Full text data of IDE
IDE
[Confidence: low (only semi-automatic identification from reviews)]
Insulin-degrading enzyme; 3.4.24.56 (Abeta-degrading protease; Insulin protease; Insulinase; Insulysin)
Insulin-degrading enzyme; 3.4.24.56 (Abeta-degrading protease; Insulin protease; Insulinase; Insulysin)
UniProt
P14735
ID IDE_HUMAN Reviewed; 1019 AA.
AC P14735; B2R721; B7ZAU2; D3DR35; Q5T5N2;
DT 01-APR-1990, integrated into UniProtKB/Swiss-Prot.
read moreDT 25-NOV-2008, sequence version 4.
DT 22-JAN-2014, entry version 142.
DE RecName: Full=Insulin-degrading enzyme;
DE EC=3.4.24.56;
DE AltName: Full=Abeta-degrading protease;
DE AltName: Full=Insulin protease;
DE Short=Insulinase;
DE AltName: Full=Insulysin;
GN Name=IDE;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND PARTIAL PROTEIN SEQUENCE.
RX PubMed=3059494; DOI=10.1126/science.3059494;
RA Affholter J.A., Fried V.A., Roth R.A.;
RT "Human insulin-degrading enzyme shares structural and functional
RT homologies with E. coli protease III.";
RL Science 242:1415-1418(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND SEQUENCE REVISION.
RX PubMed=2293021;
RA Affholter J.A., Hsieh C.L., Francke U., Roth R.A.;
RT "Insulin-degrading enzyme: stable expression of the human
RT complementary DNA, characterization of its protein product, and
RT chromosomal mapping of the human and mouse genes.";
RL Mol. Endocrinol. 4:1125-1135(1990).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Testis;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164054; DOI=10.1038/nature02462;
RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J.,
RA Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D.,
RA Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L.,
RA Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S.,
RA Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L.,
RA Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J.,
RA Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M.,
RA Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S.,
RA Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M.,
RA Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A.,
RA Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T.,
RA Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I.,
RA Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T.,
RA Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W.,
RA Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H.,
RA Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L.,
RA Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K.,
RA Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T.,
RA Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 10.";
RL Nature 429:375-381(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=10684867;
RA Vekrellis K., Ye Z., Qiu W.Q., Walsh D., Hartley D., Chesneau V.,
RA Rosner M.R., Selkoe D.J.;
RT "Neurons regulate extracellular levels of amyloid beta-protein via
RT proteolysis by insulin-degrading enzyme.";
RL J. Neurosci. 20:1657-1665(2000).
RN [8]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH VZV GLYCOPROTEIN E.
RX PubMed=17055432; DOI=10.1016/j.cell.2006.08.046;
RA Li Q., Ali M.A., Cohen J.I.;
RT "Insulin degrading enzyme is a cellular receptor mediating varicella-
RT zoster virus infection and cell-to-cell spread.";
RL Cell 127:305-316(2006).
RN [9]
RP INTERACTION WITH VZV GLYCOPROTEIN E.
RX PubMed=17553876; DOI=10.1128/JVI.00286-07;
RA Li Q., Krogmann T., Ali M.A., Tang W.-J., Cohen J.I.;
RT "The amino terminus of varicella-zoster virus (VZV) glycoprotein E is
RT required for binding to insulin-degrading enzyme, a VZV receptor.";
RL J. Virol. 81:8525-8532(2007).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [13]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 42-1019 OF MUTANT GLN-111 IN
RP COMPLEXES WITH ZINC IONS; IAPP; INSULIN; AMYLOID AND GLUCAGON,
RP MUTAGENESIS OF GLU-111; SER-132; ASN-184; ASP-426; GLU-817; GLN-828
RP AND LYS-899, COFACTOR, SUBUNIT, AND ACTIVE SITE.
RX PubMed=17051221; DOI=10.1038/nature05143;
RA Shen Y., Joachimiak A., Rosner M.R., Tang W.-J.;
RT "Structures of human insulin-degrading enzyme reveal a new substrate
RT recognition mechanism.";
RL Nature 443:870-874(2006).
RN [14]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 43-1018 OF MUTANT PHE-831 IN
RP COMPLEX WITH ZINC IONS AND SUBSTRATE PEPTIDE, CATALYTIC ACTIVITY,
RP ENZYME REGULATION, ATP-BINDING, SUBUNIT, MUTAGENESIS OF ASP-426 AND
RP LYS-899, AND FUNCTION.
RX PubMed=17613531; DOI=10.1074/jbc.M701590200;
RA Im H., Manolopoulou M., Malito E., Shen Y., Zhao J., Neant-Fery M.,
RA Sun C.-Y., Meredith S.C., Sisodia S.S., Leissring M.A., Tang W.-J.;
RT "Structure of substrate-free human insulin-degrading enzyme (IDE) and
RT biophysical analysis of ATP-induced conformational switch of IDE.";
RL J. Biol. Chem. 282:25453-25463(2007).
RN [15]
RP X-RAY CRYSTALLOGRAPHY (1.96 ANGSTROMS) OF 42-1019 OF MUTANT GLN-111 IN
RP COMPLEX WITH BRADYKININ, FUNCTION, AND ENZYME REGULATION.
RX PubMed=18986166; DOI=10.1021/bi801192h;
RA Malito E., Ralat L.A., Manolopoulou M., Tsay J.L., Wadlington N.L.,
RA Tang W.-J.;
RT "Molecular bases for the recognition of short peptide substrates and
RT cysteine-directed modifications of human insulin-degrading enzyme.";
RL Biochemistry 47:12822-12834(2008).
CC -!- FUNCTION: Plays a role in the cellular breakdown of insulin, IAPP,
CC glucagon, bradykinin, kallidin and other peptides, and thereby
CC plays a role in intercellular peptide signaling. Degrades amyloid
CC formed by APP and IAPP. May play a role in the degradation and
CC clearance of naturally secreted amyloid beta-protein by neurons
CC and microglia.
CC -!- CATALYTIC ACTIVITY: Degradation of insulin, glucagon and other
CC polypeptides. No action on proteins.
CC -!- COFACTOR: Binds 1 zinc ion per subunit.
CC -!- ENZYME REGULATION: Activated by small peptides (By similarity).
CC Activated by ATP and GTP, and to a lesser extent by CTP, TTP and
CC PPPi. Inhibited by bacitracin. Inhibited by S-nitrosylation and
CC oxidation agents.
CC -!- SUBUNIT: Homodimer. Can form higher oligomers. Interacts (via N-
CC terminus) with varicella-zoster virus (VZV) envelope glycoprotein
CC E (via N-terminus); the membrane-associated isoform may function
CC as an entry receptor for this virus.
CC -!- INTERACTION:
CC P10147:CCL3; NbExp=3; IntAct=EBI-2556886, EBI-8459634;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Cell membrane. Secreted (By
CC similarity). Note=Present at the cell surface of neuron cells. The
CC membrane-associated isoform is approximately 5 kDa larger than the
CC known cytosolic isoform.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P14735-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P14735-2; Sequence=VSP_044303;
CC -!- DOMAIN: The SlyX motif may be involved in the non-conventional
CC secretion of the protein (By similarity).
CC -!- PTM: The N-terminus is blocked.
CC -!- MISCELLANEOUS: ATP-binding induces a conformation change.
CC -!- SIMILARITY: Belongs to the peptidase M16 family.
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DR EMBL; M21188; AAA52712.1; -; mRNA.
DR EMBL; AK312810; BAG35668.1; -; mRNA.
DR EMBL; AK316407; BAH14778.1; -; mRNA.
DR EMBL; AL356128; CAI13670.1; -; Genomic_DNA.
DR EMBL; CH471066; EAW50090.1; -; Genomic_DNA.
DR EMBL; CH471066; EAW50091.1; -; Genomic_DNA.
DR EMBL; BC096336; AAH96336.1; -; mRNA.
DR EMBL; BC096337; AAH96337.1; -; mRNA.
DR EMBL; BC096339; AAH96339.1; -; mRNA.
DR PIR; A40119; SNHUIN.
DR RefSeq; NP_001159418.1; NM_001165946.1.
DR RefSeq; NP_004960.2; NM_004969.3.
DR UniGene; Hs.500546; -.
DR PDB; 2G47; X-ray; 2.10 A; A/B=42-1019.
DR PDB; 2G48; X-ray; 2.60 A; A/B=42-1019.
DR PDB; 2G49; X-ray; 2.50 A; A/B=42-1019.
DR PDB; 2G54; X-ray; 2.25 A; A/B=42-1019.
DR PDB; 2G56; X-ray; 2.20 A; A/B=42-1019.
DR PDB; 2JBU; X-ray; 3.00 A; A/B=42-1019.
DR PDB; 2JG4; X-ray; 2.80 A; A/B=43-1018.
DR PDB; 2WBY; X-ray; 2.60 A; A/B=42-1019.
DR PDB; 2WC0; X-ray; 2.80 A; A/B=42-1019.
DR PDB; 2WK3; X-ray; 2.59 A; A/B=1-1019.
DR PDB; 2YPU; X-ray; 2.80 A; A/B=42-1019.
DR PDB; 3CWW; X-ray; 1.96 A; A/B=42-1019.
