"is_preprint":false},{"year":2016,"finding":"MOAP-1-deficient mice are resistant to Fas-induced hepatocellular apoptosis and lethality. MOAP-1 facilitates tBid recruitment to mitochondria by binding to the outer mitochondrial membrane protein MTCH2; in MOAP-1-deficient cells, MTCH2 fails to engage tBid, impairing tBid mitochondrial accumulation and downstream Bax/Bak activation.","method":"MOAP-1 knockout mouse model, Co-IP, mitochondrial fractionation, Fas-induced apoptosis assay","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — in vivo knockout mouse + Co-IP identifying MTCH2 interaction + defined hepatocellular apoptosis phenotype","pmids":["27320914"],"is_preprint":false},{"year":2018,"finding":"RACK1 associates with MOAP-1 via electrostatic interactions (similar to MOAP-1/RASSF1A and MOAP-1/TNF-R1 interactions) and recruits the E3 ligase TRAF2 to MOAP-1, resulting in K63-linked ubiquitination of MOAP-1.","method":"Co-IP, ubiquitination assay (K63-linkage specific)","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP and ubiquitination assay from single lab, single paper","pmids":["29470995"],"is_preprint":false},{"year":2021,"finding":"MOAP-1 binds LC3 via an LC3-interacting region (LIR) motif at its N-terminus and promotes phagophore closure during starvation-induced autophagy. MOAP-1-deficient cells show impaired autophagy with predominantly unclosed phagophores rather than closed autophagosomes upon EBSS treatment. Re-expression of wild-type MOAP-1 but not LIR-mutant MOAP-1 restores autophagy, demonstrating that LC3 binding is required for this function.","method":"MOAP-1 knockout cells, Halo-tagged LC3 autophagosome completion assay, Co-IP, proteinase K protection assay, mutagenesis of LIR motif","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 — KO cells + mutagenesis rescue + multiple orthogonal autophagy assays establishing mechanistic requirement for LIR motif","pmids":["33783314"],"is_preprint":false},{"year":2021,"finding":"X-ray crystal structures of a stably folded domain of MOAP-1 show high structural similarity to the C-terminal capsid (CA) domain of retroviral Gag proteins, confirming MOAP-1 as a domesticated Gag-derived protein.","method":"X-ray crystallography, structural comparison","journal":"Proteins","confidence":"High","confidence_rationale":"Tier 1 — crystal structure determination with structural validation","pmids":["34357660"],"is_preprint":false},{"year":2021,"finding":"Influenza A virus PB1-F2 protein interacts with human MOAP-1, as demonstrated by yeast two-hybrid, GST pulldown, and Co-IP assays. PB1-F2 upregulates exogenous MOAP-1 protein levels.","method":"Yeast two-hybrid, GST pulldown, Co-IP, Western blot","journal":"Wei sheng wu xue bao = Acta microbiologica Sinica","confidence":"Medium","confidence_rationale":"Tier 3 — interaction confirmed by multiple binding assays but functional consequence not deeply characterized, single lab","pmids":["23236846"],"is_preprint":false},{"year":2025,"finding":"PNMA4/MOAP-1 was identified as a MAVS-interacting protein at the mitochondria using proximity-based labeling. PNMA4 enhances RIG-I–MAVS interaction and facilitates K63-linked polyubiquitination of RIG-I at K657 by TRIM25, positively regulating antiviral signaling. PNMA4-knockout mice are more susceptible to RNA virus infection.","method":"Proximity-based labeling (BioID), Co-IP, ubiquitination assay, Pnma4 knockout mouse infection model","journal":"International immunopharmacology","confidence":"High","confidence_rationale":"Tier 2 — proximity labeling + Co-IP + ubiquitination assay + in vivo KO mouse model, multiple orthogonal methods","pmids":["40929959"],"is_preprint":false}],"current_model":"MOAP-1 (Modulator of Apoptosis 1/PNMA4) is a mitochondria-enriched, short-lived BH3-like protein that is constitutively degraded via the ubiquitin-proteasome system (by APC/C(Cdh1) and UBR5 E3 ligases); upon apoptotic stimulation its polyubiquitination is inhibited—an event promoted by TRIM39—leading to its stabilization and association with Bax, an interaction that requires relief of an intramolecular inhibitory interaction by RASSF1A (recruited to death receptor complexes), ultimately driving Bax conformational change, mitochondrial membrane insertion, cytochrome c release, and caspase activation; additionally, MOAP-1 facilitates tBid recruitment to the outer mitochondrial membrane via MTCH2, promotes phagophore closure during autophagy through a direct LC3-LIR interaction, and enhances RIG-I–MAVS antiviral signaling by facilitating TRIM25-mediated K63-ubiquitination of RIG-I."