{"gene":"MGRN1","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2025,"finding":"Cryo-EM structure of the MEGF8-MOSMO-MGRN1 (MMM) complex revealed that MGRN1 is a membrane-tethered E3 ligase whose RING domain is suspended by a long flexible helix attached to a membrane platform (MEGF8-MOSMO), orienting the RING domain to ubiquitylate cytoplasmic surfaces of target receptors. The complex regulates left-right patterning and Hedgehog pathway signaling by attenuating Smoothened (SMO) signaling.","method":"Cryo-electron microscopy with integrated biophysical and functional studies","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure combined with biophysical and functional validation in a single rigorous study","pmids":["bio_10.1101_2025.09.11.675358"],"is_preprint":true},{"year":2025,"finding":"MGRN1 uses transmembrane adapters ATRN and ATRNL1 (in addition to MEGF8) to recruit and ubiquitylate melanocortin receptors MC1R and MC4R, promoting their degradation. ATRN interacts with the RING domain of MGRN1 by co-immunoprecipitation. Loss of MGRN1 or ATRN increases surface and ciliary localization of MC4R in fibroblasts and elevates MC1R levels in melanocytes, resulting in enhanced eumelanin production.","method":"Co-immunoprecipitation, functional ubiquitylation assays, receptor surface/ciliary localization assays, melanin production assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus functional assays, replicated across peer-reviewed and preprint versions from same group","pmids":["41178558","40196599"],"is_preprint":false},{"year":2016,"finding":"MGRN1 ubiquitylates the ER E3 ligase GP78 in trans through non-canonical K11 linkages, maintaining constitutively low GP78 levels in healthy cells and thereby downregulating mitophagy. When mitochondria are stressed and cytosolic Ca2+ rises, the MGRN1-GP78 interaction is reduced and GP78 ubiquitylation is compromised. Catalytic inactivation of MGRN1 elevates GP78 levels and increases mitophagy. Disease-causing (Ctm)PrP depletes functional MGRN1, impairing GP78 polyubiquitylation and degradation.","method":"Co-immunoprecipitation, ubiquitylation assays with linkage-specific antibodies, catalytic mutant analysis, Ca2+ chelation experiments","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, K11-linkage ubiquitylation assay, catalytic mutant, Ca2+ chelation) in single study","pmids":["26743086"],"is_preprint":false},{"year":2018,"finding":"Calmodulin (CaM) acts as an adapter protein that senses cytosolic Ca2+ levels and modulates Ca2+-dependent MGRN1-GP78 interactions. Under stress conditions with elevated cytosolic Ca2+, CaM binds to both MGRN1 and GP78 and inhibits their interaction, thereby regulating ER-associated protein degradation, ER-mitochondria junctions, and ER distribution.","method":"Co-immunoprecipitation, molecular docking and simulation, biophysical binding studies (different affinities/binding modes characterized), primary neuronal cells","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — biophysical interaction studies combined with Co-IP and molecular simulation, single lab with multiple orthogonal methods","pmids":["30230921"],"is_preprint":false},{"year":2009,"finding":"MGRN1 inhibits melanocortin receptor (MC1R and MC4R) signaling to cAMP by competing with Gαs for binding to the receptors. MGRN1 co-immunoprecipitated with MCRs; overexpression of Gαs abolished the inhibitory effect and decreased co-immunoprecipitation with MCRs. Inhibition was independent of receptor plasma membrane expression, ubiquitylation, internalization, or stability. Additionally, exon 12-containing MGRN1 isoforms accumulated in the nucleus upon co-expression with receptors.","method":"Co-immunoprecipitation, cAMP signaling assays, receptor surface expression assays, subcellular localization by fluorescence","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional signaling assays and competition experiment, single lab","pmids":["19737927"],"is_preprint":false},{"year":2017,"finding":"MGRN1 ubiquitylates α-tubulin via non-canonical K6-linked ubiquitin chains, regulating dynamics of EB1-labeled microtubule plus ends and intracellular transport of mitochondria and endosomes. Loss of MGRN1 function (or expression of (Ctm)PrP mutants) reduces α-tubulin ubiquitylation and causes intracellular transport defects. Brain lysates from PrP(A117V) transgenic mice show loss of tubulin polymerization.","method":"Ubiquitylation assays with linkage-specific analysis, live-cell imaging of EB1-labeled microtubules, organelle transport assays, brain lysate biochemistry from transgenic mice","journal":"Traffic (Copenhagen, Denmark)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitylation assays with linkage specificity plus functional transport assays, single lab multiple methods","pmids":["28902452"],"is_preprint":false},{"year":2013,"finding":"MGRN1 interacts and co-localizes with the cytosolic molecular chaperone Hsp70. MGRN1 expression is upregulated by stressors, and inhibition of autophagy recruits MGRN1 to cytosolic ubiquitin-positive inclusion bodies. Overexpression of MGRN1 protects against cell death from oxidative and ER stress, suggesting it targets misfolded proteins for degradation.","method":"Co-immunoprecipitation, co-localization by immunofluorescence, cell viability assays under stress, Western blot","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP/co-localization with functional overexpression protection assays, single lab","pmids":["23756845"],"is_preprint":false},{"year":2013,"finding":"MGRN1 interacts with but does not ubiquitinate NEDD4 (a HECT-domain ubiquitin ligase). Transgenic rescue experiments in mice demonstrated that pigment-type switching requires MGRN1's ubiquitin ligase activity but not its ability to bind TSG101 or NEDD4, indicating an as-yet unidentified ubiquitination target is required for agouti-mediated melanocortin signaling.","method":"Co-immunoprecipitation, in vivo transgenesis rescue experiments in mice","journal":"Pigment cell & melanoma research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic rescue in vivo combined with Co-IP, single lab","pmids":["23253940"],"is_preprint":false},{"year":2017,"finding":"MGRN1 inhibits maturation and amyloidogenic processing of amyloid precursor protein (APP) by sequestering it in the secretory pathway, delaying proteolytic processing and reducing Aβ40/Aβ42 release. Reduction of MGRN1 in hippocampal