EDEM3_MOUSE
ID EDEM3_MOUSE Reviewed; 931 AA.
AC Q2HXL6; B2RS10; B9EHZ4; Q6P9L0;
DT 05-FEB-2008, integrated into UniProtKB/Swiss-Prot.
DT 03-MAR-2009, sequence version 2.
DT 03-AUG-2022, entry version 122.
DE RecName: Full=ER degradation-enhancing alpha-mannosidase-like protein 3;
DE EC=3.2.1.113 {ECO:0000250|UniProtKB:P32906};
DE AltName: Full=Alpha-1,2-mannosidase EDEM3;
DE Flags: Precursor;
GN Name=Edem3;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION, TISSUE
RP SPECIFICITY, INDUCTION, AND MUTAGENESIS OF GLU-147.
RX PubMed=16431915; DOI=10.1074/jbc.m512191200;
RA Hirao K., Natsuka Y., Tamura T., Wada I., Morito D., Natsuka S., Romero P.,
RA Sleno B., Tremblay L.O., Herscovics A., Nagata K., Hosokawa N.;
RT "EDEM3, a soluble EDEM homolog, enhances glycoprotein endoplasmic
RT reticulum-associated degradation and mannose trimming.";
RL J. Biol. Chem. 281:9650-9658(2006).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Brain, Embryonic brain, and Testis;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP REVIEW.
RX PubMed=17499246; DOI=10.1016/j.febslet.2007.04.070;
RA Olivari S., Molinari M.;
RT "Glycoprotein folding and the role of EDEM1, EDEM2 and EDEM3 in degradation
RT of folding-defective glycoproteins.";
RL FEBS Lett. 581:3658-3664(2007).
RN [4]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brown adipose tissue, Liver, Lung, Pancreas, Spleen, and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [5]
RP DISRUPTION PHENOTYPE, AND FUNCTION.
RX PubMed=34143952; DOI=10.1016/j.ajhg.2021.05.010;
RA Polla D.L., Edmondson A.C., Duvet S., March M.E., Sousa A.B., Lehman A.,
RA Niyazov D., van Dijk F., Demirdas S., van Slegtenhorst M.A., Kievit A.J.A.,
RA Schulz C., Armstrong L., Bi X., Rader D.J., Izumi K., Zackai E.H.,
RA de Franco E., Jorge P., Huffels S.C., Hommersom M., Ellard S.,
RA Lefeber D.J., Santani A., Hand N.J., van Bokhoven H., He M.,
RA de Brouwer A.P.M.;
RT "Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause
RT a congenital disorder of glycosylation.";
RL Am. J. Hum. Genet. 108:1342-1349(2021).
CC -!- FUNCTION: Involved in endoplasmic reticulum-associated degradation
CC (ERAD). Accelerates the glycoprotein ERAD by proteasomes, by catalyzing
CC mannose trimming from Man8GlcNAc2 to Man7GlcNAc2 in the N-glycans. May
CC also participate in mannose trimming from all glycoproteins and not
CC just misfolded ones targeted to ERAD (PubMed:34143952). May have alpha
CC 1,2-mannosidase activity. {ECO:0000250|UniProtKB:Q9BZQ6,
CC ECO:0000269|PubMed:16431915, ECO:0000269|PubMed:34143952}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=4 H2O + N(4)-(alpha-D-Man-(1->2)-alpha-D-Man-(1->2)-alpha-D-
CC Man-(1->3)-[alpha-D-Man-(1->2)-alpha-D-Man-(1->3)-[alpha-D-Man-
CC (1->2)-alpha-D-Man-(1->6)]-alpha-D-Man-(1->6)]-beta-D-Man-(1->4)-
CC beta-D-GlcNAc-(1->4)-alpha-D-GlcNAc)-L-asparaginyl-[protein] (N-