DR PDB; 3E4A; X-ray; 2.60 A; A/B=1-1019.
DR PDB; 3E4Z; X-ray; 2.28 A; A/B=42-1019.
DR PDB; 3E50; X-ray; 2.30 A; A/B=42-1019.
DR PDB; 3H44; X-ray; 3.00 A; A/B=42-1019.
DR PDB; 3HGZ; X-ray; 2.91 A; A/B=43-1011.
DR PDB; 3N56; X-ray; 3.10 A; A/B=42-1019.
DR PDB; 3N57; X-ray; 3.03 A; A/B=42-1019.
DR PDB; 3OFI; X-ray; 2.35 A; A/B=42-1019.
DR PDB; 3QZ2; X-ray; 3.20 A; A/B=42-1019.
DR PDB; 4DTT; X-ray; 3.22 A; A/B=42-1019.
DR PDB; 4DWK; X-ray; 3.00 A; A/B=42-1019.
DR PDB; 4GS8; X-ray; 2.99 A; A/B=42-1019.
DR PDB; 4GSC; X-ray; 2.81 A; A/B=42-1019.
DR PDB; 4GSE; X-ray; 3.29 A; A/B=42-1019.
DR PDB; 4GSF; X-ray; 2.70 A; A/B=42-1019.
DR PDB; 4IOF; X-ray; 3.35 A; A/B=42-1018.
DR PDBsum; 2G47; -.
DR PDBsum; 2G48; -.
DR PDBsum; 2G49; -.
DR PDBsum; 2G54; -.
DR PDBsum; 2G56; -.
DR PDBsum; 2JBU; -.
DR PDBsum; 2JG4; -.
DR PDBsum; 2WBY; -.
DR PDBsum; 2WC0; -.
DR PDBsum; 2WK3; -.
DR PDBsum; 2YPU; -.
DR PDBsum; 3CWW; -.
DR PDBsum; 3E4A; -.
DR PDBsum; 3E4Z; -.
DR PDBsum; 3E50; -.
DR PDBsum; 3H44; -.
DR PDBsum; 3HGZ; -.
DR PDBsum; 3N56; -.
DR PDBsum; 3N57; -.
DR PDBsum; 3OFI; -.
DR PDBsum; 3QZ2; -.
DR PDBsum; 4DTT; -.
DR PDBsum; 4DWK; -.
DR PDBsum; 4GS8; -.
DR PDBsum; 4GSC; -.
DR PDBsum; 4GSE; -.
DR PDBsum; 4GSF; -.
DR PDBsum; 4IOF; -.
DR ProteinModelPortal; P14735; -.
DR SMR; P14735; 43-1016.
DR DIP; DIP-55771N; -.
DR IntAct; P14735; 5.
DR MINT; MINT-2801173; -.
DR STRING; 9606.ENSP00000265986; -.
DR BindingDB; P14735; -.
DR ChEMBL; CHEMBL1293287; -.
DR DrugBank; DB00626; Bacitracin.
DR DrugBank; DB00047; Insulin Glargine recombinant.
DR DrugBank; DB00046; Insulin Lyspro recombinant.
DR DrugBank; DB00030; Insulin recombinant.
DR DrugBank; DB00071; Insulin, porcine.
DR MEROPS; M16.002; -.
DR PhosphoSite; P14735; -.
DR DMDM; 215274252; -.
DR PaxDb; P14735; -.
DR PRIDE; P14735; -.
DR Ensembl; ENST00000265986; ENSP00000265986; ENSG00000119912.
DR Ensembl; ENST00000371581; ENSP00000360637; ENSG00000119912.
DR GeneID; 3416; -.
DR KEGG; hsa:3416; -.
DR UCSC; uc001kia.3; human.
DR CTD; 3416; -.
DR GeneCards; GC10M094211; -.
DR H-InvDB; HIX0009042; -.
DR HGNC; HGNC:5381; IDE.
DR HPA; CAB012303; -.
DR MIM; 146680; gene.
DR neXtProt; NX_P14735; -.
DR PharmGKB; PA29629; -.
DR eggNOG; COG1025; -.
DR HOGENOM; HOG000161331; -.
DR HOVERGEN; HBG106799; -.
DR InParanoid; P14735; -.
DR KO; K01408; -.
DR OMA; QPRKQLK; -.
DR OrthoDB; EOG7HHWRD; -.
DR PhylomeDB; P14735; -.
DR SignaLink; P14735; -.
DR EvolutionaryTrace; P14735; -.
DR GeneWiki; Insulin-degrading_enzyme; -.
DR GenomeRNAi; 3416; -.
DR NextBio; 13466; -.
DR PRO; PR:P14735; -.
DR ArrayExpress; P14735; -.
DR Bgee; P14735; -.
DR CleanEx; HS_IDE; -.
DR Genevestigator; P14735; -.
DR GO; GO:0009986; C:cell surface; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0031597; C:cytosolic proteasome complex; IEA:Ensembl.
DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0005782; C:peroxisomal matrix; IEA:Ensembl.
DR GO; GO:0005777; C:peroxisome; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB.
DR GO; GO:0016887; F:ATPase activity; IEA:Ensembl.
DR GO; GO:0001540; F:beta-amyloid binding; IEA:Ensembl.
DR GO; GO:0031626; F:beta-endorphin binding; IEA:Ensembl.
DR GO; GO:0043559; F:insulin binding; IDA:UniProtKB.
DR GO; GO:0004222; F:metalloendopeptidase activity; IDA:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB.
DR GO; GO:0050435; P:beta-amyloid metabolic process; IDA:UniProtKB.
DR GO; GO:0010815; P:bradykinin catabolic process; IDA:UniProtKB.
DR GO; GO:0008340; P:determination of adult lifespan; IDA:UniProtKB.
DR GO; GO:0042447; P:hormone catabolic process; IEA:Ensembl.
DR GO; GO:1901143; P:insulin catabolic process; IDA:UniProtKB.
DR GO; GO:0008286; P:insulin receptor signaling pathway; NAS:UniProtKB.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:0045861; P:negative regulation of proteolysis; IEA:Ensembl.
DR GO; GO:0032461; P:positive regulation of protein oligomerization; IDA:UniProtKB.
DR GO; GO:0051291; P:protein heterooligomerization; IEA:Ensembl.
DR GO; GO:0051260; P:protein homooligomerization; IDA:UniProtKB.
DR GO; GO:0051289; P:protein homotetramerization; IEA:Ensembl.
DR GO; GO:0051603; P:proteolysis involved in cellular protein catabolic process; IDA:UniProtKB.
DR GO; GO:0010992; P:ubiquitin homeostasis; IDA:UniProtKB.
DR Gene3D; 3.30.830.10; -; 4.
DR InterPro; IPR011249; Metalloenz_LuxS/M16.
DR InterPro; IPR011237; Pept_M16_dom.
DR InterPro; IPR011765; Pept_M16_N.
DR InterPro; IPR001431; Pept_M16_Zn_BS.
DR InterPro; IPR007863; Peptidase_M16_C.
DR Pfam; PF00675; Peptidase_M16; 1.
DR Pfam; PF05193; Peptidase_M16_C; 2.
DR SUPFAM; SSF63411; SSF63411; 4.
DR PROSITE; PS00143; INSULINASE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Allosteric enzyme; Alternative splicing; ATP-binding;
KW Cell membrane; Complete proteome; Cytoplasm;
KW Direct protein sequencing; Host-virus interaction; Hydrolase;
KW Membrane; Metal-binding; Metalloprotease; Nucleotide-binding;
KW Polymorphism; Protease; Reference proteome; Secreted; Zinc.
FT CHAIN 1 1019 Insulin-degrading enzyme.
FT /FTId=PRO_0000074404.
FT NP_BIND 895 901 ATP (By similarity).
FT REGION 336 342 Substrate binding exosite.
FT REGION 359 363 Substrate binding.
FT MOTIF 853 858 SlyX motif.
FT ACT_SITE 111 111 Proton acceptor (By similarity).
FT METAL 108 108 Zinc (By similarity).
FT METAL 112 112 Zinc (By similarity).
FT METAL 189 189 Zinc (By similarity).
FT BINDING 429 429 ATP (By similarity).
FT VAR_SEQ 1 555 Missing (in isoform 2).
FT /FTId=VSP_044303.
FT VARIANT 612 612 E -> K (in dbSNP:rs2229708).
FT /FTId=VAR_051571.
FT MUTAGEN 111 111 E->Q: Loss of catalytic activity.
FT MUTAGEN 132 132 S->C: Increases catalytic rate towards
FT INS and amyloid; when associated with C-
FT 817.
FT MUTAGEN 184 184 N->C: Increases catalytic rate towards
FT INS and amyloid; when associated with C-
FT 828.
FT MUTAGEN 426 426 D->C: Increases catalytic rate towards
FT INS and amyloid; when associated with C-
FT 899.
FT MUTAGEN 817 817 E->C: Increases catalytic rate towards
FT INS and amyloid; when associated with C-
FT 132.
FT MUTAGEN 828 828 Q->C: Increases catalytic rate towards
FT INS and amyloid; when associated with C-
FT 184.
FT MUTAGEN 831 831 Y->F: No effect on catalytic activity.