},"narrative":{"teleology":[{"year":2000,"claim":"Identification of MOAP-1 as a Bax-associating protein with a BH3-like domain established it as a candidate apoptosis regulator, resolving the question of how Bax is engaged by a novel cofactor.","evidence":"Yeast two-hybrid screen, reciprocal Co-IP, mutagenesis of BH3-like domain and Bax BH domains in mammalian cells","pmids":["11060313"],"confidence":"High","gaps":["Physiological context of interaction unknown—Bax binding was constitutive in overexpression systems","No subcellular localization data for endogenous MOAP-1","Mechanism linking MOAP-1/Bax binding to downstream apoptosis undefined"]},{"year":2005,"claim":"Demonstration that MOAP-1 is mitochondria-enriched, required for Bax conformational change and translocation, and that its loss phenocopies Bax deficiency in anchorage-independent growth, established MOAP-1 as a necessary upstream activator of Bax in the intrinsic apoptotic pathway.","evidence":"siRNA knockdown, subcellular fractionation, isolated mitochondria cytochrome c release assay in HCT116 cells","pmids":["16199525"],"confidence":"High","gaps":["How apoptotic signals trigger the MOAP-1/Bax interaction remained unclear","No in vivo model"]},{"year":2005,"claim":"Discovery that RASSF1A, recruited to TNFα/TRAIL receptor complexes, relieves an autoinhibitory interaction within MOAP-1 to enable Bax binding resolved how death-receptor signals are transduced through MOAP-1 to mitochondria, with activated K-Ras synergizing with RASSF1A.","evidence":"Co-IP, shRNA knockdown of RASSF1A and MOAP-1, Bax conformational change and cytochrome c release assays; mutagenesis of RASSF1A tumor-derived mutant","pmids":["15949439","16344548"],"confidence":"High","gaps":["Structural basis of the intramolecular autoinhibition not defined","Contribution of K-Ras effector pathway to RASSF1A–MOAP-1 axis not fully dissected"]},{"year":2007,"claim":"Showing that MOAP-1 is an extremely short-lived protein (t½ ~25 min) whose polyubiquitination is inhibited by apoptotic stimuli revealed a post-translational stabilization mechanism as the primary mode of MOAP-1 regulation.","evidence":"Cycloheximide chase, in vivo ubiquitination assay, isolated mitochondria reconstitution with in vitro-translated MOAP-1","pmids":["17535899"],"confidence":"High","gaps":["Identity of the responsible E3 ligase(s) was unknown","Signal that blocks polyubiquitination was uncharacterized"]},{"year":2008,"claim":"Identification of TRIM39 as a stabilizer of MOAP-1 that inhibits its polyubiquitination answered how MOAP-1 escapes constitutive degradation to accumulate at mitochondria and promote Bax-dependent apoptosis.","evidence":"Co-IP, ubiquitination assay, cycloheximide chase, isolated mitochondria cytochrome c release, siRNA knockdown","pmids":["19100260"],"confidence":"High","gaps":["Mechanism by which TRIM39 (itself a RING E3) inhibits rather than promotes ubiquitination was unclear","Identity of the E3 ligase degrading MOAP-1 still unknown"]},{"year":2012,"claim":"Identification of APC/C(Cdh1) as the E3 ligase that ubiquitylates MOAP-1, and demonstration that TRIM39 directly inhibits APC/C(Cdh1) activity toward MOAP-1, resolved the constitutive degradation pathway and the mechanism of TRIM39-mediated stabilization.","evidence":"In vitro ubiquitylation assay with purified APC/C(Cdh1), Cdh1 siRNA stabilizing MOAP-1, Bax activation assay","pmids":["22529100"],"confidence":"High","gaps":["Whether additional E3 ligases contribute to MOAP-1 turnover was unresolved","Degron motif on MOAP-1 recognized by APC/C(Cdh1) not mapped"]},{"year":2016,"claim":"Identification of UBR5/Dyrk2 as a second E3-kinase axis that ubiquitylates and degrades MOAP-1 revealed a parallel degradation pathway and showed that UBR5 loss sensitizes cisplatin-resistant cancer cells to apoptosis through MOAP-1 accumulation.","evidence":"In vitro ubiquitylation reconstitution, Co-IP, siRNA of UBR5 in ovarian cancer cells","pmids":["27721409"],"confidence":"High","gaps":["Whether APC/C(Cdh1) and UBR5 act redundantly or in distinct cell-cycle phases was not determined","Dyrk2 phosphorylation site on MOAP-1 not mapped"]},{"year":2016,"claim":"Using MOAP-1 knockout mice, MOAP-1 was shown to be required in vivo for Fas-induced hepatocellular apoptosis and to facilitate tBid recruitment to mitochondria via the outer membrane protein MTCH2, expanding its role beyond direct Bax activation.","evidence":"MOAP-1 knockout mouse, Fas agonist antibody injection, Co-IP identifying MOAP-1–MTCH2 interaction, mitochondrial fractionation","pmids":["27320914"],"confidence":"High","gaps":["Whether MOAP-1–MTCH2 interaction is independent of MOAP-1–Bax interaction was unclear","Role in tissues other than liver not characterized in vivo"]},{"year":2021,"claim":"Discovery that MOAP-1 binds LC3 through an N-terminal LIR motif and is required for phagophore closure during autophagy established a function for MOAP-1 beyond apoptosis.","evidence":"MOAP-1 knockout cells, Halo-LC3 autophagosome completion assay, proteinase K protection assay, LIR mutant rescue","pmids":["33783314"],"confidence":"High","gaps":["Mechanistic basis of how LC3 binding promotes membrane closure not defined","Whether the autophagy function is connected to or independent of Bax-binding activity"]},{"year":2021,"claim":"Crystal structure determination confirmed MOAP-1 as a domesticated retroviral Gag-derived protein with a capsid-like fold, providing the first structural framework for understanding its protein interactions.","evidence":"X-ray crystallography of a stably folded domain, structural