IDE_MOUSE
ID IDE_MOUSE Reviewed; 1019 AA.
AC Q9JHR7;
DT 20-JUN-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-2000, sequence version 1.
DT 03-AUG-2022, entry version 145.
DE RecName: Full=Insulin-degrading enzyme;
DE EC=3.4.24.56 {ECO:0000269|PubMed:12732730, ECO:0000269|PubMed:24847884, ECO:0000269|PubMed:9830016};
DE AltName: Full=Insulin protease;
DE Short=Insulinase;
DE AltName: Full=Insulysin {ECO:0000303|PubMed:12732730};
GN Name=Ide;
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].
RA Van Veldhoven P.P.;
RT "Search for PTS1-containing protein in mammals.";
RL Submitted (JUN-2000) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP FUNCTION, CATALYTIC ACTIVITY, AND SUBCELLULAR LOCATION.
RX PubMed=9830016; DOI=10.1074/jbc.273.49.32730;
RA Qiu W.Q., Walsh D.M., Ye Z., Vekrellis K., Zhang J., Podlisny M.B.,
RA Rosner M.R., Safavi A., Hersh L.B., Selkoe D.J.;
RT "Insulin-degrading enzyme regulates extracellular levels of amyloid beta-
RT protein by degradation.";
RL J. Biol. Chem. 273:32730-32738(1998).
RN [3]
RP FUNCTION, DISRUPTION PHENOTYPE, AND TISSUE SPECIFICITY.
RX PubMed=12634421; DOI=10.1073/pnas.0230450100;
RA Farris W., Mansourian S., Chang Y., Lindsley L., Eckman E.A., Frosch M.P.,
RA Eckman C.B., Tanzi R.E., Selkoe D.J., Guenette S.;
RT "Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-
RT protein, and the beta-amyloid precursor protein intracellular domain in
RT vivo.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:4162-4167(2003).
RN [4]
RP FUNCTION, CATALYTIC ACTIVITY, DISRUPTION PHENOTYPE, AND TISSUE SPECIFICITY.
RX PubMed=12732730; DOI=10.1073/pnas.1031520100;
RA Miller B.C., Eckman E.A., Sambamurti K., Dobbs N., Chow K.M., Eckman C.B.,
RA Hersh L.B., Thiele D.L.;
RT "Amyloid-beta peptide levels in brain are inversely correlated with
RT insulysin activity levels in vivo.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:6221-6226(2003).
RN [5]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Liver, Lung, Pancreas,
RC 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 [6]
RP SUBCELLULAR LOCATION, IDENTIFICATION OF SLYX MOTIF, AND MUTAGENESIS OF
RP 853-GLU--TYR-858.
RX PubMed=21576244; DOI=10.1074/jbc.c110.217893;
RA Glebov K., Schutze S., Walter J.;
RT "Functional relevance of a novel SlyX motif in non-conventional secretion
RT of insulin-degrading enzyme.";
RL J. Biol. Chem. 286:22711-22715(2011).
RN [7]
RP INDUCTION.
RX PubMed=22504074; DOI=10.1016/j.febslet.2012.03.034;
RA Zhao Y., Zhang Y., Zhou M., Wang S., Hua Z., Zhang J.;
RT "Loss of mPer2 increases plasma insulin levels by enhanced glucose-
RT stimulated insulin secretion and impaired insulin clearance in mice.";
RL FEBS Lett. 586:1306-1311(2012).
RN [8]
RP SUCCINYLATION [LARGE SCALE ANALYSIS] AT LYS-192 AND LYS-697, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=23806337; DOI=10.1016/j.molcel.2013.06.001;
RA Park J., Chen Y., Tishkoff D.X., Peng C., Tan M., Dai L., Xie Z., Zhang Y.,
RA Zwaans B.M., Skinner M.E., Lombard D.B., Zhao Y.;
RT "SIRT5-mediated lysine desuccinylation impacts diverse metabolic
RT pathways.";
RL Mol. Cell 50:919-930(2013).
RN [9]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=24847884; DOI=10.1038/nature13297;
RA Maianti J.P., McFedries A., Foda Z.H., Kleiner R.E., Du X.Q.,
RA Leissring M.A., Tang W.J., Charron M.J., Seeliger M.A., Saghatelian A.,
RA Liu D.R.;
RT "Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by
RT multiple hormones.";
RL Nature 511:94-98(2014).
RN [10]
RP FUNCTION.