CC glucan mannose isomer 9A1,2,3B1,2,3) = 4 beta-D-mannose + N(4)-
CC (alpha-D-Man-(1->3)-[alpha-D-Man-(1->3)-[alpha-D-Man-(1->6)]-alpha-D-
CC Man-(1->6)]-beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-beta-D-GlcNAc)-L-
CC asparaginyl-[protein] (N-glucan mannose isomer 5A1,2);
CC Xref=Rhea:RHEA:56008, Rhea:RHEA-COMP:14356, Rhea:RHEA-COMP:14367,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:28563, ChEBI:CHEBI:59087,
CC ChEBI:CHEBI:139493; EC=3.2.1.113;
CC Evidence={ECO:0000250|UniProtKB:P32906};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=3 H2O + N(4)-(alpha-D-Man-(1->2)-alpha-D-Man-(1->2)-alpha-D-
CC Man-(1->3)-[alpha-D-Man-(1->3)-[alpha-D-Man-(1->2)-alpha-D-Man-
CC (1->6)]-alpha-D-Man-(1->6)]-beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-
CC alpha-D-GlcNAc)-L-asparaginyl-[protein] (N-glucan mannose isomer
CC 8A1,2,3B1,3) = 3 beta-D-mannose + N(4)-(alpha-D-Man-(1->3)-[alpha-D-
CC Man-(1->3)-[alpha-D-Man-(1->6)]-alpha-D-Man-(1->6)]-beta-D-Man-
CC (1->4)-beta-D-GlcNAc-(1->4)-beta-D-GlcNAc)-L-asparaginyl-[protein]
CC (N-glucan mannose isomer 5A1,2); Xref=Rhea:RHEA:56028, Rhea:RHEA-
CC COMP:14358, Rhea:RHEA-COMP:14367, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:28563, ChEBI:CHEBI:59087, ChEBI:CHEBI:60628;
CC EC=3.2.1.113; Evidence={ECO:0000250|UniProtKB:P32906};
CC -!- COFACTOR:
CC Name=Ca(2+); Xref=ChEBI:CHEBI:29108;
CC Evidence={ECO:0000250|UniProtKB:P45700};
CC -!- PATHWAY: Protein modification; protein glycosylation.
CC {ECO:0000250|UniProtKB:P32906}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum lumen {ECO:0000255|PROSITE-
CC ProRule:PRU10138, ECO:0000269|PubMed:16431915}.
CC -!- TISSUE SPECIFICITY: Widely expressed. Expressed at higher level in
CC liver, heart and kidney. {ECO:0000269|PubMed:16431915}.
CC -!- INDUCTION: Slightly increased by endoplasmic reticulum stress.
CC {ECO:0000269|PubMed:16431915}.
CC -!- DOMAIN: Contains a protease-associated domain of unknown function.
CC -!- PTM: N-glycosylated.
CC -!- DISRUPTION PHENOTYPE: The knockout mice show largely skewed ratios of
CC homozygous knockout pups versus heterozygous and wild-type pups.
CC However knockout animals do not present with any obvious phenotype,
CC only subtle changes, such as reduced weight of brains and body, as well
CC as significantly increased abundance of circulating Man8GlcNAc2 and
CC Man9GlcNAc2 in the plasma. {ECO:0000269|PubMed:34143952}.
CC -!- SIMILARITY: Belongs to the glycosyl hydrolase 47 family. {ECO:0000305}.
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DR EMBL; AB188342; BAE79485.1; -; mRNA.
DR EMBL; BC060718; AAH60718.1; -; mRNA.
DR EMBL; BC138658; AAI38659.1; -; mRNA.
DR EMBL; BC138659; AAI38660.1; -; mRNA.
DR CCDS; CCDS35736.1; -.
DR RefSeq; NP_001034733.2; NM_001039644.2.
DR AlphaFoldDB; Q2HXL6; -.
DR SMR; Q2HXL6; -.
DR BioGRID; 211842; 8.
DR IntAct; Q2HXL6; 6.
DR STRING; 10090.ENSMUSP00000058941; -.