comparison to retroviral CA domains","pmids":["34357660"],"confidence":"High","gaps":["No structure of MOAP-1 in complex with Bax, RASSF1A, or LC3","Functional significance of the Gag-like fold for its apoptotic or autophagic activities not tested"]},{"year":2025,"claim":"Identification of MOAP-1/PNMA4 as a MAVS-interacting protein that enhances RIG-I K63-ubiquitination by TRIM25 and is required for antiviral immunity in vivo extended its functions to innate immune signaling.","evidence":"BioID proximity labeling, Co-IP, K63-ubiquitination assay, Pnma4 knockout mouse RNA virus infection model","pmids":["40929959"],"confidence":"High","gaps":["Whether the RIG-I signaling function depends on the same protein domains as apoptosis/autophagy is unknown","How MOAP-1 facilitates TRIM25 access to RIG-I mechanistically is not resolved"]},{"year":null,"claim":"Key unresolved questions include the structural basis of MOAP-1 autoinhibition and its relief by RASSF1A, the relationship between the Gag-like capsid fold and membrane-remodeling functions in apoptosis and autophagy, and whether the apoptotic, autophagic, and antiviral roles of MOAP-1 are coordinated or independently regulated.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structure of MOAP-1 in an autoinhibited versus activated conformation","Functional integration of apoptosis, autophagy, and innate immunity roles not tested","Post-translational regulation (ubiquitination, phosphorylation) of MOAP-1 in contexts beyond apoptosis is largely unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2,9,14]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[1,4,5,9,14]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,1,2,3,4,5,6,8,9]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[11]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[14]}],"complexes":["MOAP-1–Bax complex","RASSF1A–MOAP-1 complex"],"partners":["BAX","RASSF1A","TRIM39","MTCH2","UBR5","MAVS","TRIM25","RACK1"],"other_free_text":[]},"mechanistic_narrative":"MOAP-1 (PNMA4) is a short-lived, mitochondria-enriched effector of intrinsic apoptosis, autophagy, and innate antiviral signaling, whose cellular levels are tightly controlled by ubiquitin-mediated degradation. Under basal conditions, MOAP-1 is constitutively polyubiquitinated and degraded via the proteasome by the E3 ligases APC/C(Cdh1) and UBR5, whereas apoptotic stimuli inhibit its ubiquitination—an effect reinforced by the stabilizing E3 ligase TRIM39—leading to MOAP-1 accumulation at mitochondria, where it directly associates with Bax (through a BH3-like domain), drives Bax conformational change and mitochondrial insertion, promotes tBid recruitment via MTCH2, and triggers cytochrome c release and caspase activation [PMID:11060313, PMID:16199525, PMID:17535899, PMID:22529100, PMID:27721409, PMID:19100260, PMID:27320914]. RASSF1A, recruited to death-receptor complexes upon TNFα/TRAIL stimulation, relieves an intramolecular autoinhibition in MOAP-1 to license Bax binding, and activated K-Ras synergizes with this pathway [PMID:15949439, PMID:16344548]. Beyond apoptosis, MOAP-1 binds LC3 through an N-terminal LIR motif to promote phagophore closure during starvation-induced autophagy [PMID:33783314], and enhances RIG-I–MAVS antiviral signaling by facilitating TRIM25-mediated K63-ubiquitination of RIG-I, as demonstrated by increased susceptibility of PNMA4-knockout mice to RNA virus infection [PMID:40929959]."},"prefetch_data":{"uniprot":{"accession":"Q96BY2","full_name":"Modulator of apoptosis 1","aliases":["Paraneoplastic antigen Ma4"],"length_aa":351,"mass_kda":39.5,"function":"Retrotransposon-derived protein that forms virion-like capsids (By similarity). Acts as an effector of BAX during apoptosis: enriched at outer mitochondria membrane and associates with BAX upon induction of apoptosis, facilitating BAX-dependent mitochondrial outer membrane permeabilization and apoptosis (PubMed:11060313, PubMed:16199525). Required for death receptor-dependent apoptosis (PubMed:11060313). When associated with RASSF1, promotes BAX conformational change and translocation to mitochondrial membranes in response to TNF and TNFSF10 stimulation (PubMed:15949439). Also promotes autophagy: promotes phagophore closure via association with ATG8 proteins (PubMed:33783314). Acts as an inhibitor of the NFE2L2/NRF2 pathway via interaction with SQSTM1: interaction promotes dissociation of SQSTM1 inclusion bodies that sequester KEAP1, relieving inactivation of the BCR(KEAP1) complex (PubMed:33393215)","subcellular_location":"Cytoplasm, cytosol; Mitochondrion outer membrane; Extracellular vesicle membrane","url":"https://www.uniprot.org/uniprotkb/Q96BY2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MOAP1","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":[],"url":"https://opencell.sf.czbiohub.org/search/MOAP1","total_profiled":1310},"omim":[{"mim_id":"612620","title":"RAS ASSOCIATION DOMAIN FAMILY, MEMBER 6; RASSF6","url":"https://www.omim.org/entry/612620"},{"mim_id":"609485","title":"MODULATOR OF APOPTOSIS 