RX PubMed=26394692; DOI=10.1038/ncomms9250;
RA Deprez-Poulain R., Hennuyer N., Bosc D., Liang W.G., Enee E., Marechal X.,
RA Charton J., Totobenazara J., Berte G., Jahklal J., Verdelet T., Dumont J.,
RA Dassonneville S., Woitrain E., Gauriot M., Paquet C., Duplan I.,
RA Hermant P., Cantrelle F.X., Sevin E., Culot M., Landry V., Herledan A.,
RA Piveteau C., Lippens G., Leroux F., Tang W.J., van Endert P., Staels B.,
RA Deprez B.;
RT "Catalytic site inhibition of insulin-degrading enzyme by a small molecule
RT induces glucose intolerance in mice.";
RL Nat. Commun. 6:8250-8250(2015).
CC -!- FUNCTION: Plays a role in the cellular breakdown of insulin, APP
CC peptides, IAPP peptides, natriuretic peptides, glucagon, bradykinin,
CC kallidin, and other peptides, and thereby plays a role in intercellular
CC peptide signaling (PubMed:9830016, PubMed:12634421, PubMed:12732730,
CC PubMed:24847884, PubMed:26394692). Substrate binding induces important
CC conformation changes, making it possible to bind and degrade larger
CC substrates, such as insulin (By similarity). Contributes to the
CC regulation of peptide hormone signaling cascades and regulation of
CC blood glucose homeostasis via its role in the degradation of insulin,
CC glucagon and IAPP (PubMed:24847884, PubMed:26394692). Plays a role in
CC the degradation and clearance of APP-derived amyloidogenic peptides
CC that are secreted by neurons and microglia (PubMed:9830016). Degrades
CC the natriuretic peptides ANP, BNP and CNP, inactivating their ability
CC to raise intracellular cGMP (By similarity). Also degrades an aberrant
CC frameshifted 40-residue form of NPPA (fsNPPA) which is associated with
CC familial atrial fibrillation in heterozygous patients (By similarity).
CC Involved in antigen processing. Produces both the N terminus and the C
CC terminus of MAGEA3-derived antigenic peptide (EVDPIGHLY) that is
CC presented to cytotoxic T lymphocytes by MHC class I.
CC {ECO:0000250|UniProtKB:P14735, ECO:0000269|PubMed:12634421,
CC ECO:0000269|PubMed:12732730, ECO:0000269|PubMed:24847884,
CC ECO:0000269|PubMed:26394692, ECO:0000269|PubMed:9830016}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Degradation of insulin, glucagon and other polypeptides. No
CC action on proteins.; EC=3.4.24.56;
CC Evidence={ECO:0000269|PubMed:12732730, ECO:0000269|PubMed:24847884,
CC ECO:0000269|PubMed:9830016};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000250|UniProtKB:P35559};
CC Note=Binds 1 zinc ion per subunit. {ECO:0000250|UniProtKB:P35559};
CC -!- ACTIVITY REGULATION: Activated by ATP, other nucleotide triphosphates
CC and small peptides. Inhibited by bacitracin.
CC {ECO:0000250|UniProtKB:P35559}.
CC -!- SUBUNIT: Homodimer. Can also form homotetramers.
CC {ECO:0000250|UniProtKB:P35559}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:21576244,
CC ECO:0000269|PubMed:9830016}. Cell membrane
CC {ECO:0000269|PubMed:21576244}. Secreted {ECO:0000269|PubMed:21576244,
CC ECO:0000269|PubMed:9830016}.
CC -!- TISSUE SPECIFICITY: Detected in brain and liver (at protein level)
CC (PubMed:12634421, PubMed:12732730). Detected in liver
CC (PubMed:12732730). {ECO:0000269|PubMed:12634421,
CC ECO:0000269|PubMed:12732730}.
CC -!- INDUCTION: Expression oscillates diurnally.
CC {ECO:0000269|PubMed:22504074}.
CC -!- DOMAIN: The SlyX motif may be involved in the non-conventional
CC secretion of the protein. {ECO:0000269|PubMed:21576244}.
CC -!- DISRUPTION PHENOTYPE: No visible phenotype, but mice display impaired
CC degradation of insulin and APP-derived peptides (PubMed:12634421,
CC PubMed:12732730). At 17 to 20 weeks after birth, mutant mice display
CC increased serum insulin levels and decreased glucose tolerance
CC (PubMed:12634421). {ECO:0000269|PubMed:12634421,
CC ECO:0000269|PubMed:12732730}.
CC -!- MISCELLANEOUS: ATP-binding induces a conformation change.
CC {ECO:0000250|UniProtKB:P14735}.
CC -!- SIMILARITY: Belongs to the peptidase M16 family. {ECO:0000305}.
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DR EMBL; AJ278422; CAC01233.1; -; mRNA.
DR AlphaFoldDB; Q9JHR7; -.
DR SMR; Q9JHR7; -.
