| 2025 |
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. |
Cryo-electron microscopy with integrated biophysical and functional studies |
bioRxivpreprint |
High |
bio_10.1101_2025.09.11.675358
|
| 2025 |
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. |
Co-immunoprecipitation, functional ubiquitylation assays, receptor surface/ciliary localization assays, melanin production assays |
Journal of cell science |
High |
40196599 41178558
|
| 2016 |
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. |
Co-immunoprecipitation, ubiquitylation assays with linkage-specific antibodies, catalytic mutant analysis, Ca2+ chelation experiments |
Journal of cell science |
High |
26743086
|
| 2018 |
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. |
Co-immunoprecipitation, molecular docking and simulation, biophysical binding studies (different affinities/binding modes characterized), primary neuronal cells |
FASEB journal |
High |
30230921
|
| 2009 |
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. |
Co-immunoprecipitation, cAMP signaling assays, receptor surface expression assays, subcellular localization by fluorescence |
The Journal of biological chemistry |
Medium |
19737927
|
| 2017 |
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. |
Ubiquitylation assays with linkage-specific analysis, live-cell imaging of EB1-labeled microtubules, organelle transport assays, brain lysate biochemistry from transgenic mice |
Traffic (Copenhagen, Denmark) |
Medium |
28902452
|
| 2013 |
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. |
Co-immunoprecipitation, co-localization by immunofluorescence, cell viability assays under stress, Western blot |
Scientific reports |
Medium |
23756845
|
| 2013 |
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. |
Co-immunoprecipitation, in vivo transgenesis rescue experiments in mice |
Pigment cell & melanoma research |
Medium |
23253940
|
| 2017 |
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. |
Cellular APP trafficking assays, Aβ secretion measurement (ELISA), MGRN1 overexpression and knockdown in neurons |
Oncotarget |
Medium |
29163761
|
| 2019 |
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. |
Subcellular fractionation, mitochondrial morphology and membrane potential assays, genetic double-mutant mice, Western blot/qPCR for parkin |
Mammalian genome |
Medium |
31089807
|
| 2006 |
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. |
Genetic analysis of Mgrn1 null mutant mice, in situ hybridization for LR asymmetry markers, cardiac phenotyping |
Developmental dynamics |
Medium |
17075880
|
| 2021 |
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. |
In vivo interaction assay in Drosophila using MASRPF motif mutants |
microPublication biology |
Medium |
34235405
|
| 2013 |
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. |
In vitro ubiquitylation assay, plant genetic complementation, phylogenetic analysis |
FEBS letters |
Medium |
24036454
|
| 2007 |
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. |
Proteomics of mutant brains, enzymatic activity assays for complex IV, oxidative stress markers, genetic comparison of Mgrn1 and Atrn mutants |
Neurobiology of aging |
Medium |
17720281
|
| 2023 |
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. |
CRISPR/siRNA knockdown, pulldown assay for active CDC42, co-localization by immunofluorescence, gene expression analysis |
Cancer letters |
Medium |
38008393
|
| 2021 |
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. |
RNAi knockdown in SSCs, Western blot for mitophagy markers, electron microscopy |
Zhonghua nan ke xue |
Low |
37422866
|