1; MOAP1","url":"https://www.omim.org/entry/609485"},{"mim_id":"605082","title":"RAS ASSOCIATION DOMAIN FAMILY PROTEIN 1; RASSF1","url":"https://www.omim.org/entry/605082"},{"mim_id":"604010","title":"PARANEOPLASTIC MA ANTIGEN 1; PNMA1","url":"https://www.omim.org/entry/604010"},{"mim_id":"300675","title":"PARANEOPLASTIC MA ANTIGEN 3; PNMA3","url":"https://www.omim.org/entry/300675"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cell Junctions","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":132.0}],"url":"https://www.proteinatlas.org/search/MOAP1"},"hgnc":{"alias_symbol":["MAP-1","PNMA4"],"prev_symbol":[]},"alphafold":{"accession":"Q96BY2","domains":[{"cath_id":"3.30.70.330","chopping":"2-94","consensus_level":"high","plddt":78.6946,"start":2,"end":94},{"cath_id":"-","chopping":"182-242","consensus_level":"high","plddt":87.7492,"start":182,"end":242},{"cath_id":"-","chopping":"248-349","consensus_level":"high","plddt":88.0424,"start":248,"end":349}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96BY2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96BY2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96BY2-F1-predicted_aligned_error_v6.png","plddt_mean":78.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MOAP1","jax_strain_url":"https://www.jax.org/strain/search?query=MOAP1"},"sequence":{"accession":"Q96BY2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96BY2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96BY2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96BY2"}},"corpus_meta":[{"pmid":"21383978","id":"PMC_21383978","title":"The bZIP transcription factor MoAP1 mediates the oxidative stress response and is critical for pathogenicity of the rice blast fungus Magnaporthe oryzae.","date":"2011","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/21383978","citation_count":246,"is_preprint":false},{"pmid":"6368569","id":"PMC_6368569","title":"Widespread distribution of the major polypeptide component of MAP 1 (microtubule-associated protein 1) in the nervous system.","date":"1984","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/6368569","citation_count":241,"is_preprint":false},{"pmid":"15949439","id":"PMC_15949439","title":"The tumor suppressor RASSF1A and MAP-1 link death receptor signaling to Bax conformational change and cell death.","date":"2005","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/15949439","citation_count":148,"is_preprint":false},{"pmid":"6572393","id":"PMC_6572393","title":"Low molecular weight microtubule-associated proteins are light chains of microtubule-associated protein 1 (MAP 1).","date":"1983","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/6572393","citation_count":133,"is_preprint":false},{"pmid":"11060313","id":"PMC_11060313","title":"MAP-1, a novel proapoptotic protein containing a BH3-like motif that associates with Bax through its Bcl-2 homology domains.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11060313","citation_count":118,"is_preprint":false},{"pmid":"16344548","id":"PMC_16344548","title":"The RASSF1A tumor suppressor activates Bax via MOAP-1.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16344548","citation_count":118,"is_preprint":false},{"pmid":"16199525","id":"PMC_16199525","title":"MAP-1 is a mitochondrial effector of Bax.","date":"2005","source":"Proceedings of the National Academy of Sciences of the 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(MAP-1).","date":"1987","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/3803603","citation_count":56,"is_preprint":false},{"pmid":"22529100","id":"PMC_22529100","title":"The Trim39 ubiquitin ligase inhibits APC/CCdh1-mediated degradation of the Bax activator MOAP-1.","date":"2012","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/22529100","citation_count":54,"is_preprint":false},{"pmid":"17535899","id":"PMC_17535899","title":"Inhibition of ubiquitin-mediated degradation of MOAP-1 by apoptotic stimuli promotes Bax function in mitochondria.","date":"2007","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/17535899","citation_count":54,"is_preprint":false},{"pmid":"19100260","id":"PMC_19100260","title":"TRIM39 is a MOAP-1-binding protein that stabilizes MOAP-1 through inhibition of its poly-ubiquitination process.","date":"2008","source":"Experimental cell 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It homodimerizes and associates with proapoptotic Bax and prosurvival Bcl-2/Bcl-XL in vitro and in vivo. The BH3-like domain is required for Bax association and apoptosis induction but not for Bcl-XL binding. Bax binding requires all three BH domains (BH1, BH2, BH3) of Bax.\",\n      \"method\": \"Yeast two-hybrid screen, Co-IP, in vitro binding assays, mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — yeast two-hybrid discovery + reciprocal Co-IP + mutagenesis of both MOAP-1 and Bax domains, multiple orthogonal methods\",\n      \"pmids\": [\"11060313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MOAP-1 is a mitochondria-enriched protein that associates with Bax only upon apoptotic induction, coinciding with cytochrome c release. siRNA-mediated knockdown of MOAP-1 selectively inhibits Bax-mediated apoptosis, blocks Bax conformational change and translocation, and impairs recombinant Bax- or tBid-mediated cytochrome c release from isolated mitochondria. MOAP-1-deficient cells show aggressive anchorage-independent growth similar to Bax-deficient cells.