DR DIP; DIP-60044N; -.
DR IntAct; Q9JHR7; 1.
DR STRING; 10090.ENSMUSP00000121358; -.
DR BindingDB; Q9JHR7; -.
DR ChEMBL; CHEMBL3232680; -.
DR MEROPS; M16.002; -.
DR iPTMnet; Q9JHR7; -.
DR PhosphoSitePlus; Q9JHR7; -.
DR EPD; Q9JHR7; -.
DR jPOST; Q9JHR7; -.
DR MaxQB; Q9JHR7; -.
DR PaxDb; Q9JHR7; -.
DR PeptideAtlas; Q9JHR7; -.
DR PRIDE; Q9JHR7; -.
DR ProteomicsDB; 273090; -.
DR MGI; MGI:96412; Ide.
DR eggNOG; KOG0959; Eukaryota.
DR InParanoid; Q9JHR7; -.
DR BRENDA; 3.4.24.56; 3474.
DR Reactome; R-MMU-5689880; Ub-specific processing proteases.
DR Reactome; R-MMU-9033241; Peroxisomal protein import.
DR ChiTaRS; Ide; mouse.
DR PRO; PR:Q9JHR7; -.
DR Proteomes; UP000000589; Unplaced.
DR RNAct; Q9JHR7; protein.
DR GO; GO:0016323; C:basolateral plasma membrane; ISO:MGI.
DR GO; GO:0009986; C:cell surface; ISO:MGI.
DR GO; GO:0005737; C:cytoplasm; ISO:MGI.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0031597; C:cytosolic proteasome complex; ISO:MGI.
DR GO; GO:0009897; C:external side of plasma membrane; ISO:MGI.
DR GO; GO:0070062; C:extracellular exosome; IMP:ARUK-UCL.
DR GO; GO:0005615; C:extracellular space; ISO:MGI.
DR GO; GO:0005739; C:mitochondrion; HDA:MGI.
DR GO; GO:0005634; C:nucleus; ISO:MGI.
DR GO; GO:0005782; C:peroxisomal matrix; ISO:MGI.
DR GO; GO:0005777; C:peroxisome; ISO:MGI.
DR GO; GO:0001540; F:amyloid-beta binding; ISO:MGI.
DR GO; GO:0005524; F:ATP binding; ISS:UniProtKB.
DR GO; GO:0016887; F:ATP hydrolysis activity; ISO:MGI.
DR GO; GO:0031626; F:beta-endorphin binding; ISO:MGI.
DR GO; GO:0004175; F:endopeptidase activity; ISS:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; ISO:MGI.
DR GO; GO:0043559; F:insulin binding; ISO:MGI.
DR GO; GO:0004222; F:metalloendopeptidase activity; ISS:UniProtKB.
DR GO; GO:0042277; F:peptide binding; ISO:MGI.
DR GO; GO:0017046; F:peptide hormone binding; ISO:MGI.
DR GO; GO:0042803; F:protein homodimerization activity; ISS:UniProtKB.
DR GO; GO:0044877; F:protein-containing complex binding; ISO:MGI.
DR GO; GO:0140036; F:ubiquitin-dependent protein binding; ISO:MGI.
DR GO; GO:0008270; F:zinc ion binding; ISS:UniProtKB.
DR GO; GO:0097242; P:amyloid-beta clearance; IDA:MGI.
DR GO; GO:0150094; P:amyloid-beta clearance by cellular catabolic process; ISO:MGI.
DR GO; GO:0050435; P:amyloid-beta metabolic process; ISS:UniProtKB.
DR GO; GO:0019885; P:antigen processing and presentation of endogenous peptide antigen via MHC class I; ISS:UniProtKB.
DR GO; GO:0010815; P:bradykinin catabolic process; ISS:UniProtKB.
DR GO; GO:0008340; P:determination of adult lifespan; ISO:MGI.
DR GO; GO:0042447; P:hormone catabolic process; ISS:UniProtKB.
DR GO; GO:1901143; P:insulin catabolic process; IMP:UniProtKB.
DR GO; GO:1901142; P:insulin metabolic process; ISO:MGI.
DR GO; GO:0045861; P:negative regulation of proteolysis; ISO:MGI.
DR GO; GO:0043171; P:peptide catabolic process; ISS:UniProtKB.
DR GO; GO:0032092; P:positive regulation of protein binding; ISO:MGI.
DR GO; GO:0030163; P:protein catabolic process; IMP:ARUK-UCL.
DR GO; GO:0006508; P:proteolysis; ISO:MGI.
DR GO; GO:0051603; P:proteolysis involved in protein catabolic process; ISO:MGI.
DR GO; GO:1903715; P:regulation of aerobic respiration; ISO:MGI.