neurons (as occurs during aging) leads to increased Aβ peptide release.","method":"Cellular APP trafficking assays, Aβ secretion measurement (ELISA), MGRN1 overexpression and knockdown in neurons","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional assays with both overexpression and knockdown, single lab","pmids":["29163761"],"is_preprint":false},{"year":2019,"finding":"MGRN1 localizes to mitochondria, most likely due to N-myristoylation. Loss of MGRN1 causes mitochondrial fragmentation and depolarization without recruitment of parkin. Parkin mRNA and protein levels decline in the brains of aged Mgrn1 null mutant mice. Double Mgrn1;parkin mutant mice show more severe early mitochondrial dysfunction but no change in spongiform neurodegeneration onset.","method":"Subcellular fractionation, mitochondrial morphology and membrane potential assays, genetic double-mutant mice, Western blot/qPCR for parkin","journal":"Mammalian genome","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — fractionation-based localization with functional consequence plus genetic double-mutant analysis, single lab","pmids":["31089807"],"is_preprint":false},{"year":2006,"finding":"MGRN1 acts early in the left-right signaling cascade during mouse embryonic development. Mgrn1 mutant embryos show abnormal expression of asymmetrically expressed LR patterning genes, and Nodal expression was uncoupled from expression of other Nodal-responsive genes, placing MGRN1 upstream of Nodal-responsive gene regulation.","method":"Genetic analysis of Mgrn1 null mutant mice, in situ hybridization for LR asymmetry markers, cardiac phenotyping","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in mouse model with multiple molecular readouts, single lab","pmids":["17075880"],"is_preprint":false},{"year":2021,"finding":"The conserved MASRPF motif in the Drosophila Attractin ortholog Distracted is required for association with Drosophila Mgrn1 (dMgrn1) in vivo, consistent with the conserved MASRPF motif in mammalian MEGF8 being required for Mgrn1 binding.","method":"In vivo interaction assay in Drosophila using MASRPF motif mutants","journal":"microPublication biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — in vivo genetic interaction with domain mutant, ortholog system","pmids":["34235405"],"is_preprint":false},{"year":2013,"finding":"Mammalian MGRN1 can functionally replace the plant E3 ligase LOG2 in Arabidopsis: MGRN1 ubiquitylates the plant membrane protein GDU1 in vitro and partially restores amino acid resistance in a log2 mutant overexpressing GDU1-myc, demonstrating conserved N-terminal domain function in substrate interaction.","method":"In vitro ubiquitylation assay, plant genetic complementation, phylogenetic analysis","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro ubiquitylation assay plus partial in vivo complementation, cross-kingdom system, single lab","pmids":["24036454"],"is_preprint":false},{"year":2007,"finding":"Loss of MGRN1 in mice causes reduced mitochondrial complex IV expression and activity, increased oxidative stress in the brain, and these mitochondrial defects precede spongiform vacuolation by many months. Compatible mitochondrial dysfunction was also observed in Atrn mutant mice, supporting a common pathway for MGRN1 and ATRN.","method":"Proteomics of mutant brains, enzymatic activity assays for complex IV, oxidative stress markers, genetic comparison of Mgrn1 and Atrn mutants","journal":"Neurobiology of aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics plus enzymatic activity assays plus genetic epistasis with Atrn mutant, single lab","pmids":["17720281"],"is_preprint":false},{"year":2023,"finding":"MGRN1 depletion in human melanoma cells promotes intercellular adhesion by upregulation of E-cadherin (likely through downregulation of the ZEB1 repressor) and increased co-localization of E-cadherin with β-catenin. Pulldown assays showed reduced CDC42 activation in the absence of MGRN1, which was reverted by E-cadherin silencing, placing CDC42 downstream of E-cadherin in this pathway.","method":"CRISPR/siRNA knockdown, pulldown assay for active CDC42, co-localization by immunofluorescence, gene expression analysis","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pulldown for CDC42 activity plus genetic epistasis (E-cadherin silencing rescue), single lab","pmids":["38008393"],"is_preprint":false},{"year":2021,"finding":"Knockdown of MGRN1 in mouse spermatogonial stem cells increases mitochondrial damage, reduces mitochondrial autophagosomes, upregulates CK2 expression, and increases FUNDC1 phosphorylation, suggesting MGRN1 regulates mitophagy in these cells possibly via CK2-mediated FUNDC1 phosphorylation.","method":"RNAi knockdown in SSCs, Western blot for mitophagy markers, electron microscopy","journal":"Zhonghua nan ke xue","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (Western blot + EM), mechanistic pathway only proposed not confirmed","pmids":["37422866"],"is_preprint":false}],"current_model":"MGRN1 is a membrane-tethered RING-type E3 ubiquitin ligase that operates in multiple cellular compartments; structurally, it forms a complex with transmembrane adapters (MEGF8/MOSMO, ATRN, ATRNL1) that orient its RING domain to ubiquitylate cytoplasmic regions of surface receptors (MC1R, MC4R, SMO), regulating their degradation and signaling output. In parallel, cytosolic MGRN1 ubiquitylates the ER E3 ligase GP78 via K11 linkages (modulated by calmodulin/Ca2+) to suppress mitophagy, and ubiquitylates α-tubulin via K6 linkages to regulate microtubule dynamics and organelle transport; loss of MGRN1 causes mitochondrial fragmentation, impaired intracellular transport, and ultimately age-dependent spongiform neurodegeneration."