DR CAZy; GH47; Glycoside Hydrolase Family 47.
DR GlyConnect; 2299; 1 N-Linked glycan (1 site).
DR GlyGen; Q2HXL6; 7 sites, 1 N-linked glycan (1 site).
DR iPTMnet; Q2HXL6; -.
DR PhosphoSitePlus; Q2HXL6; -.
DR EPD; Q2HXL6; -.
DR MaxQB; Q2HXL6; -.
DR PaxDb; Q2HXL6; -.
DR PeptideAtlas; Q2HXL6; -.
DR PRIDE; Q2HXL6; -.
DR ProteomicsDB; 277679; -.
DR Antibodypedia; 20607; 131 antibodies from 25 providers.
DR Ensembl; ENSMUST00000059498; ENSMUSP00000058941; ENSMUSG00000043019.
DR GeneID; 66967; -.
DR KEGG; mmu:66967; -.
DR UCSC; uc007czc.2; mouse.
DR CTD; 80267; -.
DR MGI; MGI:1914217; Edem3.
DR VEuPathDB; HostDB:ENSMUSG00000043019; -.
DR eggNOG; KOG2430; Eukaryota.
DR GeneTree; ENSGT00940000159391; -.
DR InParanoid; Q2HXL6; -.
DR OrthoDB; 434316at2759; -.
DR PhylomeDB; Q2HXL6; -.
DR TreeFam; TF300807; -.
DR BRENDA; 3.2.1.209; 3474.
DR UniPathway; UPA00378; -.
DR BioGRID-ORCS; 66967; 3 hits in 73 CRISPR screens.
DR ChiTaRS; Edem3; mouse.
DR PRO; PR:Q2HXL6; -.
DR Proteomes; UP000000589; Chromosome 1.
DR RNAct; Q2HXL6; protein.
DR Bgee; ENSMUSG00000043019; Expressed in lacrimal gland and 257 other tissues.
DR ExpressionAtlas; Q2HXL6; baseline and differential.
DR Genevisible; Q2HXL6; MM.
DR GO; GO:0005783; C:endoplasmic reticulum; IBA:GO_Central.
DR GO; GO:0005788; C:endoplasmic reticulum lumen; IDA:MGI.
DR GO; GO:0044322; C:endoplasmic reticulum quality control compartment; IEA:GOC.
DR GO; GO:0016020; C:membrane; IEA:InterPro.
DR GO; GO:0004559; F:alpha-mannosidase activity; IBA:GO_Central.
DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR GO; GO:0004571; F:mannosyl-oligosaccharide 1,2-alpha-mannosidase activity; IDA:MGI.
DR GO; GO:0005975; P:carbohydrate metabolic process; IEA:InterPro.
DR GO; GO:1904380; P:endoplasmic reticulum mannose trimming; IBA:GO_Central.
DR GO; GO:0006516; P:glycoprotein catabolic process; IDA:MGI.
DR GO; GO:1904382; P:mannose trimming involved in glycoprotein ERAD pathway; IDA:ParkinsonsUK-UCL.
DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IDA:MGI.
DR GO; GO:0006486; P:protein glycosylation; IEA:UniProtKB-UniPathway.
DR GO; GO:0006986; P:response to unfolded protein; IEA:UniProtKB-KW.
DR CDD; cd02126; PA_EDEM3_like; 1.
DR Gene3D; 1.50.10.10; -; 1.
DR InterPro; IPR012341; 6hp_glycosidase-like_sf.
DR InterPro; IPR044674; EDEM1/2/3.
DR InterPro; IPR037322; EDEM3_PA.
DR InterPro; IPR001382; Glyco_hydro_47.
DR InterPro; IPR003137; PA_domain.
DR InterPro; IPR036026; Seven-hairpin_glycosidases.
DR PANTHER; PTHR45679; PTHR45679; 1.
DR Pfam; PF01532; Glyco_hydro_47; 1.