FT MUTAGEN 899 899 K->C: Increases catalytic rate towards
FT INS and amyloid; when associated with C-
FT 426.
FT CONFLICT 78 78 I -> M (in Ref. 2; AAA52712).
FT CONFLICT 472 472 R -> G (in Ref. 3; BAG35668).
FT CONFLICT 555 555 A -> V (in Ref. 2; AAA52712).
FT CONFLICT 567 569 FFL -> KKK (in Ref. 2; AAA52712).
FT CONFLICT 586 586 D -> G (in Ref. 3; BAG35668).
FT CONFLICT 845 845 G -> S (in Ref. 2; AAA52712).
FT STRAND 47 50
FT STRAND 63 69
FT STRAND 74 79
FT STRAND 84 93
FT HELIX 96 98
FT STRAND 101 103
FT HELIX 106 113
FT HELIX 114 116
FT STRAND 118 121
FT HELIX 126 132
FT TURN 133 135
FT STRAND 137 142
FT STRAND 147 154
FT HELIX 155 157
FT HELIX 158 166
FT HELIX 167 169
FT HELIX 176 194
FT HELIX 197 207
FT HELIX 214 216
FT HELIX 223 226
FT HELIX 228 232
FT HELIX 237 248
FT HELIX 251 253
FT STRAND 254 262
FT HELIX 264 275
FT HELIX 295 297
FT STRAND 298 304
FT STRAND 307 309
FT STRAND 312 319
FT HELIX 323 325
FT TURN 326 328
FT HELIX 330 338
FT HELIX 346 352
FT STRAND 359 367
FT STRAND 370 378
FT HELIX 381 385
FT HELIX 387 404
FT HELIX 408 423
FT HELIX 430 440
FT TURN 441 443
FT HELIX 446 448
FT TURN 449 454
FT HELIX 461 468
FT HELIX 473 475
FT STRAND 477 481
FT HELIX 483 485
FT TURN 486 488
FT TURN 494 496
FT STRAND 499 504
FT HELIX 507 514
FT STRAND 549 553
FT STRAND 555 563
FT STRAND 565 567
FT STRAND 570 579
FT HELIX 581 583
FT STRAND 584 586
FT HELIX 587 613
FT STRAND 616 623
FT STRAND 626 635
FT HELIX 638 650
FT HELIX 656 672
FT HELIX 673 675
FT HELIX 678 690
FT STRAND 691 693
FT HELIX 697 704
FT HELIX 709 721
FT STRAND 722 732
FT HELIX 735 753
FT HELIX 760 762
FT STRAND 775 782
FT STRAND 787 799
FT HELIX 802 823
FT TURN 824 827
FT STRAND 831 840
FT STRAND 843 854
FT HELIX 856 876
FT HELIX 879 894
FT HELIX 900 912
FT HELIX 920 928
FT HELIX 933 943
FT STRAND 952 959
FT STRAND 990 992
FT HELIX 995 1000
SQ SEQUENCE 1019 AA; 117968 MW; 8A28AEF75EDA0EDA CRC64;
MRYRLAWLLH PALPSTFRSV LGARLPPPER LCGFQKKTYS KMNNPAIKRI GNHITKSPED
KREYRGLELA NGIKVLLISD PTTDKSSAAL DVHIGSLSDP PNIAGLSHFC EHMLFLGTKK
YPKENEYSQF LSEHAGSSNA FTSGEHTNYY FDVSHEHLEG ALDRFAQFFL CPLFDESCKD
REVNAVDSEH EKNVMNDAWR LFQLEKATGN PKHPFSKFGT GNKYTLETRP NQEGIDVRQE
LLKFHSAYYS SNLMAVCVLG RESLDDLTNL VVKLFSEVEN KNVPLPEFPE HPFQEEHLKQ
LYKIVPIKDI RNLYVTFPIP DLQKYYKSNP GHYLGHLIGH EGPGSLLSEL KSKGWVNTLV
GGQKEGARGF MFFIINVDLT EEGLLHVEDI ILHMFQYIQK LRAEGPQEWV FQECKDLNAV
AFRFKDKERP RGYTSKIAGI LHYYPLEEVL TAEYLLEEFR PDLIEMVLDK LRPENVRVAI
VSKSFEGKTD RTEEWYGTQY KQEAIPDEVI KKWQNADLNG KFKLPTKNEF IPTNFEILPL
EKEATPYPAL IKDTAMSKLW FKQDDKFFLP KACLNFEFFS PFAYVDPLHC NMAYLYLELL
KDSLNEYAYA AELAGLSYDL QNTIYGMYLS VKGYNDKQPI LLKKIIEKMA TFEIDEKRFE
IIKEAYMRSL NNFRAEQPHQ HAMYYLRLLM TEVAWTKDEL KEALDDVTLP RLKAFIPQLL
SRLHIEALLH GNITKQAALG IMQMVEDTLI EHAHTKPLLP SQLVRYREVQ LPDRGWFVYQ
QRNEVHNNCG IEIYYQTDMQ STSENMFLEL FCQIISEPCF NTLRTKEQLG YIVFSGPRRA
NGIQGLRFII QSEKPPHYLE SRVEAFLITM EKSIEDMTEE AFQKHIQALA IRRLDKPKKL
SAECAKYWGE IISQQYNFDR DNTEVAYLKT LTKEDIIKFY KEMLAVDAPR RHKVSVHVLA
REMDSCPVVG EFPCQNDINL SQAPALPQPE VIQNMTEFKR GLPLFPLVKP HINFMAAKL
//
ID IDE_HUMAN Reviewed; 1019 AA.
AC P14735; B2R721; B7ZAU2; D3DR35; Q5T5N2;
DT 01-APR-1990, integrated into UniProtKB/Swiss-Prot.
read moreDT 25-NOV-2008, sequence version 4.
DT 22-JAN-2014, entry version 142.
DE RecName: Full=Insulin-degrading enzyme;
DE EC=3.4.24.56;
DE AltName: Full=Abeta-degrading protease;
DE AltName: Full=Insulin protease;
DE Short=Insulinase;
DE AltName: Full=Insulysin;
GN Name=IDE;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND PARTIAL PROTEIN SEQUENCE.
RX PubMed=3059494; DOI=10.1126/science.3059494;
RA Affholter J.A., Fried V.A., Roth R.A.;
RT "Human insulin-degrading enzyme shares structural and functional
RT homologies with E. coli protease III.";
RL Science 242:1415-1418(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND SEQUENCE REVISION.
RX PubMed=2293021;
RA Affholter J.A., Hsieh C.L., Francke U., Roth R.A.;
RT "Insulin-degrading enzyme: stable expression of the human
RT complementary DNA, characterization of its protein product, and
RT chromosomal mapping of the human and mouse genes.";
RL Mol. Endocrinol. 4:1125-1135(1990).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Testis;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164054; DOI=10.1038/nature02462;
RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J.,
RA Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D.,
RA Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L.,
RA Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S.,
RA Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L.,
RA Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J.,
RA Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M.,
RA Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S.,
RA Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M.,
RA Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A.,
RA Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T.,
RA Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I.,
RA Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T.,
RA Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W.,
RA Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H.,
RA Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L.,
RA Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K.,
RA Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T.,
RA Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 10.";
RL Nature 429:375-381(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=10684867;
RA Vekrellis K., Ye Z., Qiu W.Q., Walsh D., Hartley D., Chesneau V.,
RA Rosner M.R., Selkoe D.J.;
RT "Neurons regulate extracellular levels of amyloid beta-protein via
RT proteolysis by insulin-degrading enzyme.";
RL J. Neurosci. 20:1657-1665(2000).
RN [8]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH VZV GLYCOPROTEIN E.
RX PubMed=17055432; DOI=10.1016/j.cell.2006.08.046;
RA Li Q., Ali M.A., Cohen J.I.;
RT "Insulin degrading enzyme is a cellular receptor mediating varicella-
RT zoster virus infection and cell-to-cell spread.";
RL Cell 127:305-316(2006).
RN [9]
RP INTERACTION WITH VZV GLYCOPROTEIN E.
RX PubMed=17553876; DOI=10.1128/JVI.00286-07;
RA Li Q., Krogmann T., Ali M.A., Tang W.-J., Cohen J.I.;
RT "The amino terminus of varicella-zoster virus (VZV) glycoprotein E is
RT required for binding to insulin-degrading enzyme, a VZV receptor.";
RL J. Virol. 81:8525-8532(2007).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [13]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 42-1019 OF MUTANT GLN-111 IN
RP COMPLEXES WITH ZINC IONS; IAPP; INSULIN; AMYLOID AND GLUCAGON,
RP MUTAGENESIS OF GLU-111; SER-132; ASN-184; ASP-426; GLU-817; GLN-828
RP AND LYS-899, COFACTOR, SUBUNIT, AND ACTIVE SITE.
RX PubMed=17051221; DOI=10.1038/nature05143;
RA Shen Y., Joachimiak A., Rosner M.R., Tang W.-J.;
RT "Structures of human insulin-degrading enzyme reveal a new substrate
RT recognition mechanism.";
RL Nature 443:870-874(2006).