\",\n      \"method\": \"siRNA knockdown, subcellular fractionation, isolated mitochondria cytochrome c release assay, anchorage-independent growth assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including in vitro reconstitution with isolated mitochondria, siRNA KD with defined phenotypic readouts\",\n      \"pmids\": [\"16199525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"RASSF1A is required for death receptor (TNFα/TRAIL)-induced Bax conformational change and apoptosis. TNFα or TRAIL stimulation recruits RASSF1A and MOAP-1 to receptor complexes and promotes RASSF1A/MOAP-1 complex formation. RASSF1A binding to MOAP-1 relieves an intramolecular inhibitory interaction in MOAP-1, enabling MOAP-1 to associate with Bax and trigger Bax conformational change, mitochondrial membrane insertion, and cytochrome c release.\",\n      \"method\": \"Co-IP, shRNA knockdown, Bax conformational change assay, cytochrome c release assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, shRNA knockdown of both RASSF1A and MOAP-1 with defined apoptotic phenotypes, replicated pathway placement\",\n      \"pmids\": [\"15949439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"RASSF1A and MOAP-1 interact directly, and this interaction is enhanced by activated K-Ras. RASSF1A activates Bax via MOAP-1, and activated K-Ras, RASSF1A, and MOAP-1 synergize to induce Bax activation and cell death. A tumor-derived RASSF1A point mutant defective for MOAP-1 interaction fails to activate Bax.\",\n      \"method\": \"Co-IP, pulldown, shRNA knockdown, Bax activation assay, mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct interaction confirmed by Co-IP/pulldown + mutagenesis + functional epistasis, corroborated by independent lab (Baksh et al., same year)\",\n      \"pmids\": [\"16344548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MOAP-1 is a short-lived protein (t1/2 ~25 min) constitutively degraded by the ubiquitin-proteasome system. Apoptotic stimuli rapidly upregulate MOAP-1 by inhibiting its polyubiquitination. Elevated MOAP-1 promotes recombinant Bax-mediated cytochrome c release from isolated mitochondria, and in vitro-translated MOAP-1 can restore Bax-mediated cytochrome c release in mitochondria depleted of short-lived proteins.\",\n      \"method\": \"Cycloheximide chase, ubiquitination assay, isolated mitochondria cytochrome c release assay, in vitro translation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro reconstitution with isolated mitochondria + biochemical ubiquitination assay, multiple orthogonal approaches\",\n      \"pmids\": [\"17535899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TRIM39 was identified as a MOAP-1-binding protein that stabilizes MOAP-1 by inhibiting its polyubiquitination. TRIM39 overexpression extends MOAP-1 half-life, elevates MOAP-1 in mitochondria, and promotes cytochrome c release from isolated mitochondria stimulated by recombinant Bax. TRIM39 knockdown reduces sensitivity to etoposide-induced apoptosis.\",\n      \"method\": \"Co-IP, ubiquitination assay, cycloheximide chase, isolated mitochondria cytochrome c release assay, siRNA knockdown\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, ubiquitination assay, in vitro mitochondria reconstitution, multiple orthogonal methods\",\n      \"pmids\": [\"19100260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MOAP-1 is a substrate of the APC/C(Cdh1) ubiquitin ligase. TRIM39, a RING domain E3 ligase, directly inhibits APC/C(Cdh1)-mediated ubiquitylation of MOAP-1 (not just competing for substrate), thereby stabilizing MOAP-1. Cdh1 siRNA knockdown stabilizes MOAP-1 and enhances etoposide-induced Bax activation and apoptosis.\",\n      \"method\": \"In vitro ubiquitylation assay, siRNA knockdown of Cdh1, Co-IP, Bax activation assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro ubiquitylation assay identifying APC/C(Cdh1) as E3 ligase + siRNA epistasis + functional apoptosis readout\",\n      \"pmids\": [\"22529100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"miR-1228 targets MOAP-1 mRNA, reduces MOAP-1 protein expression, and delays stress-induced apoptosis. Rescue experiments showed that miR-1228 inhibition of apoptosis is attenuated by repressing MOAP-1 expression, establishing MOAP-1 as a direct target.\",\n      \"method\": \"miRNA overexpression, siRNA, apoptosis assays\",\n      \"journal\": \"Apoptosis : an international journal on programmed cell death\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, miRNA-target interaction demonstrated by rescue experiment but limited mechanistic depth\",\n      \"pmids\": [\"22434376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"UBR5, a HECT family E3 ubiquitin ligase, physically interacts with MOAP-1, ubiquitylates MOAP-1 in vitro, and destabilizes MOAP-1 in cultured cells. Dyrk2 kinase cooperates with UBR5 in mediating MOAP-1 ubiquitylation. UBR5 knockdown increases MOAP-1 levels, enhances Bax activation, and sensitizes cisplatin-resistant ovarian cancer cells to apoptosis.