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 08-NOV-2023, entry version 150. 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, RC 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 [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}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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; 10090-ENSMUSP00000121358; -. DR PeptideAtlas; Q9JHR7; -. DR ProteomicsDB; 273090; -. DR Pumba; Q9JHR7; -. DR AGR; MGI:96412; -. 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-77387; Insulin receptor recycling. 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:0031904; C:endosome lumen; IDA: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: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; IDA:MGI. 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:0042447; P:hormone catabolic process; ISS:UniProtKB. DR GO; GO:1901143; P:insulin catabolic process; IDA:MGI. DR GO; GO:1901142; P:insulin metabolic process; ISO:MGI. DR GO; GO:0038020; P:insulin receptor recycling; IDA: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: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 Gene3D; 3.30.830.10; Metalloenzyme, LuxS/M16 peptidase-like; 4. 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 PANTHER; PTHR43690:SF18; INSULIN-DEGRADING ENZYME-RELATED; 1. DR PANTHER; PTHR43690; NARDILYSIN; 1. DR Pfam; PF00675; Peptidase_M16; 1. DR Pfam; PF05193; Peptidase_M16_C; 2. DR Pfam; PF16187; Peptidase_M16_M; 1. DR SUPFAM; SSF63411; LuxS/MPP-like metallohydrolase; 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 //