RN [14]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 43-1018 OF MUTANT PHE-831 IN
RP COMPLEX WITH ZINC IONS AND SUBSTRATE PEPTIDE, CATALYTIC ACTIVITY,
RP ENZYME REGULATION, ATP-BINDING, SUBUNIT, MUTAGENESIS OF ASP-426 AND
RP LYS-899, AND FUNCTION.
RX PubMed=17613531; DOI=10.1074/jbc.M701590200;
RA Im H., Manolopoulou M., Malito E., Shen Y., Zhao J., Neant-Fery M.,
RA Sun C.-Y., Meredith S.C., Sisodia S.S., Leissring M.A., Tang W.-J.;
RT "Structure of substrate-free human insulin-degrading enzyme (IDE) and
RT biophysical analysis of ATP-induced conformational switch of IDE.";
RL J. Biol. Chem. 282:25453-25463(2007).
RN [15]
RP X-RAY CRYSTALLOGRAPHY (1.96 ANGSTROMS) OF 42-1019 OF MUTANT GLN-111 IN
RP COMPLEX WITH BRADYKININ, FUNCTION, AND ENZYME REGULATION.
RX PubMed=18986166; DOI=10.1021/bi801192h;
RA Malito E., Ralat L.A., Manolopoulou M., Tsay J.L., Wadlington N.L.,
RA Tang W.-J.;
RT "Molecular bases for the recognition of short peptide substrates and
RT cysteine-directed modifications of human insulin-degrading enzyme.";
RL Biochemistry 47:12822-12834(2008).
CC -!- FUNCTION: Plays a role in the cellular breakdown of insulin, IAPP,
CC glucagon, bradykinin, kallidin and other peptides, and thereby
CC plays a role in intercellular peptide signaling. Degrades amyloid
CC formed by APP and IAPP. May play a role in the degradation and
CC clearance of naturally secreted amyloid beta-protein by neurons
CC and microglia.
CC -!- CATALYTIC ACTIVITY: Degradation of insulin, glucagon and other
CC polypeptides. No action on proteins.
CC -!- COFACTOR: Binds 1 zinc ion per subunit.
CC -!- ENZYME REGULATION: Activated by small peptides (By similarity).
CC Activated by ATP and GTP, and to a lesser extent by CTP, TTP and
CC PPPi. Inhibited by bacitracin. Inhibited by S-nitrosylation and
CC oxidation agents.
CC -!- SUBUNIT: Homodimer. Can form higher oligomers. Interacts (via N-
CC terminus) with varicella-zoster virus (VZV) envelope glycoprotein
CC E (via N-terminus); the membrane-associated isoform may function
CC as an entry receptor for this virus.
CC -!- INTERACTION:
CC P10147:CCL3; NbExp=3; IntAct=EBI-2556886, EBI-8459634;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Cell membrane. Secreted (By
CC similarity). Note=Present at the cell surface of neuron cells. The
CC membrane-associated isoform is approximately 5 kDa larger than the
CC known cytosolic isoform.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P14735-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P14735-2; Sequence=VSP_044303;
CC -!- DOMAIN: The SlyX motif may be involved in the non-conventional
CC secretion of the protein (By similarity).
CC -!- PTM: The N-terminus is blocked.
CC -!- MISCELLANEOUS: ATP-binding induces a conformation change.
CC -!- SIMILARITY: Belongs to the peptidase M16 family.
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DR EMBL; M21188; AAA52712.1; -; mRNA.
DR EMBL; AK312810; BAG35668.1; -; mRNA.
DR EMBL; AK316407; BAH14778.1; -; mRNA.
DR EMBL; AL356128; CAI13670.1; -; Genomic_DNA.
DR EMBL; CH471066; EAW50090.1; -; Genomic_DNA.
DR EMBL; CH471066; EAW50091.1; -; Genomic_DNA.
DR EMBL; BC096336; AAH96336.1; -; mRNA.
DR EMBL; BC096337; AAH96337.1; -; mRNA.
DR EMBL; BC096339; AAH96339.1; -; mRNA.
DR PIR; A40119; SNHUIN.
DR RefSeq; NP_001159418.1; NM_001165946.1.
DR RefSeq; NP_004960.2; NM_004969.3.
DR UniGene; Hs.500546; -.
DR PDB; 2G47; X-ray; 2.10 A; A/B=42-1019.
DR PDB; 2G48; X-ray; 2.60 A; A/B=42-1019.
DR PDB; 2G49; X-ray; 2.50 A; A/B=42-1019.
DR PDB; 2G54; X-ray; 2.25 A; A/B=42-1019.
DR PDB; 2G56; X-ray; 2.20 A; A/B=42-1019.
DR PDB; 2JBU; X-ray; 3.00 A; A/B=42-1019.
DR PDB; 2JG4; X-ray; 2.80 A; A/B=43-1018.
DR PDB; 2WBY; X-ray; 2.60 A; A/B=42-1019.
DR PDB; 2WC0; X-ray; 2.80 A; A/B=42-1019.
DR PDB; 2WK3; X-ray; 2.59 A; A/B=1-1019.
DR PDB; 2YPU; X-ray; 2.80 A; A/B=42-1019.
DR PDB; 3CWW; X-ray; 1.96 A; A/B=42-1019.
DR PDB; 3E4A; X-ray; 2.60 A; A/B=1-1019.
DR PDB; 3E4Z; X-ray; 2.28 A; A/B=42-1019.
DR PDB; 3E50; X-ray; 2.30 A; A/B=42-1019.
DR PDB; 3H44; X-ray; 3.00 A; A/B=42-1019.
DR PDB; 3HGZ; X-ray; 2.91 A; A/B=43-1011.
DR PDB; 3N56; X-ray; 3.10 A; A/B=42-1019.
DR PDB; 3N57; X-ray; 3.03 A; A/B=42-1019.
DR PDB; 3OFI; X-ray; 2.35 A; A/B=42-1019.
DR PDB; 3QZ2; X-ray; 3.20 A; A/B=42-1019.
DR PDB; 4DTT; X-ray; 3.22 A; A/B=42-1019.
DR PDB; 4DWK; X-ray; 3.00 A; A/B=42-1019.
DR PDB; 4GS8; X-ray; 2.99 A; A/B=42-1019.
DR PDB; 4GSC; X-ray; 2.81 A; A/B=42-1019.
DR PDB; 4GSE; X-ray; 3.29 A; A/B=42-1019.
DR PDB; 4GSF; X-ray; 2.70 A; A/B=42-1019.
DR PDB; 4IOF; X-ray; 3.35 A; A/B=42-1018.
DR PDBsum; 2G47; -.
DR PDBsum; 2G48; -.
DR PDBsum; 2G49; -.
DR PDBsum; 2G54; -.
DR PDBsum; 2G56; -.
DR PDBsum; 2JBU; -.
DR PDBsum; 2JG4; -.
DR PDBsum; 2WBY; -.
DR PDBsum; 2WC0; -.
DR PDBsum; 2WK3; -.
DR PDBsum; 2YPU; -.
DR PDBsum; 3CWW; -.
DR PDBsum; 3E4A; -.
DR PDBsum; 3E4Z; -.
DR PDBsum; 3E50; -.
DR PDBsum; 3H44; -.
DR PDBsum; 3HGZ; -.
DR PDBsum; 3N56; -.
DR PDBsum; 3N57; -.
DR PDBsum; 3OFI; -.
DR PDBsum; 3QZ2; -.
DR PDBsum; 4DTT; -.
DR PDBsum; 4DWK; -.
DR PDBsum; 4GS8; -.
DR PDBsum; 4GSC; -.
DR PDBsum; 4GSE; -.
DR PDBsum; 4GSF; -.
DR PDBsum; 4IOF; -.
DR ProteinModelPortal; P14735; -.
DR SMR; P14735; 43-1016.
DR DIP; DIP-55771N; -.
DR IntAct; P14735; 5.
DR MINT; MINT-2801173; -.
DR STRING; 9606.ENSP00000265986; -.
DR BindingDB; P14735; -.
DR ChEMBL; CHEMBL1293287; -.
DR DrugBank; DB00626; Bacitracin.
DR DrugBank; DB00047; Insulin Glargine recombinant.
DR DrugBank; DB00046; Insulin Lyspro recombinant.
DR DrugBank; DB00030; Insulin recombinant.
DR DrugBank; DB00071; Insulin, porcine.
DR MEROPS; M16.002; -.
DR PhosphoSite; P14735; -.
DR DMDM; 215274252; -.
DR PaxDb; P14735; -.
DR PRIDE; P14735; -.
DR Ensembl; ENST00000265986; ENSP00000265986; ENSG00000119912.
DR Ensembl; ENST00000371581; ENSP00000360637; ENSG00000119912.
DR GeneID; 3416; -.
DR KEGG; hsa:3416; -.
DR UCSC; uc001kia.3; human.
DR CTD; 3416; -.
DR GeneCards; GC10M094211; -.
DR H-InvDB; HIX0009042; -.
DR HGNC; HGNC:5381; IDE.
DR HPA; CAB012303; -.
DR MIM; 146680; gene.
DR neXtProt; NX_P14735; -.
DR PharmGKB; PA29629; -.
DR eggNOG; COG1025; -.
DR HOGENOM; HOG000161331; -.
DR HOVERGEN; HBG106799; -.
DR InParanoid; P14735; -.
DR KO; K01408; -.