\",\n      \"method\": \"Co-IP, in vitro ubiquitylation assay, siRNA knockdown, Bax activation assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro ubiquitylation reconstitution + Co-IP + siRNA functional rescue, multiple orthogonal methods\",\n      \"pmids\": [\"27721409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MOAP-1-deficient mice are resistant to Fas-induced hepatocellular apoptosis and lethality. MOAP-1 facilitates tBid recruitment to mitochondria by binding to the outer mitochondrial membrane protein MTCH2; in MOAP-1-deficient cells, MTCH2 fails to engage tBid, impairing tBid mitochondrial accumulation and downstream Bax/Bak activation.\",\n      \"method\": \"MOAP-1 knockout mouse model, Co-IP, mitochondrial fractionation, Fas-induced apoptosis assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo knockout mouse + Co-IP identifying MTCH2 interaction + defined hepatocellular apoptosis phenotype\",\n      \"pmids\": [\"27320914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RACK1 associates with MOAP-1 via electrostatic interactions (similar to MOAP-1/RASSF1A and MOAP-1/TNF-R1 interactions) and recruits the E3 ligase TRAF2 to MOAP-1, resulting in K63-linked ubiquitination of MOAP-1.\",\n      \"method\": \"Co-IP, ubiquitination assay (K63-linkage specific)\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP and ubiquitination assay from single lab, single paper\",\n      \"pmids\": [\"29470995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MOAP-1 binds LC3 via an LC3-interacting region (LIR) motif at its N-terminus and promotes phagophore closure during starvation-induced autophagy. MOAP-1-deficient cells show impaired autophagy with predominantly unclosed phagophores rather than closed autophagosomes upon EBSS treatment. Re-expression of wild-type MOAP-1 but not LIR-mutant MOAP-1 restores autophagy, demonstrating that LC3 binding is required for this function.\",\n      \"method\": \"MOAP-1 knockout cells, Halo-tagged LC3 autophagosome completion assay, Co-IP, proteinase K protection assay, mutagenesis of LIR motif\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO cells + mutagenesis rescue + multiple orthogonal autophagy assays establishing mechanistic requirement for LIR motif\",\n      \"pmids\": [\"33783314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"X-ray crystal structures of a stably folded domain of MOAP-1 show high structural similarity to the C-terminal capsid (CA) domain of retroviral Gag proteins, confirming MOAP-1 as a domesticated Gag-derived protein.\",\n      \"method\": \"X-ray crystallography, structural comparison\",\n      \"journal\": \"Proteins\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure determination with structural validation\",\n      \"pmids\": [\"34357660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Influenza A virus PB1-F2 protein interacts with human MOAP-1, as demonstrated by yeast two-hybrid, GST pulldown, and Co-IP assays. PB1-F2 upregulates exogenous MOAP-1 protein levels.\",\n      \"method\": \"Yeast two-hybrid, GST pulldown, Co-IP, Western blot\",\n      \"journal\": \"Wei sheng wu xue bao = Acta microbiologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — interaction confirmed by multiple binding assays but functional consequence not deeply characterized, single lab\",\n      \"pmids\": [\"23236846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PNMA4/MOAP-1 was identified as a MAVS-interacting protein at the mitochondria using proximity-based labeling. PNMA4 enhances RIG-I–MAVS interaction and facilitates K63-linked polyubiquitination of RIG-I at K657 by TRIM25, positively regulating antiviral signaling. PNMA4-knockout mice are more susceptible to RNA virus infection.\",\n      \"method\": \"Proximity-based labeling (BioID), Co-IP, ubiquitination assay, Pnma4 knockout mouse infection model\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — proximity labeling + Co-IP + ubiquitination assay + in vivo KO mouse model, multiple orthogonal methods\",\n      \"pmids\": [\"40929959\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MOAP-1 (Modulator of Apoptosis 1/PNMA4) is a mitochondria-enriched, short-lived BH3-like protein that is constitutively degraded via the ubiquitin-proteasome system (by APC/C(Cdh1) and UBR5 E3 ligases); upon apoptotic stimulation its polyubiquitination is inhibited—an event promoted by TRIM39—leading to its stabilization and association with Bax, an interaction that requires relief of an intramolecular inhibitory interaction by RASSF1A (recruited to death receptor complexes), ultimately driving Bax conformational change, mitochondrial membrane insertion, cytochrome c release, and caspase activation; additionally, MOAP-1 facilitates tBid recruitment to the outer mitochondrial membrane via MTCH2, promotes phagophore closure during autophagy through a direct LC3-LIR interaction, and enhances RIG-I–MAVS antiviral signaling by facilitating TRIM25-mediated K63-ubiquitination of RIG-I.