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   27-MAR-2024, entry version 131.
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
RC   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)-beta-D-GlcNAc)-L-asparaginyl-[protein] (N-glucan
CC         mannose isomer 9A1,2,3B1,2,3) = 4 beta-D-mannose + N(4)-(alpha-D-Man-
CC         (1->3)-[alpha-D-Man-(1->3)-[alpha-D-Man-(1->6)]-alpha-D-Man-(1->6)]-
CC         beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-beta-D-GlcNAc)-L-asparaginyl-
CC         [protein] (N-glucan mannose isomer 5A1,2); Xref=Rhea:RHEA:56008,
CC         Rhea:RHEA-COMP:14356, Rhea:RHEA-COMP:14367, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:28563, ChEBI:CHEBI:59087, ChEBI:CHEBI:139493;
CC         EC=3.2.1.113; 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         beta-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   GlyCosmos; Q2HXL6; 7 sites, 1 glycan.
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; 10090-ENSMUSP00000058941; -.
DR   PeptideAtlas; Q2HXL6; -.
DR   ProteomicsDB; 277679; -.
DR   Pumba; Q2HXL6; -.
DR   Antibodypedia; 20607; 146 antibodies from 25 providers.
DR   Ensembl; ENSMUST00000059498.12; ENSMUSP00000058941.6; ENSMUSG00000043019.13.
DR   GeneID; 66967; -.
DR   KEGG; mmu:66967; -.
DR   UCSC; uc007czc.2; mouse.
DR   AGR; MGI:1914217; -.
DR   CTD; 80267; -.
DR   MGI; MGI:1914217; Edem3.
DR   VEuPathDB; HostDB:ENSMUSG00000043019; -.
DR   eggNOG; KOG2430; Eukaryota.
DR   GeneTree; ENSGT00940000159391; -.
DR   InParanoid; Q2HXL6; -.
DR   OrthoDB; 942598at2759; -.
DR   PhylomeDB; Q2HXL6; -.
DR   TreeFam; TF300807; -.
DR   BRENDA; 3.2.1.209; 3474.
DR   UniPathway; UPA00378; -.
DR   BioGRID-ORCS; 66967; 4 hits in 78 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 259 other cell types or tissues.
DR   ExpressionAtlas; Q2HXL6; baseline and differential.
DR   GO; GO:0005783; C:endoplasmic reticulum; IBA:GO_Central.
DR   GO; GO:0005788; C:endoplasmic reticulum lumen; IDA:MGI.
DR   GO; GO:0016020; C:membrane; IEA:InterPro.
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:0036503; P:ERAD pathway; IDA:ParkinsonsUK-UCL.
DR   GO; GO:0006516; P:glycoprotein catabolic process; IDA:MGI.
DR   GO; GO:0006058; P:mannoprotein catabolic process; 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   Gene3D; 3.50.30.30; -; 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; IPR046450; PA_dom_sf.
DR   InterPro; IPR003137; PA_domain.
DR   InterPro; IPR036026; Seven-hairpin_glycosidases.
DR   PANTHER; PTHR45679; ER DEGRADATION-ENHANCING ALPHA-MANNOSIDASE-LIKE PROTEIN 2; 1.
DR   PANTHER; PTHR45679:SF2; ER DEGRADATION-ENHANCING ALPHA-MANNOSIDASE-LIKE PROTEIN 3; 1.
DR   Pfam; PF01532; Glyco_hydro_47; 1.
DR   Pfam; PF02225; PA; 1.
DR   PRINTS; PR00747; GLYHDRLASE47.
DR   SUPFAM; SSF52025; PA domain; 1.
DR   SUPFAM; SSF48225; Seven-hairpin glycosidases; 1.
DR   PROSITE; PS00014; ER_TARGET; 1.
DR   Genevisible; Q2HXL6; MM.
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
//