DR OMA; QPRKQLK; -.
DR OrthoDB; EOG7HHWRD; -.
DR PhylomeDB; P14735; -.
DR SignaLink; P14735; -.
DR EvolutionaryTrace; P14735; -.
DR GeneWiki; Insulin-degrading_enzyme; -.
DR GenomeRNAi; 3416; -.
DR NextBio; 13466; -.
DR PRO; PR:P14735; -.
DR ArrayExpress; P14735; -.
DR Bgee; P14735; -.
DR CleanEx; HS_IDE; -.
DR Genevestigator; P14735; -.
DR GO; GO:0009986; C:cell surface; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0031597; C:cytosolic proteasome complex; IEA:Ensembl.
DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0005782; C:peroxisomal matrix; IEA:Ensembl.
DR GO; GO:0005777; C:peroxisome; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB.
DR GO; GO:0016887; F:ATPase activity; IEA:Ensembl.
DR GO; GO:0001540; F:beta-amyloid binding; IEA:Ensembl.
DR GO; GO:0031626; F:beta-endorphin binding; IEA:Ensembl.
DR GO; GO:0043559; F:insulin binding; IDA:UniProtKB.
DR GO; GO:0004222; F:metalloendopeptidase activity; IDA:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB.
DR GO; GO:0050435; P:beta-amyloid metabolic process; IDA:UniProtKB.
DR GO; GO:0010815; P:bradykinin catabolic process; IDA:UniProtKB.
DR GO; GO:0008340; P:determination of adult lifespan; IDA:UniProtKB.
DR GO; GO:0042447; P:hormone catabolic process; IEA:Ensembl.
DR GO; GO:1901143; P:insulin catabolic process; IDA:UniProtKB.
DR GO; GO:0008286; P:insulin receptor signaling pathway; NAS:UniProtKB.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:0045861; P:negative regulation of proteolysis; IEA:Ensembl.
DR GO; GO:0032461; P:positive regulation of protein oligomerization; IDA:UniProtKB.
DR GO; GO:0051291; P:protein heterooligomerization; IEA:Ensembl.
DR GO; GO:0051260; P:protein homooligomerization; IDA:UniProtKB.
DR GO; GO:0051289; P:protein homotetramerization; IEA:Ensembl.
DR GO; GO:0051603; P:proteolysis involved in cellular protein catabolic process; IDA:UniProtKB.
DR GO; GO:0010992; P:ubiquitin homeostasis; IDA:UniProtKB.
DR Gene3D; 3.30.830.10; -; 4.
DR InterPro; IPR011249; Metalloenz_LuxS/M16.
DR InterPro; IPR011237; Pept_M16_dom.
DR InterPro; IPR011765; Pept_M16_N.
DR InterPro; IPR001431; Pept_M16_Zn_BS.
DR InterPro; IPR007863; Peptidase_M16_C.
DR Pfam; PF00675; Peptidase_M16; 1.
DR Pfam; PF05193; Peptidase_M16_C; 2.
DR SUPFAM; SSF63411; SSF63411; 4.
DR PROSITE; PS00143; INSULINASE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Allosteric enzyme; Alternative splicing; ATP-binding;
KW Cell membrane; Complete proteome; Cytoplasm;
KW Direct protein sequencing; Host-virus interaction; Hydrolase;
KW Membrane; Metal-binding; Metalloprotease; Nucleotide-binding;
KW Polymorphism; Protease; Reference proteome; Secreted; Zinc.
FT CHAIN 1 1019 Insulin-degrading enzyme.
FT /FTId=PRO_0000074404.
FT NP_BIND 895 901 ATP (By similarity).
FT REGION 336 342 Substrate binding exosite.
FT REGION 359 363 Substrate binding.
FT MOTIF 853 858 SlyX motif.
FT ACT_SITE 111 111 Proton acceptor (By similarity).
FT METAL 108 108 Zinc (By similarity).
FT METAL 112 112 Zinc (By similarity).
FT METAL 189 189 Zinc (By similarity).
FT BINDING 429 429 ATP (By similarity).
FT VAR_SEQ 1 555 Missing (in isoform 2).
FT /FTId=VSP_044303.
FT VARIANT 612 612 E -> K (in dbSNP:rs2229708).
FT /FTId=VAR_051571.
FT MUTAGEN 111 111 E->Q: Loss of catalytic activity.
FT MUTAGEN 132 132 S->C: Increases catalytic rate towards
FT INS and amyloid; when associated with C-
FT 817.
FT MUTAGEN 184 184 N->C: Increases catalytic rate towards
FT INS and amyloid; when associated with C-
FT 828.
FT MUTAGEN 426 426 D->C: Increases catalytic rate towards
FT INS and amyloid; when associated with C-
FT 899.
FT MUTAGEN 817 817 E->C: Increases catalytic rate towards
FT INS and amyloid; when associated with C-
FT 132.
FT MUTAGEN 828 828 Q->C: Increases catalytic rate towards
FT INS and amyloid; when associated with C-
FT 184.
FT MUTAGEN 831 831 Y->F: No effect on catalytic activity.
FT MUTAGEN 899 899 K->C: Increases catalytic rate towards
FT INS and amyloid; when associated with C-
FT 426.
FT CONFLICT 78 78 I -> M (in Ref. 2; AAA52712).
FT CONFLICT 472 472 R -> G (in Ref. 3; BAG35668).
FT CONFLICT 555 555 A -> V (in Ref. 2; AAA52712).
FT CONFLICT 567 569 FFL -> KKK (in Ref. 2; AAA52712).
FT CONFLICT 586 586 D -> G (in Ref. 3; BAG35668).
FT CONFLICT 845 845 G -> S (in Ref. 2; AAA52712).
FT STRAND 47 50
FT STRAND 63 69
FT STRAND 74 79
FT STRAND 84 93
FT HELIX 96 98
FT STRAND 101 103
FT HELIX 106 113
FT HELIX 114 116
FT STRAND 118 121
FT HELIX 126 132
FT TURN 133 135
FT STRAND 137 142
FT STRAND 147 154
FT HELIX 155 157
FT HELIX 158 166
FT HELIX 167 169
FT HELIX 176 194
FT HELIX 197 207
FT HELIX 214 216
FT HELIX 223 226
FT HELIX 228 232
FT HELIX 237 248
FT HELIX 251 253
FT STRAND 254 262
FT HELIX 264 275
FT HELIX 295 297
FT STRAND 298 304
FT STRAND 307 309
FT STRAND 312 319
FT HELIX 323 325
FT TURN 326 328
FT HELIX 330 338
FT HELIX 346 352
FT STRAND 359 367
FT STRAND 370 378
FT HELIX 381 385
FT HELIX 387 404
FT HELIX 408 423
FT HELIX 430 440
FT TURN 441 443
FT HELIX 446 448
FT TURN 449 454
FT HELIX 461 468
FT HELIX 473 475
FT STRAND 477 481
FT HELIX 483 485
FT TURN 486 488
FT TURN 494 496
FT STRAND 499 504
FT HELIX 507 514
FT STRAND 549 553
FT STRAND 555 563
FT STRAND 565 567
FT STRAND 570 579
FT HELIX 581 583
FT STRAND 584 586
FT HELIX 587 613
FT STRAND 616 623
FT STRAND 626 635
FT HELIX 638 650
FT HELIX 656 672
FT HELIX 673 675
FT HELIX 678 690
FT STRAND 691 693
FT HELIX 697 704
FT HELIX 709 721
FT STRAND 722 732
FT HELIX 735 753
FT HELIX 760 762
FT STRAND 775 782
FT STRAND 787 799
FT HELIX 802 823
FT TURN 824 827
FT STRAND 831 840
FT STRAND 843 854
FT HELIX 856 876
FT HELIX 879 894
FT HELIX 900 912
FT HELIX 920 928
FT HELIX 933 943
FT STRAND 952 959
FT STRAND 990 992
FT HELIX 995 1000
SQ SEQUENCE 1019 AA; 117968 MW; 8A28AEF75EDA0EDA CRC64;
MRYRLAWLLH PALPSTFRSV LGARLPPPER LCGFQKKTYS KMNNPAIKRI GNHITKSPED
KREYRGLELA NGIKVLLISD PTTDKSSAAL DVHIGSLSDP PNIAGLSHFC EHMLFLGTKK
YPKENEYSQF LSEHAGSSNA FTSGEHTNYY FDVSHEHLEG ALDRFAQFFL CPLFDESCKD
REVNAVDSEH EKNVMNDAWR LFQLEKATGN PKHPFSKFGT GNKYTLETRP NQEGIDVRQE
LLKFHSAYYS SNLMAVCVLG RESLDDLTNL VVKLFSEVEN KNVPLPEFPE HPFQEEHLKQ
LYKIVPIKDI RNLYVTFPIP DLQKYYKSNP GHYLGHLIGH EGPGSLLSEL KSKGWVNTLV
GGQKEGARGF MFFIINVDLT EEGLLHVEDI ILHMFQYIQK LRAEGPQEWV FQECKDLNAV
AFRFKDKERP RGYTSKIAGI LHYYPLEEVL TAEYLLEEFR PDLIEMVLDK LRPENVRVAI
VSKSFEGKTD RTEEWYGTQY KQEAIPDEVI KKWQNADLNG KFKLPTKNEF IPTNFEILPL
EKEATPYPAL IKDTAMSKLW FKQDDKFFLP KACLNFEFFS PFAYVDPLHC NMAYLYLELL
KDSLNEYAYA AELAGLSYDL QNTIYGMYLS VKGYNDKQPI LLKKIIEKMA TFEIDEKRFE
IIKEAYMRSL NNFRAEQPHQ HAMYYLRLLM TEVAWTKDEL KEALDDVTLP RLKAFIPQLL
SRLHIEALLH GNITKQAALG IMQMVEDTLI EHAHTKPLLP SQLVRYREVQ LPDRGWFVYQ
QRNEVHNNCG IEIYYQTDMQ STSENMFLEL FCQIISEPCF NTLRTKEQLG YIVFSGPRRA
NGIQGLRFII QSEKPPHYLE SRVEAFLITM EKSIEDMTEE AFQKHIQALA IRRLDKPKKL
SAECAKYWGE IISQQYNFDR DNTEVAYLKT LTKEDIIKFY KEMLAVDAPR RHKVSVHVLA
REMDSCPVVG EFPCQNDINL SQAPALPQPE VIQNMTEFKR GLPLFPLVKP HINFMAAKL
//
MIM
146680
*RECORD*
*FIELD* NO
146680
*FIELD* TI
*146680 INSULIN-DEGRADING ENZYME; IDE
;;INSULYSIN;;
INSULINASE
*FIELD* TX
DESCRIPTION
read more
Insulin-degrading enzyme (EC 3.4.24.56), also known as insulysin, is a
110-kD neutral metallopeptidase that can degrade a number of peptides,
including insulin (176730) and beta-amyloid (104760) (Qiu et al., 1998).