DR Pfam; PF02225; PA; 1.
DR PRINTS; PR00747; GLYHDRLASE47.
DR SUPFAM; SSF48225; SSF48225; 1.
DR PROSITE; PS00014; ER_TARGET; 1.
PE 1: Evidence at protein level;
KW Endoplasmic reticulum; Glycoprotein; Hydrolase; Metal-binding;
KW Reference proteome; Signal; Unfolded protein response.
FT SIGNAL 1..42
FT /evidence="ECO:0000255"
FT CHAIN 43..931
FT /note="ER degradation-enhancing alpha-mannosidase-like
FT protein 3"
FT /id="PRO_0000316958"
FT DOMAIN 675..780
FT /note="PA"
FT REGION 790..908
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 928..931
FT /note="Prevents secretion from ER"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10138"
FT COMPBIAS 790..804
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 808..830
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 831..848
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 860..906
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 147
FT /note="Proton donor"
FT /evidence="ECO:0000250"
FT ACT_SITE 294
FT /evidence="ECO:0000250"
FT ACT_SITE 388
FT /note="Proton donor"
FT /evidence="ECO:0000250|UniProtKB:P31723"
FT ACT_SITE 406
FT /evidence="ECO:0000250"
FT BINDING 492
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P32906"
FT CARBOHYD 119
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 196
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 505
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 512
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 811
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 815
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 899
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT MUTAGEN 147
FT /note="E->Q: Loss of ERAD activity."
FT /evidence="ECO:0000269|PubMed:16431915"
FT CONFLICT 784
FT /note="E -> K (in Ref. 1; BAE79485)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 931 AA; 104200 MW; 4F010D17E84E542C CRC64;
MSKAGGCRGC GCRVPQRASW SLVAATAALC LVLATSVCTA GAAPMSREEK QKLGNQVLEM
FDHAYGNYME HAYPADELMP LTCRGRVRGQ EPSRGDVDDA LGKFSLTLID SLDTLVVLNK
TKEFEDAVRK VLRDVNLDND VVVSVFETNI RVLGGLLGGH SLAIMLKEKG EHMQWYNDEL
LHMAKQLGYK LLPAFNTTSG LPYPRINLKF GIRKPEARTG TETDTCTACA GTLILEFAAL
SRFTGATIFE EYARKALDFL WEKRQRSSNL VGVTINIHTG DWVRKDSGVG AGIDSYYEYL
LKAYVLLGDD SFLERFNTHY DAIMRYISQP PLLLDVHIHK PMLNARTWMD ALLAFFPGLQ
VLKGDIRPAI ETHEMLYQVI KKHNFLPEAF TTDFRVHWAQ HPLRPEFAES TYFLYKATGD
PYYLEVGKTL IENLNKYARV PCGFAAMKDV RTGSHEDRMD SFFLAEMFKY LYLLFADKED
IIFDIEDYIF TTEAHLLPLW LSTTNRSISK KNTTSEYTEL DDSNFDWTCP NTQILFPNDP
LYAQSIREPL KNVVDKSCPR GIIRVEESFR SGAKPPLRAR DFMATNPEHL EILKKMGVSL
IHLKDGRVQL VQHAIQAASS IDAEDGLRFM QEMIELSSQQ QKEQQLPPRA VQIISHPFFG
RVVLTAGPAQ FGLDLSKHKE TRGFVASSKP YNGCSELTNP EAVMGKIALI QRGQCMFAEK
ARNIQNAGAI GGIVIDDNEG SSSDTAPLFQ MAGDGKDTDD IKIPMLFLFS KEGSIILDAI
REHEQVEVLL SDKARDRDPE MENEDQPSSE NDSQNQSAEQ MLSLSQTVDL ADKESPEHPA
DSHSEASPSD SEEAAGFAPS EQISGSTENH ETTSLDGECT DLDNQVQEQS ETEEDSSPNV
SWGTKAQPID SILADWNEDI EAFEMMEKDE L