},"narrative":{"mechanistic_narrative":"MGRN1 is a membrane-tethered RING-type E3 ubiquitin ligase that controls the surface abundance and signaling output of cytoplasmically accessible receptors and that, in the brain, maintains mitochondrial and cytoskeletal homeostasis to prevent age-dependent neurodegeneration [PMID:bio_10.1101_2025.09.11.675358, PMID:41178558, PMID:40196599]. Structurally, its RING domain is suspended by a long flexible helix from a transmembrane platform formed with MEGF8-MOSMO, an arrangement that positions the catalytic domain to ubiquitylate the cytoplasmic faces of target receptors; through this complex MGRN1 attenuates Smoothened-dependent Hedgehog signaling and governs left-right embryonic patterning [PMID:bio_10.1101_2025.09.11.675358, PMID:17075880]. Related transmembrane adapters ATRN and ATRNL1 recruit MGRN1 to the melanocortin receptors MC1R and MC4R, where it promotes receptor degradation and limits surface and ciliary localization, thereby restraining eumelanin production and melanocortin signaling [PMID:41178558, PMID:40196599]; the conserved MASRPF motif in these Attractin/MEGF8-family adapters mediates binding to the MGRN1 RING region [PMID:41178558, PMID:40196599, PMID:34235405]. MGRN1 additionally inhibits melanocortin signaling to cAMP by competing with Gαs for receptor binding independently of its ubiquitin ligase activity [PMID:19737927], and pigment-type switching in vivo requires its catalytic activity acting on an as-yet unidentified substrate rather than its TSG101 or NEDD4 binding [PMID:23253940]. In the cytosol and at the ER, MGRN1 ubiquitylates the ER E3 ligase GP78 through non-canonical K11 linkages to keep GP78 low and suppress mitophagy, an interaction released when rising cytosolic Ca2+ is sensed by calmodulin [PMID:26743086, PMID:30230921]. It also ubiquitylates α-tubulin via K6-linked chains to regulate microtubule plus-end dynamics and the transport of mitochondria and endosomes [PMID:28902452]. Loss of MGRN1 causes mitochondrial fragmentation, depolarization, reduced complex IV activity, increased oxidative stress, and impaired intracellular transport, defects that precede spongiform neurodegeneration in mutant mice [PMID:31089807, PMID:17720281, PMID:28902452].","teleology":[{"year":2006,"claim":"Established that MGRN1 acts in early developmental signaling, placing it upstream of Nodal-responsive gene regulation in the left-right patterning cascade before any molecular activity was known.","evidence":"Genetic analysis of Mgrn1 null mouse embryos with in situ hybridization for asymmetry markers and cardiac phenotyping","pmids":["17075880"],"confidence":"Medium","gaps":["Did not identify the molecular substrate or biochemical activity linking MGRN1 to Nodal regulation","Mechanism connecting MGRN1 to the LR signaling pathway unresolved at this stage"]},{"year":2007,"claim":"Linked MGRN1 loss to mitochondrial dysfunction as an early event preceding neurodegeneration, and tied MGRN1 to ATRN in a shared pathway.","evidence":"Proteomics, complex IV enzymatic assays, and oxidative stress markers in Mgrn1 and Atrn mutant mouse brains","pmids":["17720281"],"confidence":"Medium","gaps":["Did not establish whether mitochondrial defects are a direct ubiquitylation consequence or downstream","Molecular mechanism of complex IV reduction not defined"]},{"year":2009,"claim":"Showed MGRN1 can regulate melanocortin receptor signaling non-catalytically by competing with Gαs, revealing a ubiquitylation-independent mode of action.","evidence":"Co-IP, cAMP signaling and competition assays, and subcellular localization in cells","pmids":["19737927"],"confidence":"Medium","gaps":["Inhibition was independent of ubiquitylation, leaving the in vivo relevance versus the degradative mode unclear","Functional role of nuclear-accumulating exon-12 isoforms not defined"]},{"year":2013,"claim":"Defined MGRN1 as a stress-responsive ligase engaging the protein quality-control machinery and identified interaction partners that constrain its catalytic substrate repertoire.","evidence":"Co-IP and co-localization with Hsp70, stress-protection viability assays, plus in vivo transgenic rescue distinguishing NEDD4/TSG101 binding from catalytic requirement; cross-kingdom complementation of plant LOG2 with in vitro GDU1 ubiquitylation","pmids":["23756845","23253940","24036454"],"confidence":"Medium","gaps":["The substrate required for agouti/pigment-type switching remained unidentified","Direct misfolded-protein substrates of MGRN1 not enumerated"]},{"year":2016,"claim":"Identified GP78 as a direct MGRN1 substrate ubiquitylated via non-canonical K11 chains, defining a mechanism by which MGRN1 suppresses mitophagy.","evidence":"Co-IP, linkage-specific ubiquitylation assays, catalytic mutant analysis, and Ca2+ chelation in cells","pmids":["26743086"],"confidence":"High","gaps":["Did not resolve how Ctm-PrP depletes functional MGRN1","Quantitative contribution of GP78 regulation to neurodegeneration not established"]},{"year":2017,"claim":"Extended MGRN1 substrate range to α-tubulin via K6 chains and linked this to microtubule dynamics and organelle transport, and to APP processing via secretory sequestration.","evidence":"Linkage-specific ubiquitylation assays, live-cell EB1 imaging, organelle transport assays, transgenic mouse brain biochemistry; separate APP trafficking and Aβ ELISA assays with overexpression/knockdown","pmids":["28902452","29163761"],"confidence":"Medium","gaps":["Whether tubulin K6 ubiquitylation directly drives transport defects in vivo not fully separated from other defects","Mechanism of APP sequestration (direct vs indirect) not resolved"]},{"year":2018,"claim":"Revealed calmodulin as the Ca2+ sensor that gates the MGRN1-GP78 interaction, coupling cytosolic Ca2+ to ER-associated degradation and ER-mitochondria contacts.","evidence":"Co-IP, molecular docking/simulation, and biophysical binding studies in primary neurons","pmids":["30230921"],"confidence":"High","gaps":["In vivo demonstration of Ca2+/CaM-gated switching during physiological stress not established","Structural basis of competitive CaM binding not resolved"]},{"year":2019,"claim":"Localized MGRN1 to mitochondria and showed its loss causes parkin-independent fragmentation and depolarization, positioning it within mitochondrial quality control.","evidence":"Subcellular fractionation, mitochondrial morphology/potential assays, and Mgrn1;parkin double-mutant mice","pmids":["31089807"],"confidence":"Medium","gaps":["Mitochondrial substrate(s) of MGRN1 not identified","Causal link between mitochondrial fragmentation and spongiform degeneration onset unresolved (double mutant did not change onset)"]},{"year":2023,"claim":"Connected MGRN1 to cell adhesion and motility control in melanoma via an E-cadherin/ZEB1/CDC42 axis, broadening its role beyond ligase substrate degradation.","evidence":"CRISPR/siRNA knockdown, active CDC42 pulldown, co-localization, and gene expression analysis with E-cadherin rescue","pmids":["38008393"],"confidence":"Medium","gaps":["Whether MGRN1 controls E-cadherin/ZEB1 directly via ubiquitylation or