DR GO; GO:0006979; P:response to oxidative stress; IDA:MGI.
DR GO; GO:0010992; P:ubiquitin recycling; ISO:MGI.
DR InterPro; IPR011249; Metalloenz_LuxS/M16.
DR InterPro; IPR011765; Pept_M16_N.
DR InterPro; IPR001431; Pept_M16_Zn_BS.
DR InterPro; IPR007863; Peptidase_M16_C.
DR InterPro; IPR032632; Peptidase_M16_M.
DR Pfam; PF00675; Peptidase_M16; 1.
DR Pfam; PF05193; Peptidase_M16_C; 2.
DR Pfam; PF16187; Peptidase_M16_M; 1.
DR SUPFAM; SSF63411; SSF63411; 4.
DR PROSITE; PS00143; INSULINASE; 1.
PE 1: Evidence at protein level;
KW Allosteric enzyme; ATP-binding; Cell membrane; Cytoplasm; Hydrolase;
KW Membrane; Metal-binding; Metalloprotease; Nucleotide-binding; Protease;
KW Reference proteome; Secreted; Zinc.
FT CHAIN 1..1019
FT /note="Insulin-degrading enzyme"
FT /id="PRO_0000074405"
FT MOTIF 853..858
FT /note="SlyX motif"
FT /evidence="ECO:0000305|PubMed:21576244"
FT ACT_SITE 111
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10096"
FT BINDING 108
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10096"
FT BINDING 112
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10096"
FT BINDING 189
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10096"
FT BINDING 359..363
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P14735"
FT BINDING 429
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P35559"
FT BINDING 895..901
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P35559"
FT MOD_RES 192
FT /note="N6-succinyllysine"
FT /evidence="ECO:0007744|PubMed:23806337"
FT MOD_RES 697
FT /note="N6-succinyllysine"
FT /evidence="ECO:0007744|PubMed:23806337"
FT MUTAGEN 853..858
FT /note="Missing: Marked decrease in secretion."
FT /evidence="ECO:0000269|PubMed:21576244"
SQ SEQUENCE 1019 AA; 117772 MW; 9443A6886110BE86 CRC64;
MRNGLVWLLH PALPGTLRSI LGARPPPAKR LCGFPKQTYS TMSNPAIQRI EDQIVKSPED
KREYRGLELA NGIKVLLISD PTTDKSSAAL DVHIGSLSDP PNIPGLSHFC EHMLFLGTKK
YPKENEYSQF LSEHAGSSNA FTSGEHTNYY FDVSHEHLEG ALDRFAQFFL CPLLDASCKD
REVNAVDSEH EKNVMNDAWR LFQLEKATGN PKHPFSKFGT GNKYTLETRP NQEGIDVREE
LLKFHSTYYS SNLMAICVLG RESLDDLTNL VVKLFSEVEN KNVPLPEFPE HPFQEEHLRQ
LYKIVPIKDI RNLYVTFPIP DLQQYYKSNP GYYLGHLIGH EGPGSLLSEL KSKGWVNTLV
GGQKEGARGF MFFIINVDLT EEGLLHVEDI ILHMFQYIQK LRAEGPQEWV FQECKDLNAV
AFRFKDKERP RGYTSKIAGK LHYYPLNGVL TAEYLLEEFR PDLIDMVLDK LRPENVRVAI
VSKSFEGKTD RTEQWYGTQY KQEAIPEDVI QKWQNADLNG KFKLPTKNEF IPTNFEILSL
EKDATPYPAL IKDTAMSKLW FKQDDKFFLP KACLNFEFFS PFAYVDPLHC NMAYLYLELL
KDSLNEYAYA AELAGLSYDL QNTIYGMYLS VKRYNDKQPI LLKKITEKMA TFEIDKKRFE
IIKEAYMRSL NNFRAEQPHQ HAMYYLRLLM TEVAWTKDEL KEALDDVTLP RLKAFIPQLL
SRLHIEALLH GNITKQAALG VMQMVEDTLI EHAHTKPLLP SQLVRYREVQ LPDRGWFVYQ
QRNEVHNNCG IEIYYQTDMQ STSENMFLEL FCQIISEPCF NTLRTKEQLG YIVFSGPRRA
NGIQGLRFII QSEKPPHYLE SRVEAFLITM EKAIEDMTEE AFQKHIQALA IRRLDKPKKL
SAECAKYWGE IISQQYNYDR DNIEVAYLKT LTKDDIIRFY QEMLAVDAPR RHKVSVHVLA
REMDSCPVVG EFPSQNDINL SEAPPLPQPE VIHNMTEFKR GLPLFPLVKP HINFMAAKL