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MOAP-1 (PNMA4) is a short-lived, mitochondria-enriched effector of intrinsic apoptosis, autophagy, and innate antiviral signaling, whose cellular levels are tightly controlled by ubiquitin-mediated degradation. Under basal conditions, MOAP-1 is constitutively polyubiquitinated and degraded via the proteasome by the E3 ligases APC/C(Cdh1) and UBR5, whereas apoptotic stimuli inhibit its ubiquitination—an effect reinforced by the stabilizing E3 ligase TRIM39—leading to MOAP-1 accumulation at mitochondria, where it directly associates with Bax (through a BH3-like domain), drives Bax conformational change and mitochondrial insertion, promotes tBid recruitment via MTCH2, and triggers cytochrome c release and caspase activation [PMID:11060313, PMID:16199525, PMID:17535899, PMID:22529100, PMID:27721409, PMID:19100260, PMID:27320914]. RASSF1A, recruited to death-receptor complexes upon TNFα/TRAIL stimulation, relieves an intramolecular autoinhibition in MOAP-1 to license Bax binding, and activated K-Ras synergizes with this pathway [PMID:15949439, PMID:16344548]. Beyond apoptosis, MOAP-1 binds LC3 through an N-terminal LIR motif to promote phagophore closure during starvation-induced autophagy [PMID:33783314], and enhances RIG-I–MAVS antiviral signaling by facilitating TRIM25-mediated K63-ubiquitination of RIG-I, as demonstrated by increased susceptibility of PNMA4-knockout mice to RNA virus infection [PMID:40929959].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Identification of MOAP-1 as a Bax-associating protein with a BH3-like domain established it as a candidate apoptosis regulator, resolving the question of how Bax is engaged by a novel cofactor.\",\n      \"evidence\": \"Yeast two-hybrid screen, reciprocal Co-IP, mutagenesis of BH3-like domain and Bax BH domains in mammalian cells\",\n      \"pmids\": [\"11060313\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Physiological context of interaction unknown—Bax binding was constitutive in overexpression systems\",\n        \"No subcellular localization data for endogenous MOAP-1\",\n        \"Mechanism linking MOAP-1/Bax binding to downstream apoptosis undefined\"\n      ]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstration that MOAP-1 is mitochondria-enriched, required for Bax conformational change and translocation, and that its loss phenocopies Bax deficiency in anchorage-independent growth, established MOAP-1 as a necessary upstream activator of Bax in the intrinsic apoptotic pathway.\",\n      \"evidence\": \"siRNA knockdown, subcellular fractionation, isolated mitochondria cytochrome c release assay in HCT116 cells\",\n      \"pmids\": [\"16199525\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How apoptotic signals trigger the MOAP-1/Bax interaction remained unclear\",\n        \"No in vivo model\"\n      ]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Discovery that RASSF1A, recruited to TNFα/TRAIL receptor complexes, relieves an autoinhibitory interaction within MOAP-1 to enable Bax binding resolved how death-receptor signals are transduced through MOAP-1 to mitochondria, with activated K-Ras synergizing with RASSF1A.\",\n      \"evidence\": \"Co-IP, shRNA knockdown of RASSF1A and MOAP-1, Bax conformational change and cytochrome c release assays; mutagenesis of RASSF1A tumor-derived mutant\",\n      \"pmids\": [\"15949439\", \"16344548\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of the intramolecular autoinhibition not defined\",\n        \"Contribution of K-Ras effector pathway to RASSF1A–MOAP-1 axis not fully dissected\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showing that MOAP-1 is an extremely short-lived protein (t½ ~25 min) whose polyubiquitination is inhibited by apoptotic stimuli revealed a post-translational stabilization mechanism as the primary mode of MOAP-1 regulation.\",\n      \"evidence\": \"Cycloheximide chase, in vivo ubiquitination assay, isolated mitochondria reconstitution with in vitro-translated MOAP-1\",\n      \"pmids\": [\"17535899\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Identity of the responsible E3 ligase(s) was unknown\",\n        \"Signal that blocks polyubiquitination was uncharacterized\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identification of TRIM39 as a stabilizer of MOAP-1 that inhibits its polyubiquitination answered how MOAP-1 escapes constitutive degradation to accumulate at mitochondria and promote Bax-dependent apoptosis.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, cycloheximide chase, isolated mitochondria cytochrome c release, siRNA knockdown\",\n      \"pmids\": [\"19100260\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which TRIM39 (itself a RING E3) inhibits rather than promotes ubiquitination was unclear\",\n        \"Identity of the E3 ligase degrading MOAP-1 still unknown\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of APC/C(Cdh1) as the E3 ligase that ubiquitylates MOAP-1, and demonstration that TRIM39 directly inhibits APC/C(Cdh1) activity toward MOAP-1, resolved the constitutive degradation pathway and the mechanism of TRIM39-mediated stabilization.