indirectly is unknown","No direct substrate in this pathway identified"]},{"year":2025,"claim":"Provided the structural and mechanistic basis for MGRN1 as a membrane-tethered ligase, showing how transmembrane adapters orient its RING domain to ubiquitylate receptor cytoplasmic surfaces and regulate Hedgehog and melanocortin signaling.","evidence":"Cryo-EM of the MEGF8-MOSMO-MGRN1 complex with biophysics (preprint); reciprocal Co-IP and functional ubiquitylation/localization/melanin assays for ATRN/ATRNL1-MC1R/MC4R","pmids":["bio_10.1101_2025.09.11.675358","41178558","40196599"],"confidence":"High","gaps":["Full set of receptor substrates engaged by each adapter not enumerated","How adapter choice (MEGF8/MOSMO vs ATRN/ATRNL1) is regulated is unknown"]},{"year":null,"claim":"The identity of the catalytic substrate required for agouti-mediated pigment-type switching and the unifying mechanism linking MGRN1's receptor, mitochondrial, and cytoskeletal activities to neurodegeneration remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No single substrate accounts for the spongiform neurodegeneration phenotype","Relative contribution of GP78, tubulin, and receptor pathways to disease unweighted"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,2,5]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2,5]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,2,12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[9]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,6]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[2,3]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,4]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,10]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[2]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,2]}],"complexes":["MEGF8-MOSMO-MGRN1 (MMM) complex"],"partners":["MEGF8","MOSMO","ATRN","ATRNL1","GP78","CALM1","HSPA8","NEDD4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O60291","full_name":"E3 ubiquitin-protein ligase MGRN1","aliases":["Mahogunin RING finger protein 1","RING finger protein 156","RING-type E3 ubiquitin transferase MGRN1"],"length_aa":552,"mass_kda":60.8,"function":"E3 ubiquitin-protein ligase. Mediates monoubiquitination at multiple sites of TSG101 in the presence of UBE2D1, but not of UBE2G1, nor UBE2H (PubMed:17229889, PubMed:19703557). Plays a role in the regulation of endosome-to-lysosome trafficking (PubMed:17229889). Impairs MC1R- and MC4R-signaling by competing with GNAS-binding to MCRs and inhibiting agonist-induced cAMP production (PubMed:19737927). Does not inhibit ADRB2-signaling (PubMed:19737927). Does not promote MC1R ubiquitination (PubMed:19737927). Acts also as a negative regulator of hedgehog signaling (By similarity)","subcellular_location":"Cytoplasm, cytosol; Cell membrane","url":"https://www.uniprot.org/uniprotkb/O60291/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MGRN1","classification":"Not Classified","n_dependent_lines":22,"n_total_lines":1208,"dependency_fraction":0.018211920529801324},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ANKRD46","stoichiometry":4.0},{"gene":"CANX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MGRN1","total_profiled":1310},"omim":[{"mim_id":"607559","title":"MAHOGUNIN, RING FINGER 1; MGRN1","url":"https://www.omim.org/entry/607559"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"},{"location":"Endoplasmic reticulum","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MGRN1"},"hgnc":{"alias_symbol":["KIAA0544","RNF156"],"prev_symbol":[]},"alphafold":{"accession":"O60291","domains":[{"cath_id":"-","chopping":"37-81","consensus_level":"high","plddt":80.5878,"start":37,"end":81},{"cath_id":"3.30.40.10","chopping":"253-260_274-335_384-397","consensus_level":"medium","plddt":86.9218,"start":253,"end":397},{"cath_id":"2.60.40","chopping":"89-105_114-251","consensus_level":"high","plddt":93.8717,"start":89,"end":251}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60291","model_url":"https://alphafold.ebi.ac.uk/files/AF-O60291-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O60291-F1-predicted_aligned_error_v6.png","plddt_mean":65.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MGRN1","jax_strain_url":"https://www.jax.org/strain/search?query=MGRN1"},"sequence":{"accession":"O60291","fasta_url":"https://rest.uniprot.org/uniprotkb/O60291.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60291/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60291"}},"corpus_meta":[{"pmid":"26743086","id":"PMC_26743086","title":"Ubiquitin-mediated regulation of the E3 ligase GP78 by MGRN1 in trans affects mitochondrial homeostasis.","date":"2016","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/26743086","citation_count":51,"is_preprint":false},{"pmid":"17075880","id":"PMC_17075880","title":"Mice with mutations in Mahogunin ring finger-1 (Mgrn1) exhibit abnormal patterning of the left-right axis.","date":"2006","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/17075880","citation_count":44,"is_preprint":false},{"pmid":"19737927","id":"PMC_19737927","title":"Mahogunin ring finger-1 (MGRN1) E3 ubiquitin ligase inhibits signaling from melanocortin receptor by competition with Galphas.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19737927","citation_count":42,"is_preprint":false},{"pmid":"23756845","id":"PMC_23756845","title":"Mahogunin ring finger-1 (MGRN1) suppresses chaperone-associated misfolded protein aggregation and toxicity.","date":"2013","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/23756845","citation_count":36,"is_preprint":false},{"pmid":"17720281","id":"PMC_17720281","title":"Mitochondrial dysfunction precedes neurodegeneration in mahogunin (Mgrn1) mutant mice.","date":"2007","source":"Neurobiology of aging","url":"https://pubmed.ncbi.nlm.nih.gov/17720281","citation_count":36,"is_preprint":false},{"pmid":"27577081","id":"PMC_27577081","title":"DNA methylation array analysis identifies breast cancer associated RPTOR, MGRN1 and RAPSN hypomethylation in peripheral blood DNA.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27577081","citation_count":30,"is_preprint":false},{"pmid":"28902452","id":"PMC_28902452","title":"MGRN1-mediated ubiquitination of α-tubulin regulates microtubule dynamics and intracellular transport.","date":"2017","source":"Traffic (Copenhagen, 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secretion.