CLONING
Affholter et al. (1988) isolated and sequenced a cDNA coding for IDE.
The deduced amino acid sequence of the enzyme contained the sequences of
13 peptides derived from the isolated protein. The cDNA transcribed in
vitro yielded a synthetic RNA that in cell-free translations produced a
protein that coelectrophoresed with the native proteinase and could be
immunoprecipitated with monoclonal antibodies to IDE. Since the deduced
sequence of this proteinase did not contain the consensus sequences for
any of the known classes of proteinases (i.e., metallo, cysteine,
aspartic, or serine), it may be a member of a family of proteases that
are involved in intercellular peptide signaling. It did show homology to
an Escherichia coli proteinase (called protease III), which also cleaves
insulin and is present in the periplasmic space; thus, they may be
members of the same family of proteases.
GENE FUNCTION
Qiu et al. (1998) determined that the extracellular thiol
metalloprotease capable of degrading amyloid-beta protein identified by
Qiu et al. (1997) is the same as IDE. By Western blot analysis, they
found a full-length 110-kD IDE band in the CSF of normal individuals and
of patients with Alzheimer disease (AD; 104300) or non-Alzheimer
dementia. They found no difference in IDE levels of the normal and
patient populations. By biochemical analysis of IDE purified from the
medium of a mouse microglial cell line, they determined that IDE could
degrade both endogenous and synthetic amyloid-beta protein and that it
could catalyze the oligomerization of this protein.
Through a series of inhibitor studies, in vitro translation, and
biochemical assays of rat IDE expressed by transfected human kidney
cells, Edbauer et al. (2002) determined that IDE may be the protease
responsible for the clearance of the cytoplasmic fragment of the
amyloid-beta precursor protein (APP) following liberation of the
amyloid-beta protein.
IDE has a preferential affinity for insulin such that the presence of
insulin will inhibit IDE-mediated degradation of other substances,
including beta-amyloid. Cook et al. (2003) found that hippocampal IDE
levels were reduced by approximately 50% in AD patients with the APOE4
(107741) allele compared to AD patients without the APOE4 allele and to
controls with or without the APOE4 allele. The findings suggested that
reduced IDE expression may be a risk factor for AD, and that IDE may
interact with APOE status to affect beta-amyloid metabolism.
Varicella-zoster virus (VZV) causes chickenpox and shingles. While
varicella is likely spread as cell-free virus to susceptible hosts, the
virus is transmitted by cell-to-cell spread in the body and in vitro. Li
et al. (2006) found that the extracellular domain of IDE interacted with
VZV glycoprotein E (gE), a protein essential for viral infection.
Downregulation of IDE by small interfering RNA or blocking IDE with
antibody, with soluble IDE protein extracted from liver, or with
bacitracin inhibited VZV infection. Cell-to-cell spread of virus was
also impaired by blocking IDE. Transfection of cell lines impaired for
VZV infection with a plasmid expressing human IDE resulted in increased
entry and enhanced infection with cell-free and cell-associated virus.
Li et al. (2006) concluded that IDE is a cellular receptor for both
cell-free and cell-associated VZV.
MAPPING
Affholter et al. (1990) mapped the IDE gene to human chromosome 10 and
mouse chromosome 19 by hybridization of cDNA probes to human-rodent or
mouse-hamster somatic cell hybrids, respectively. By a combination of
somatic cell hybrid analysis and in situ hybridization, Espinosa et al.
(1991) localized the IDE gene to 10q23-q25.
MOLECULAR GENETICS
For a discussion of a possible association between variation in the IDE
gene and late-onset Alzheimer disease, see AD6 (605526), which maps to
chromosome 10q23-q25.
Abraham et al. (2001) analyzed all of the coding exons, untranslated
regions, and 1,000 bp of 5-prime flanking sequence of IDE by means of
denaturing HPLC and sequencing. They detected 8 single nucleotide
polymorphisms (SNPs), of which 3 were found at lower than 5% frequency.
None of them changed the amino acid sequence. Abraham et al. (2001)
found no significant association between any individual SNP and
late-onset AD (LOAD) or with any haplotypes. They concluded that IDE
does not make a substantial contribution to the etiology of late-onset
AD and therefore cannot account for the linkage between late-onset AD
and 10q.
Prince et al. (2003) used a SNP genetic association strategy to
investigate AD in relation to a 480-kb region encompassing IDE. They
interpreted the results as providing 'substantial' evidence that genetic
variation within or very close to IDE impacts both disease risk and
traits related to the severity of AD.
Risk for LOAD and plasma amyloid-beta levels (APP; 104760), an
intermediate phenotype for LOAD, show linkage to chromosome 10q.
Ertekin-Taner et al. (2004) reported pathogenic variants in the 276-kb
region of 10q harboring the IDE gene that influence intermediate DNA
phenotypes and risk for AD.
Bian et al. (2004) reported an association between a T/C polymorphism
(dbSNP rs4646953) in the 5-prime untranslated region of the the IDE
gene, and AD in Han Chinese patients with the APOE4 allele. They found
no association between several IDE polymorphisms and AD among patients
without the E4 allele.
BIOCHEMICAL FEATURES
- Crystal Structure
Shen et al. (2006) reported the crystal structure of human IDE in
complex with 4 substrates, the insulin B chain (see 176730), amyloid
beta(1-40), amylin (147940), and glucagon (138030). The amino- and
carboxy-terminal domains of IDE form an enclosed cage just large enough
to encapsulate insulin. Extensive contacts between these domains keep
the degradation chamber of IDE inaccessible to substrates. Repositioning
of the IDE domains enables substrate access to the catalytic cavity. IDE
uses size and charge distribution of the substrate-binding cavity
selectively to entrap structurally diverse polypeptides. The enclosed
substrate undergoes conformational changes to form beta-sheets with 2
discrete regions of IDE for its degradation. Consistent with this model,
mutations disrupting the contacts between the amino- and carboxy-termini
of IDE increase IDE catalytic activity 40-fold.
ANIMAL MODEL
Genetic analysis of the diabetic GK rat has revealed several diabetes
susceptibility loci (see 125853). Fakhrai-Rad et al. (2000) mapped one
such locus, NIDDM1B, to a 1-cM region by genetic and pathophysiologic
characterization of new congenic substrains for the locus. The IDE gene
was also mapped to this 1-cM region, and 2 amino acid substitutions
(H18R and A890V) were identified in the GK allele which reduced
insulin-degrading activity by 31% in transfected cells. However, when
the H18R and A890V variants were studied separately, no effects were
observed, suggesting a synergistic effect of the 2 variants on insulin
degradation. No effect on insulin degradation was observed in cell
lysates, suggesting that the effect may be coupled to receptor-mediated
internalization of insulin. Congenic rats with the IDE GK allele
displayed postprandial hyperglycemia, reduced lipogenesis in fat cells,
blunted insulin-stimulated glucose transmembrane uptake, and reduced
insulin degradation in isolated muscle. Analysis of additional rat
strains demonstrated that the dysfunctional IDE allele was unique to GK
rats. The authors concluded that IDE plays an important role in the
diabetic phenotype in GK rats.
