Gene Ontology annotation through association of InterPro records with GO terms
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
Annotation inferences using phylogenetic trees
Electronic Gene Ontology annotations created by ARBA machine learning models
Combined Automated Annotation using Multiple IEA Methods
EDEM2 initiates mammalian glycoprotein ERAD by catalyzing the first mannose trimming step.
EDEM3, a soluble EDEM homolog, enhances glycoprotein endoplasmic reticulum-associated degradation and mannose trimming.
-
EDEM3 is a 931-aa soluble Class I GH47 alpha-mannosidase homolog with a C-terminal protease-associated motif; overexpression accelerates gpERAD of misfolded alpha-1-antitrypsin NHK and TCRalpha and stimulates mannose trimming from misfolded and total glycoproteins, while the catalytic-site E147Q mutant abolishes trimming and greatly decreases ERAD enhancement, showing EDEM3 has alpha-1,2-mannosidase activity in vivo.
ER-resident protein 46 (ERp46) triggers the mannose-trimming activity of ER degradation-enhancing alpha-mannosidase-like protein 3 (EDEM3).
-
EDEM3 stably associates with the ER oxidoreductase ERp46 (TXNDC5) via a disulfide bond between ERp46 redox-active cysteines and the EDEM3 alpha-mannosidase domain; this redox-dependent covalent interaction is required to reconstitute EDEM3 mannose-trimming activity toward the misfolded substrate TCRalpha in vitro, coupling demannosylation to ER redox state.
EDEM3 Domains Cooperate to Perform Its Overall Cell Functioning.
-
EDEM3 comprises four modules - GH47 mannosidase-like, intermediate (IMD), protease-associated (PA), and intrinsically disordered (IDD) domains; the GH47 domain provides substrate binding even without mannose trimming and requires the IMD for folding, while PA and IDD domains do not affect trimming per se but modulate the ERAD turnover timing of specific misfolded clients (NHK, soluble tyrosinase mutant). EDEM3 has few stable ER interactors, consistent with transient substrate engagement.
The endoplasmic reticulum degradation-enhancing alpha-mannosidase-like protein 3 attenuates the unfolded protein response and has pro-survival and pro-viral roles in hepatoma cells and hepatocellular carcinoma patients.
-
EDEM3 is significantly upregulated in hepatocellular carcinoma tissues, with the highest levels in HBV-infected patients, and its expression associates with tumor progression and poor prognosis; EDEM3 overexpression attenuates the UPR and activates secretory autophagy to promote HBV production, whereas EDEM3 depletion induces ER stress and pro-apoptotic cell death.
EDEM1,3 hydrolyse (GlcNAc)2 (Man)8b to (GlcNAc)2 (Man)5
UniProt entry Q9BZQ6 (EDEM3_HUMAN), ER degradation-enhancing alpha-mannosidase-like protein 3