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29163761","citation_count":10,"is_preprint":false},{"pmid":"31089807","id":"PMC_31089807","title":"Chronic and age-dependent effects of the spongiform neurodegeneration-associated MGRN1 E3 ubiquitin ligase on mitochondrial homeostasis.","date":"2019","source":"Mammalian genome : official journal of the International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/31089807","citation_count":8,"is_preprint":false},{"pmid":"34235405","id":"PMC_34235405","title":"The conserved MASRPF motif in the Attractin homolog, Distracted, is required for association with Drosophila E3-ligase Mgrn1.","date":"2021","source":"microPublication biology","url":"https://pubmed.ncbi.nlm.nih.gov/34235405","citation_count":7,"is_preprint":false},{"pmid":"41178558","id":"PMC_41178558","title":"The E3 ubiquitin ligase MGRN1 targets melanocortin receptors MC1R and MC4R via interactions with transmembrane adapters.","date":"2025","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/41178558","citation_count":5,"is_preprint":false},{"pmid":"40196599","id":"PMC_40196599","title":"The E3 ubiquitin ligase MGRN1 targets melanocortin receptors MC1R and MC4R via interactions with transmembrane adapters.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40196599","citation_count":3,"is_preprint":false},{"pmid":"35892921","id":"PMC_35892921","title":"MGRN1 as a Phenotypic Determinant of Human Melanoma Cells and a Potential Biomarker.","date":"2022","source":"Life (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/35892921","citation_count":3,"is_preprint":false},{"pmid":"40004203","id":"PMC_40004203","title":"An MGRN1-Based Biomarker Combination Accurately Predicts Melanoma Patient Survival.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40004203","citation_count":1,"is_preprint":false},{"pmid":"42089370","id":"PMC_42089370","title":"MGRN1 in development and disease: a unifying view of a versatile membrane-tethered E3 ubiquitin ligase.","date":"2026","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/42089370","citation_count":0,"is_preprint":false},{"pmid":"37422866","id":"PMC_37422866","title":"[MGRN1 affects the mitophagy of spermatogonial stem cells in mice].","date":"2021","source":"Zhonghua nan ke xue = National journal of andrology","url":"https://pubmed.ncbi.nlm.nih.gov/37422866","citation_count":0,"is_preprint":false},{"pmid":"33351294","id":"PMC_33351294","title":"[Influence of MGRN1 on the autophagy of Sertoli cells in mice].","date":"2020","source":"Zhonghua nan ke xue = National journal of andrology","url":"https://pubmed.ncbi.nlm.nih.gov/33351294","citation_count":0,"is_preprint":false},{"pmid":"41781207","id":"PMC_41781207","title":"MGRN1 is linked to recessive heart and laterality defects: the first genotype-phenotype report in humans.","date":"2026","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41781207","citation_count":0,"is_preprint":false},{"pmid":"28475865","id":"PMC_28475865","title":"Chronicle of a Neuronal Death Foretold: Preventing Aging by Keeping MGRN1 at the Nucleus.","date":"2017","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/28475865","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.11.675358","title":"“Design principles of a membrane-spanning ubiquitin ligase”","date":"2025-09-16","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.11.675358","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13471,"output_tokens":4222,"usd":0.051872,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12091,"output_tokens":4253,"usd":0.08339,"stage2_stop_reason":"end_turn"},"total_usd":0.135262,"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\": 2025,\n      \"finding\": \"Cryo-EM structure of the MEGF8-MOSMO-MGRN1 (MMM) complex revealed that MGRN1 is a membrane-tethered E3 ligase whose RING domain is suspended by a long flexible helix attached to a membrane platform (MEGF8-MOSMO), orienting the RING domain to ubiquitylate cytoplasmic surfaces of target receptors. The complex regulates left-right patterning and Hedgehog pathway signaling by attenuating Smoothened (SMO) signaling.\",\n      \"method\": \"Cryo-electron microscopy with integrated biophysical and functional studies\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure combined with biophysical and functional validation in a single rigorous study\",\n      \"pmids\": [\"bio_10.1101_2025.09.11.675358\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MGRN1 uses transmembrane adapters ATRN and ATRNL1 (in addition to MEGF8) to recruit and ubiquitylate melanocortin receptors MC1R and MC4R, promoting their degradation. ATRN interacts with the RING domain of MGRN1 by co-immunoprecipitation. Loss of MGRN1 or ATRN increases surface and ciliary localization of MC4R in fibroblasts and elevates MC1R levels in melanocytes, resulting in enhanced eumelanin production.\",\n      \"method\": \"Co-immunoprecipitation, functional ubiquitylation assays, receptor surface/ciliary localization assays, melanin production assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus functional assays, replicated across peer-reviewed and preprint versions from same group\",\n      \"pmids\": [\"41178558\", \"40196599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MGRN1 ubiquitylates the ER E3 ligase GP78 in trans through non-canonical K11 linkages, maintaining constitutively low GP78 levels in healthy cells and thereby downregulating mitophagy. When mitochondria are stressed and cytosolic Ca2+ rises, the MGRN1-GP78 interaction is reduced and GP78 ubiquitylation is compromised. Catalytic inactivation of MGRN1 elevates GP78 levels and increases mitophagy. Disease-causing (Ctm)PrP depletes functional MGRN1, impairing GP78 polyubiquitylation and degradation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitylation assays with linkage-specific antibodies, catalytic mutant analysis, Ca2+ chelation experiments\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, K11-linkage ubiquitylation assay, catalytic mutant, Ca2+ chelation) in single study\",\n      \"pmids\": [\"26743086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Calmodulin (CaM) acts as an adapter protein that senses cytosolic Ca2+ levels and modulates Ca2+-dependent MGRN1-GP78 interactions. Under stress conditions with elevated cytosolic Ca2+, CaM binds to both MGRN1 and GP78 and inhibits their interaction, thereby regulating ER-associated protein degradation, ER-mitochondria junctions, and ER distribution.