Factors that elevate amyloid-beta (104760) peptide levels are associated
with an increased risk for Alzheimer disease. Insulysin is one of
several proteases potentially involved in degradation of amyloid-beta,
based on its hydrolysis of amyloid-beta peptides in vitro. In an
insulysin-deficient gene-trap mouse model, Miller et al. (2003) found
that in vivo levels of brain A-beta-40 and A-beta-42 peptides were
increased significantly. A 6-fold increase in the level of the
gamma-secretase-generated C-terminal fragment of the A-beta precursor
protein also was found in the insulysin-deficient mouse. In mice
heterozygous for the insulysin gene trap, in which insulysin activity
levels were decreased approximately 50%, brain A-beta peptides were
increased to levels intermediate between those in wildtype mice and
homozygous insulysin gene-trap mice that had no detectable insulysin
activity. These findings indicated that there is an inverse correlation
between in vivo insulysin activity levels and brain A-beta peptide
levels and suggested that modulation of insulysin activity may alter the
risk for Alzheimer disease.
Farris et al. (2003) generated mice deficient in IDE by targeted
disruption. Ide deficiency resulted in a greater than 50% decrease in
amyloid-beta degradation in both membrane fractions and primary neuronal
cultures and a similar deficit in insulin degradation in liver. The
Ide-null mice showed increased cerebral accumulation of endogenous
amyloid-beta, a hallmark of Alzheimer disease, and had hyperinsulinemia
and glucose intolerance (see 176730), hallmarks of type II diabetes.
Moreover, the mice had elevated levels of the intracellular signaling
domain of the beta-amyloid precursor protein, which had recently been
found to be degraded by IDE in vitro. Farris et al. (2003) concluded
that, together with emerging genetic evidence, their in vivo findings
suggest that IDE hypofunction may underlie or contribute to some forms
of Alzheimer disease and type II diabetes and provide a mechanism for
the recognized association among hyperinsulinemia, diabetes, and
Alzheimer disease.
Leissring et al. (2003) found that developmentally delayed,
neuron-specific overexpression of Ide or neprilysin (MME; 120520) in
mice significantly reduced brain beta-amyloid levels, retarded or
prevented amyloid plaque formation and its associated cytopathology, and
rescued the premature lethality in APP transgenic mice. They concluded
that chronic upregulation of beta-amyloid-degrading proteases may combat
Alzheimer-type pathology in vivo.
*FIELD* RF
1. Abraham, R.; Myers, A.; Wavrant-DeVrieze, F.; Hamshere, M. L.;
Thomas, H. V.; Marshall, H.; Compton, D.; Spurlock, G.; Turic, D.;
Hoogendoorn, B.; Kwon, J. M.; Petersen, R. C.; and 12 others: Substantial
linkage disequilibrium across the insulin-degrading enzyme locus but
no association with late-onset Alzheimer's disease. Hum. Genet. 109:
646-652, 2001.
2. Affholter, J. A.; Fried, V. A.; Roth, R. A.: Human insulin-degrading
enzyme shares structural and functional homologies with E. coli protease
III. Science 242: 1415-1418, 1988.
3. Affholter, J. A.; Hsieh, C.-L.; Francke, U.; Roth, R. A.: Insulin-degrading
enzyme: stable expression of the human complementary DNA, characterization
of its protein product, and chromosomal mapping of the human and mouse
genes. Molec. Endocr. 4: 1125-1135, 1990.
4. Bian, L.; Yang, J. D.; Guo, T. W.; Sun, Y.; Duan, S. W.; Chen,
W. Y.; Pan, Y. X.; Feng, G. Y.; He, L.: Insulin-degrading enzyme
and Alzheimer disease: a genetic association study in the Han Chinese. Neurology 63:
241-245, 2004.
5. Cook, D. G.; Leverenz, J. B.; McMillan, P. J.; Kulstad, J. J.;
Ericksen, S.; Roth, R. A.; Schellenberg, G. D.; Jin, L.-W.; Kovacina,
K. S.; Craft, S.: Reduced hippocampal insulin-degrading enzyme in
late-onset Alzheimer's disease is associated with the apolipoprotein
E-epsilon-4 allele. Am. J. Path. 162: 313-319, 2003.
6. Edbauer, D.; Willem, M.; Lammich, S.; Steiner, H.; Haass, C.:
Insulin-degrading enzyme rapidly removes the beta-amyloid precursor
protein intracellular domain (AICD). J. Biol. Chem. 277: 13389-13393,
2002.
7. Ertekin-Taner, N.; Allen, M.; Fadale, D.; Scanlin, L.; Younkin,
L.; Petersen, R. C.; Graff-Radford, N.; Younkin, S. G.: Genetic variants
in a haplotype block spanning IDE are significantly associated with
plasma A-beta-42 levels and risk for Alzheimer disease. Hum. Mutat. 23:
334-342, 2004.
8. Espinosa, R., III; Lemons, R. S.; Perlman, R. K.; Kuo, W.-L.; Rosner,
M. R.; Le Beau, M. M.: Localization of the gene encoding insulin-degrading
enzyme to human chromosome 10, bands q23-q25. Cytogenet. Cell Genet. 57:
184-186, 1991.
9. Fakhrai-Rad, H.; Nikoshkov, A.; Kamel, A.; Fernstrom, M.; Zierath,
J. R.; Norgren, S.; Luthman, H.; Galli, J.: Insulin-degrading enzyme
identified as a candidate diabetes susceptibility gene in GK rats. Hum.
Molec. Genet. 9: 2149-2158, 2000.
10. Farris, W.; Mansourian, S.; Chang, Y.; Lindsley, L.; Eckman, E.
A.; Frosch, M. P.; Eckman, C. B.; Tanzi, R. E.; Selkoe, D. J.; Guenette,
S.: Insulin-degrading enzyme regulates the levels of insulin, amyloid
beta-protein, and the beta-amyloid precursor protein intracellular
domain in vivo. Proc. Nat. Acad. Sci. 100: 4162-4167, 2003.
11. Leissring, M. A.; Farris, W.; Chang, A. Y.; Walsh, D. M.; Wu,
X.; Sun, X.; Frosch, M. P.; Selkoe, D. J.: Enhanced proteolysis of
beta-amyloid in APP transgenic mice prevents plaque formation, secondary
pathology, and premature death. Neuron 40: 1087-1093, 2003.
12. Li, Q.; Ali, M. A.; Cohen, J. I.: Insulin degrading enzyme is
a cellular receptor mediating varicella-zoster virus infection and
cell-to-cell spread. Cell 127: 305-316, 2006.
13. Miller, B. C.; Eckman, E. A.; Sambamurti, K.; Dobbs, N.; Chow,
K. M.; Eckman, C. B.; Hersh, L. B.; Thiele, D. L.: Amyloid-beta peptide
levels in brain are inversely correlated with insulysin activity levels
in vivo. Proc. Nat. Acad. Sci. 100: 6221-6226, 2003.
14. Prince, J. A.; Feuk, L.; Gu, H. F.; Johansson, B.; Gatz, M.; Blennow,
K.; Brookes, A. J.: Genetic variation in a haplotype block spanning
IDE influences Alzheimer disease. Hum. Mutat. 22: 363-371, 2003.
15. Qiu, W. Q.; Walsh, D. M.; Ye, Z.; Vekrellis, K.; Zhang, J.; Podlisny,
M. B.; Rosner, M. R.; Safavi, A.; Hersh, L. B.; Selkoe, D. J.: Insulin-degrading
enzyme regulates extracellular levels of amyloid beta-protein by degradation. J.
Biol. Chem. 273: 32730-32738, 1998.
16. Qiu, W. Q.; Ye, Z.; Kholodenko, D.; Seubert, P.; Selkoe, D. J.
: Degradation of amyloid beta-protein by a metalloprotease secreted
by microglia and other neural and non-neural cells. J. Biol. Chem. 272:
6641-6646, 1997.
17. Shen, Y.; Joachimiak, A.; Rosner, M. R.; Tang, W.-J.: Structures
of human insulin-degrading enzyme reveal a new substrate recognition
mechanism. Nature 443: 870-874, 2006.
*FIELD* CN
Stylianos E. Antonarakis - updated: 3/20/2007
Ada Hamosh - updated: 10/31/2006
Cassandra L. Kniffin - updated: 9/7/2005
Patricia A. Hartz - updated: 6/18/2004
Victor A. McKusick - updated: 5/5/2004
Victor A. McKusick - updated: 11/19/2003
Ada Hamosh - updated: 7/24/2003
Victor A. McKusick - updated: 6/19/2003
Patricia A. Hartz - updated: 5/24/2002
Victor A. McKusick - updated: 1/2/2002
George E. Tiller - updated: 11/17/2000
*FIELD* CD
Victor A. McKusick: 1/3/1989
*FIELD* ED
ckniffin: 05/06/2010
mgross: 9/28/2009
mgross: 3/20/2007
alopez: 11/3/2006
terry: 10/31/2006
wwang: 9/29/2005
ckniffin: 9/7/2005
terry: 3/16/2005
mgross: 6/24/2004
terry: 6/18/2004
tkritzer: 5/7/2004
terry: 5/5/2004
tkritzer: 11/21/2003
terry: 11/19/2003
carol: 7/24/2003
terry: 7/24/2003
alopez: 6/27/2003
terry: 6/19/2003
carol: 5/28/2002
terry: 5/24/2002
carol: 1/16/2002
mcapotos: 1/8/2002
terry: 1/2/2002
mcapotos: 12/4/2000
terry: 11/17/2000
supermim: 3/16/1992
carol: 2/5/1992
carol: 10/22/1990
supermim: 3/20/1990
ddp: 10/27/1989
root: 1/3/1989
*RECORD*
*FIELD* NO
146680
*FIELD* TI
*146680 INSULIN-DEGRADING ENZYME; IDE
;;INSULYSIN;;
INSULINASE
*FIELD* TX
DESCRIPTION
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Insulin-degrading enzyme (EC 3.4.24.56), also known as insulysin, is a
110-kD neutral metallopeptidase that can degrade a number of peptides,
including insulin (176730) and beta-amyloid (104760) (Qiu et al., 1998).