\",\n      \"evidence\": \"In vitro ubiquitylation assay with purified APC/C(Cdh1), Cdh1 siRNA stabilizing MOAP-1, Bax activation assay\",\n      \"pmids\": [\"22529100\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether additional E3 ligases contribute to MOAP-1 turnover was unresolved\",\n        \"Degron motif on MOAP-1 recognized by APC/C(Cdh1) not mapped\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identification of UBR5/Dyrk2 as a second E3-kinase axis that ubiquitylates and degrades MOAP-1 revealed a parallel degradation pathway and showed that UBR5 loss sensitizes cisplatin-resistant cancer cells to apoptosis through MOAP-1 accumulation.\",\n      \"evidence\": \"In vitro ubiquitylation reconstitution, Co-IP, siRNA of UBR5 in ovarian cancer cells\",\n      \"pmids\": [\"27721409\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether APC/C(Cdh1) and UBR5 act redundantly or in distinct cell-cycle phases was not determined\",\n        \"Dyrk2 phosphorylation site on MOAP-1 not mapped\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Using MOAP-1 knockout mice, MOAP-1 was shown to be required in vivo for Fas-induced hepatocellular apoptosis and to facilitate tBid recruitment to mitochondria via the outer membrane protein MTCH2, expanding its role beyond direct Bax activation.\",\n      \"evidence\": \"MOAP-1 knockout mouse, Fas agonist antibody injection, Co-IP identifying MOAP-1–MTCH2 interaction, mitochondrial fractionation\",\n      \"pmids\": [\"27320914\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether MOAP-1–MTCH2 interaction is independent of MOAP-1–Bax interaction was unclear\",\n        \"Role in tissues other than liver not characterized in vivo\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Discovery that MOAP-1 binds LC3 through an N-terminal LIR motif and is required for phagophore closure during autophagy established a function for MOAP-1 beyond apoptosis.\",\n      \"evidence\": \"MOAP-1 knockout cells, Halo-LC3 autophagosome completion assay, proteinase K protection assay, LIR mutant rescue\",\n      \"pmids\": [\"33783314\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanistic basis of how LC3 binding promotes membrane closure not defined\",\n        \"Whether the autophagy function is connected to or independent of Bax-binding activity\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Crystal structure determination confirmed MOAP-1 as a domesticated retroviral Gag-derived protein with a capsid-like fold, providing the first structural framework for understanding its protein interactions.\",\n      \"evidence\": \"X-ray crystallography of a stably folded domain, structural comparison to retroviral CA domains\",\n      \"pmids\": [\"34357660\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structure of MOAP-1 in complex with Bax, RASSF1A, or LC3\",\n        \"Functional significance of the Gag-like fold for its apoptotic or autophagic activities not tested\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of MOAP-1/PNMA4 as a MAVS-interacting protein that enhances RIG-I K63-ubiquitination by TRIM25 and is required for antiviral immunity in vivo extended its functions to innate immune signaling.\",\n      \"evidence\": \"BioID proximity labeling, Co-IP, K63-ubiquitination assay, Pnma4 knockout mouse RNA virus infection model\",\n      \"pmids\": [\"40929959\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the RIG-I signaling function depends on the same protein domains as apoptosis/autophagy is unknown\",\n        \"How MOAP-1 facilitates TRIM25 access to RIG-I mechanistically is not resolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of MOAP-1 autoinhibition and its relief by RASSF1A, the relationship between the Gag-like capsid fold and membrane-remodeling functions in apoptosis and autophagy, and whether the apoptotic, autophagic, and antiviral roles of MOAP-1 are coordinated or independently regulated.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structure of MOAP-1 in an autoinhibited versus activated conformation\",\n        \"Functional integration of apoptosis, autophagy, and innate immunity roles not tested\",\n        \"Post-translational regulation (ubiquitination, phosphorylation) of MOAP-1 in contexts beyond apoptosis is largely unexplored\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2, 9, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [1, 4, 5, 9, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4, 5, 6, 8, 9]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"complexes\": [\n      \"MOAP-1–Bax complex\",\n      \"RASSF1A–MOAP-1 complex\"\n    ],\n    \"partners\": [\n      \"BAX\",\n      \"RASSF1A\",\n      \"TRIM39\",\n      \"MTCH2\",\n      \"UBR5\",\n      \"MAVS\",\n      \"TRIM25\",\n      \"RACK1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}