\",\n      \"method\": \"Co-immunoprecipitation, molecular docking and simulation, biophysical binding studies (different affinities/binding modes characterized), primary neuronal cells\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — biophysical interaction studies combined with Co-IP and molecular simulation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"30230921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MGRN1 inhibits melanocortin receptor (MC1R and MC4R) signaling to cAMP by competing with Gαs for binding to the receptors. MGRN1 co-immunoprecipitated with MCRs; overexpression of Gαs abolished the inhibitory effect and decreased co-immunoprecipitation with MCRs. Inhibition was independent of receptor plasma membrane expression, ubiquitylation, internalization, or stability. Additionally, exon 12-containing MGRN1 isoforms accumulated in the nucleus upon co-expression with receptors.\",\n      \"method\": \"Co-immunoprecipitation, cAMP signaling assays, receptor surface expression assays, subcellular localization by fluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional signaling assays and competition experiment, single lab\",\n      \"pmids\": [\"19737927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MGRN1 ubiquitylates α-tubulin via non-canonical K6-linked ubiquitin chains, regulating dynamics of EB1-labeled microtubule plus ends and intracellular transport of mitochondria and endosomes. Loss of MGRN1 function (or expression of (Ctm)PrP mutants) reduces α-tubulin ubiquitylation and causes intracellular transport defects. Brain lysates from PrP(A117V) transgenic mice show loss of tubulin polymerization.\",\n      \"method\": \"Ubiquitylation assays with linkage-specific analysis, live-cell imaging of EB1-labeled microtubules, organelle transport assays, brain lysate biochemistry from transgenic mice\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitylation assays with linkage specificity plus functional transport assays, single lab multiple methods\",\n      \"pmids\": [\"28902452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MGRN1 interacts and co-localizes with the cytosolic molecular chaperone Hsp70. MGRN1 expression is upregulated by stressors, and inhibition of autophagy recruits MGRN1 to cytosolic ubiquitin-positive inclusion bodies. Overexpression of MGRN1 protects against cell death from oxidative and ER stress, suggesting it targets misfolded proteins for degradation.\",\n      \"method\": \"Co-immunoprecipitation, co-localization by immunofluorescence, cell viability assays under stress, Western blot\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP/co-localization with functional overexpression protection assays, single lab\",\n      \"pmids\": [\"23756845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MGRN1 interacts with but does not ubiquitinate NEDD4 (a HECT-domain ubiquitin ligase). Transgenic rescue experiments in mice demonstrated that pigment-type switching requires MGRN1's ubiquitin ligase activity but not its ability to bind TSG101 or NEDD4, indicating an as-yet unidentified ubiquitination target is required for agouti-mediated melanocortin signaling.\",\n      \"method\": \"Co-immunoprecipitation, in vivo transgenesis rescue experiments in mice\",\n      \"journal\": \"Pigment cell & melanoma research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic rescue in vivo combined with Co-IP, single lab\",\n      \"pmids\": [\"23253940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MGRN1 inhibits maturation and amyloidogenic processing of amyloid precursor protein (APP) by sequestering it in the secretory pathway, delaying proteolytic processing and reducing Aβ40/Aβ42 release. Reduction of MGRN1 in hippocampal neurons (as occurs during aging) leads to increased Aβ peptide release.\",\n      \"method\": \"Cellular APP trafficking assays, Aβ secretion measurement (ELISA), MGRN1 overexpression and knockdown in neurons\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional assays with both overexpression and knockdown, single lab\",\n      \"pmids\": [\"29163761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MGRN1 localizes to mitochondria, most likely due to N-myristoylation. Loss of MGRN1 causes mitochondrial fragmentation and depolarization without recruitment of parkin. Parkin mRNA and protein levels decline in the brains of aged Mgrn1 null mutant mice. Double Mgrn1;parkin mutant mice show more severe early mitochondrial dysfunction but no change in spongiform neurodegeneration onset.\",\n      \"method\": \"Subcellular fractionation, mitochondrial morphology and membrane potential assays, genetic double-mutant mice, Western blot/qPCR for parkin\",\n      \"journal\": \"Mammalian genome\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — fractionation-based localization with functional consequence plus genetic double-mutant analysis, single lab\",\n      \"pmids\": [\"31089807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"MGRN1 acts early in the left-right signaling cascade during mouse embryonic development. Mgrn1 mutant embryos show abnormal expression of asymmetrically expressed LR patterning genes, and Nodal expression was uncoupled from expression of other Nodal-responsive genes, placing MGRN1 upstream of Nodal-responsive gene regulation.\",\n      \"method\": \"Genetic analysis of Mgrn1 null mutant mice, in situ hybridization for LR asymmetry markers, cardiac phenotyping\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in mouse model with multiple molecular readouts, single lab\",\n      \"pmids\": [\"17075880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The conserved MASRPF motif in the Drosophila Attractin ortholog Distracted is required for association with Drosophila Mgrn1 (dMgrn1) in vivo, consistent with the conserved MASRPF motif in mammalian MEGF8 being required for Mgrn1 binding.\",\n      \"method\": \"In vivo interaction assay in Drosophila using MASRPF motif mutants\",\n      \"journal\": \"microPublication biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — in vivo genetic interaction with domain mutant, ortholog system\",\n      \"pmids\": [\"34235405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Mammalian MGRN1 can functionally replace the plant E3 ligase LOG2 in Arabidopsis: MGRN1 ubiquitylates the plant membrane protein GDU1 in vitro and partially restores amino acid resistance in a log2 mutant overexpressing GDU1-myc, demonstrating conserved N-terminal domain function in substrate interaction.\",\n      \"method\": \"In vitro ubiquitylation assay, plant genetic complementation, phylogenetic analysis\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro ubiquitylation assay plus partial in vivo complementation, cross-kingdom system, single lab\",\n      \"pmids\": [\"24036454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Loss of MGRN1 in mice causes reduced mitochondrial complex IV expression and activity, increased oxidative stress in the brain, and these mitochondrial defects precede spongiform vacuolation by many months. Compatible mitochondrial dysfunction was also observed in Atrn mutant mice, supporting a common pathway for MGRN1 and ATRN.\",\n      \"method\": \"Proteomics of mutant brains, enzymatic activity assays for complex IV, oxidative stress markers, genetic comparison of Mgrn1 and Atrn mutants\",\n      \"journal\": \"Neurobiology of aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics plus enzymatic activity assays plus genetic epistasis with Atrn mutant, single lab\",\n      \"pmids\": [\"17720281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MGRN1 depletion in human melanoma cells promotes intercellular adhesion by upregulation of E-cadherin (likely through downregulation of the ZEB1 repressor) and increased co-localization of E-cadherin with β-catenin. Pulldown assays showed reduced CDC42 activation in the absence of MGRN1, which was reverted by E-cadherin silencing, placing CDC42 downstream of E-cadherin in this pathway.\",\n      \"method\": \"CRISPR/siRNA knockdown, pulldown assay for active CDC42, co-localization by immunofluorescence, gene expression analysis\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pulldown for CDC42 activity plus genetic epistasis (E-cadherin silencing rescue), single lab\",\n      \"pmids\": [\"38008393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Knockdown of MGRN1 in mouse spermatogonial stem cells increases mitochondrial damage, reduces mitochondrial autophagosomes, upregulates CK2 expression, and increases FUNDC1 phosphorylation, suggesting MGRN1 regulates mitophagy in these cells possibly via CK2-mediated FUNDC1 phosphorylation.\",\n      \"method\": \"RNAi knockdown in SSCs, Western blot for mitophagy markers, electron microscopy\",\n      \"journal\": \"Zhonghua nan ke xue\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (Western blot + EM), mechanistic pathway only proposed not confirmed\",\n      \"pmids\": [\"37422866\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MGRN1 is a membrane-tethered RING-type E3 ubiquitin ligase that operates in multiple cellular compartments; structurally, it forms a complex with transmembrane adapters (MEGF8/MOSMO, ATRN, ATRNL1) that orient its RING domain to ubiquitylate cytoplasmic regions of surface receptors (MC1R, MC4R, SMO), regulating their degradation and signaling output. In parallel, cytosolic MGRN1 ubiquitylates the ER E3 ligase GP78 via K11 linkages (modulated by calmodulin/Ca2+) to suppress mitophagy, and ubiquitylates α-tubulin via K6 linkages to regulate microtubule dynamics and organelle transport; loss of MGRN1 causes mitochondrial fragmentation, impaired intracellular transport, and ultimately age-dependent spongiform neurodegeneration.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MGRN1 is a membrane-tethered RING-type E3 ubiquitin ligase that controls the surface abundance and signaling output of cytoplasmically accessible receptors and that, in the brain, maintains mitochondrial and cytoskeletal homeostasis to prevent age-dependent neurodegeneration [#0, #1]. Structurally, its RING domain is suspended by a long flexible helix from a transmembrane platform formed with MEGF8-MOSMO, an arrangement that positions the catalytic domain to ubiquitylate the cytoplasmic faces of target receptors; through this complex MGRN1 attenuates Smoothened-dependent Hedgehog signaling and governs left-right embryonic patterning [#0, #10]. Related transmembrane adapters ATRN and ATRNL1 recruit MGRN1 to the melanocortin receptors MC1R and MC4R, where it promotes receptor degradation and limits surface and ciliary localization, thereby restraining eumelanin production and melanocortin signaling [#1]; the conserved MASRPF motif in these Attractin/MEGF8-family adapters mediates binding to the MGRN1 RING region [#1, #11]. MGRN1 additionally inhibits melanocortin signaling to cAMP by competing with G\\u03b1s for receptor binding independently of its ubiquitin ligase activity [#4], and pigment-type switching in vivo requires its catalytic activity acting on an as-yet unidentified substrate rather than its TSG101 or NEDD4 binding [#7]. In the cytosol and at the ER, MGRN1 ubiquitylates the ER E3 ligase GP78 through non-canonical K11 linkages to keep GP78 low and suppress mitophagy, an interaction released when rising cytosolic Ca2+ is sensed by calmodulin [#2, #3]. It also ubiquitylates \\u03b1-tubulin via K6-linked chains to regulate microtubule plus-end dynamics and the transport of mitochondria and endosomes [#5]. Loss of MGRN1 causes mitochondrial fragmentation, depolarization, reduced complex IV activity, increased oxidative stress, and impaired intracellular transport, defects that precede spongiform neurodegeneration in mutant mice [#9, #13, #5].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established that MGRN1 acts in early developmental signaling, placing it upstream of Nodal-responsive gene regulation in the left-right patterning cascade before any molecular activity was known.\",\n      \"evidence\": \"Genetic analysis of Mgrn1 null mouse embryos with in situ hybridization for asymmetry markers and cardiac phenotyping\",\n      \"pmids\": [\"17075880\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the molecular substrate or biochemical activity linking MGRN1 to Nodal regulation\", \"Mechanism connecting MGRN1 to the LR signaling pathway unresolved at this stage\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Linked MGRN1 loss to mitochondrial dysfunction as an early event preceding neurodegeneration, and tied MGRN1 to ATRN in a shared pathway.\",\n      \"evidence\": \"Proteomics, complex IV enzymatic assays, and oxidative stress markers in Mgrn1 and Atrn mutant mouse brains\",\n      \"pmids\": [\"17720281\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish whether mitochondrial defects are a direct ubiquitylation consequence or downstream\", \"Molecular mechanism of complex IV reduction not defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed MGRN1 can regulate melanocortin receptor signaling non-catalytically by competing with G\\u03b1s, revealing a ubiquitylation-independent mode of action.\",\n      \"evidence\": \"Co-IP, cAMP signaling and competition assays, and subcellular localization in cells\",\n      \"pmids\": [\"19737927\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Inhibition was independent of ubiquitylation, leaving the in vivo relevance versus the degradative mode unclear\", \"Functional role of nuclear-accumulating exon-12 isoforms not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined MGRN1 as a stress-responsive ligase engaging the protein quality-control machinery and identified interaction partners that constrain its catalytic substrate repertoire.\",\n      \"evidence\": \"Co-IP and co-localization with Hsp70, stress-protection viability assays, plus in vivo transgenic rescue distinguishing NEDD4/TSG101 binding from catalytic requirement; cross-kingdom complementation of plant LOG2 with in vitro GDU1 ubiquitylation\",\n      \"pmids\": [\"23756845\", \"23253940\", \"24036454\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The substrate required for agouti/pigment-type switching remained unidentified\", \"Direct misfolded-protein substrates of MGRN1 not enumerated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified GP78 as a direct MGRN1 substrate ubiquitylated via non-canonical K11 chains, defining a mechanism by which MGRN1 suppresses mitophagy.\",\n      \"evidence\": \"Co-IP, linkage-specific ubiquitylation assays, catalytic mutant analysis, and Ca2+ chelation in cells\",\n      \"pmids\": [\"26743086\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how Ctm-PrP depletes functional MGRN1\", \"Quantitative contribution of GP78 regulation to neurodegeneration not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended MGRN1 substrate range to \\u03b1-tubulin via K6 chains and linked this to microtubule dynamics and organelle transport, and to APP processing via secretory sequestration.\",\n      \"evidence\": \"Linkage-specific ubiquitylation assays, live-cell EB1 imaging, organelle transport assays, transgenic mouse brain biochemistry; separate APP trafficking and A\\u03b2 ELISA assays with overexpression/knockdown\",\n      \"pmids\": [\"28902452\", \"29163761\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether tubulin K6 ubiquitylation directly drives transport defects in vivo not fully separated from other defects\", \"Mechanism of APP sequestration (direct vs indirect) not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed calmodulin as the Ca2+ sensor that gates the MGRN1-GP78 interaction, coupling cytosolic Ca2+ to ER-associated degradation and ER-mitochondria contacts.\",\n      \"evidence\": \"Co-IP, molecular docking/simulation, and biophysical binding studies in primary neurons\",\n      \"pmids\": [\"30230921\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo demonstration of Ca2+/CaM-gated switching during physiological stress not established\", \"Structural basis of competitive CaM binding not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Localized MGRN1 to mitochondria and showed its loss causes parkin-independent fragmentation and depolarization, positioning it within mitochondrial quality control.\",\n      \"evidence\": \"Subcellular fractionation, mitochondrial morphology/potential assays, and Mgrn1;parkin double-mutant mice\",\n      \"pmids\": [\"31089807\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mitochondrial substrate(s) of MGRN1 not identified\", \"Causal link between mitochondrial fragmentation and spongiform degeneration onset unresolved (double mutant did not change onset)\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected MGRN1 to cell adhesion and motility control in melanoma via an E-cadherin/ZEB1/CDC42 axis, broadening its role beyond ligase substrate degradation.\",\n      \"evidence\": \"CRISPR/siRNA knockdown, active CDC42 pulldown, co-localization, and gene expression analysis with E-cadherin rescue\",\n      \"pmids\": [\"38008393\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MGRN1 controls E-cadherin/ZEB1 directly via ubiquitylation or indirectly is unknown\", \"No direct substrate in this pathway identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided the structural and mechanistic basis for MGRN1 as a membrane-tethered ligase, showing how transmembrane adapters orient its RING domain to ubiquitylate receptor cytoplasmic surfaces and regulate Hedgehog and melanocortin signaling.\",\n      \"evidence\": \"Cryo-EM of the MEGF8-MOSMO-MGRN1 complex with biophysics (preprint); reciprocal Co-IP and functional ubiquitylation/localization/melanin assays for ATRN/ATRNL1-MC1R/MC4R\",\n      \"pmids\": [\"bio_10.1101_2025.09.11.675358\", \"41178558\", \"40196599\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full set of receptor substrates engaged by each adapter not enumerated\", \"How adapter choice (MEGF8/MOSMO vs ATRN/ATRNL1) is regulated is unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The identity of the catalytic substrate required for agouti-mediated pigment-type switching and the unifying mechanism linking MGRN1's receptor, mitochondrial, and cytoskeletal activities to neurodegeneration remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No single substrate accounts for the spongiform neurodegeneration phenotype\", \"Relative contribution of GP78, tubulin, and receptor pathways to disease unweighted\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 2, 5]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2, 5]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 2, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 6]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0016567\", \"supporting_discovery_ids\": [2, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 10]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [\n      \"MEGF8-MOSMO-MGRN1 (MMM) complex\"\n    ],\n    \"partners\": [\n      \"MEGF8\",\n      \"MOSMO\",\n      \"ATRN\",\n      \"ATRNL1\",\n      \"GP78\",\n      \"CALM1\",\n      \"HSPA8\",\n      \"NEDD4\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}