CLONING
Affholter et al. (1988) isolated and sequenced a cDNA coding for IDE.
The deduced amino acid sequence of the enzyme contained the sequences of
13 peptides derived from the isolated protein. The cDNA transcribed in
vitro yielded a synthetic RNA that in cell-free translations produced a
protein that coelectrophoresed with the native proteinase and could be
immunoprecipitated with monoclonal antibodies to IDE. Since the deduced
sequence of this proteinase did not contain the consensus sequences for
any of the known classes of proteinases (i.e., metallo, cysteine,
aspartic, or serine), it may be a member of a family of proteases that
are involved in intercellular peptide signaling. It did show homology to
an Escherichia coli proteinase (called protease III), which also cleaves
insulin and is present in the periplasmic space; thus, they may be
members of the same family of proteases.
GENE FUNCTION
Qiu et al. (1998) determined that the extracellular thiol
metalloprotease capable of degrading amyloid-beta protein identified by
Qiu et al. (1997) is the same as IDE. By Western blot analysis, they
found a full-length 110-kD IDE band in the CSF of normal individuals and
of patients with Alzheimer disease (AD; 104300) or non-Alzheimer
dementia. They found no difference in IDE levels of the normal and
patient populations. By biochemical analysis of IDE purified from the
medium of a mouse microglial cell line, they determined that IDE could
degrade both endogenous and synthetic amyloid-beta protein and that it
could catalyze the oligomerization of this protein.
Through a series of inhibitor studies, in vitro translation, and
biochemical assays of rat IDE expressed by transfected human kidney
cells, Edbauer et al. (2002) determined that IDE may be the protease
responsible for the clearance of the cytoplasmic fragment of the
amyloid-beta precursor protein (APP) following liberation of the
amyloid-beta protein.
IDE has a preferential affinity for insulin such that the presence of
insulin will inhibit IDE-mediated degradation of other substances,
including beta-amyloid. Cook et al. (2003) found that hippocampal IDE
levels were reduced by approximately 50% in AD patients with the APOE4
(107741) allele compared to AD patients without the APOE4 allele and to
controls with or without the APOE4 allele. The findings suggested that
reduced IDE expression may be a risk factor for AD, and that IDE may
interact with APOE status to affect beta-amyloid metabolism.
Varicella-zoster virus (VZV) causes chickenpox and shingles. While
varicella is likely spread as cell-free virus to susceptible hosts, the
virus is transmitted by cell-to-cell spread in the body and in vitro. Li
et al. (2006) found that the extracellular domain of IDE interacted with
VZV glycoprotein E (gE), a protein essential for viral infection.
Downregulation of IDE by small interfering RNA or blocking IDE with
antibody, with soluble IDE protein extracted from liver, or with
bacitracin inhibited VZV infection. Cell-to-cell spread of virus was
also impaired by blocking IDE. Transfection of cell lines impaired for
VZV infection with a plasmid expressing human IDE resulted in increased
entry and enhanced infection with cell-free and cell-associated virus.
Li et al. (2006) concluded that IDE is a cellular receptor for both
cell-free and cell-associated VZV.
MAPPING
Affholter et al. (1990) mapped the IDE gene to human chromosome 10 and
mouse chromosome 19 by hybridization of cDNA probes to human-rodent or
mouse-hamster somatic cell hybrids, respectively. By a combination of
somatic cell hybrid analysis and in situ hybridization, Espinosa et al.
(1991) localized the IDE gene to 10q23-q25.
MOLECULAR GENETICS
For a discussion of a possible association between variation in the IDE
gene and late-onset Alzheimer disease, see AD6 (605526), which maps to
chromosome 10q23-q25.
Abraham et al. (2001) analyzed all of the coding exons, untranslated
regions, and 1,000 bp of 5-prime flanking sequence of IDE by means of
denaturing HPLC and sequencing. They detected 8 single nucleotide
polymorphisms (SNPs), of which 3 were found at lower than 5% frequency.
None of them changed the amino acid sequence. Abraham et al. (2001)
found no significant association between any individual SNP and
late-onset AD (LOAD) or with any haplotypes. They concluded that IDE
does not make a substantial contribution to the etiology of late-onset
AD and therefore cannot account for the linkage between late-onset AD
and 10q.
Prince et al. (2003) used a SNP genetic association strategy to
investigate AD in relation to a 480-kb region encompassing IDE. They
interpreted the results as providing 'substantial' evidence that genetic
variation within or very close to IDE impacts both disease risk and
traits related to the severity of AD.
Risk for LOAD and plasma amyloid-beta levels (APP; 104760), an
intermediate phenotype for LOAD, show linkage to chromosome 10q.
Ertekin-Taner et al. (2004) reported pathogenic variants in the 276-kb
region of 10q harboring the IDE gene that influence intermediate DNA
phenotypes and risk for AD.
Bian et al. (2004) reported an association between a T/C polymorphism
(dbSNP rs4646953) in the 5-prime untranslated region of the the IDE
gene, and AD in Han Chinese patients with the APOE4 allele. They found
no association between several IDE polymorphisms and AD among patients
without the E4 allele.
BIOCHEMICAL FEATURES
- Crystal Structure
Shen et al. (2006) reported the crystal structure of human IDE in
complex with 4 substrates, the insulin B chain (see 176730), amyloid
beta(1-40), amylin (147940), and glucagon (138030). The amino- and
carboxy-terminal domains of IDE form an enclosed cage just large enough
to encapsulate insulin. Extensive contacts between these domains keep
the degradation chamber of IDE inaccessible to substrates. Repositioning
of the IDE domains enables substrate access to the catalytic cavity. IDE
uses size and charge distribution of the substrate-binding cavity
selectively to entrap structurally diverse polypeptides. The enclosed
substrate undergoes conformational changes to form beta-sheets with 2
discrete regions of IDE for its degradation. Consistent with this model,
mutations disrupting the contacts between the amino- and carboxy-termini
of IDE increase IDE catalytic activity 40-fold.
ANIMAL MODEL
Genetic analysis of the diabetic GK rat has revealed several diabetes
susceptibility loci (see 125853). Fakhrai-Rad et al. (2000) mapped one
such locus, NIDDM1B, to a 1-cM region by genetic and pathophysiologic
characterization of new congenic substrains for the locus. The IDE gene
was also mapped to this 1-cM region, and 2 amino acid substitutions
(H18R and A890V) were identified in the GK allele which reduced
insulin-degrading activity by 31% in transfected cells. However, when
the H18R and A890V variants were studied separately, no effects were
observed, suggesting a synergistic effect of the 2 variants on insulin
degradation. No effect on insulin degradation was observed in cell
lysates, suggesting that the effect may be coupled to receptor-mediated
internalization of insulin. Congenic rats with the IDE GK allele
displayed postprandial hyperglycemia, reduced lipogenesis in fat cells,
blunted insulin-stimulated glucose transmembrane uptake, and reduced
insulin degradation in isolated muscle. Analysis of additional rat
strains demonstrated that the dysfunctional IDE allele was unique to GK
rats. The authors concluded that IDE plays an important role in the
diabetic phenotype in GK rats.
Factors that elevate amyloid-beta (104760) peptide levels are associated
with an increased risk for Alzheimer disease. Insulysin is one of
several proteases potentially involved in degradation of amyloid-beta,
based on its hydrolysis of amyloid-beta peptides in vitro. In an
insulysin-deficient gene-trap mouse model, Miller et al. (2003) found
that in vivo levels of brain A-beta-40 and A-beta-42 peptides were
increased significantly. A 6-fold increase in the level of the
gamma-secretase-generated C-terminal fragment of the A-beta precursor
protein also was found in the insulysin-deficient mouse. In mice
heterozygous for the insulysin gene trap, in which insulysin activity
levels were decreased approximately 50%, brain A-beta peptides were
increased to levels intermediate between those in wildtype mice and
homozygous insulysin gene-trap mice that had no detectable insulysin
activity. These findings indicated that there is an inverse correlation
between in vivo insulysin activity levels and brain A-beta peptide
levels and suggested that modulation of insulysin activity may alter the
risk for Alzheimer disease.
Farris et al. (2003) generated mice deficient in IDE by targeted
disruption. Ide deficiency resulted in a greater than 50% decrease in
amyloid-beta degradation in both membrane fractions and primary neuronal
cultures and a similar deficit in insulin degradation in liver. The
Ide-null mice showed increased cerebral accumulation of endogenous
amyloid-beta, a hallmark of Alzheimer disease, and had hyperinsulinemia
and glucose intolerance (see 176730), hallmarks of type II diabetes.
Moreover, the mice had elevated levels of the intracellular signaling
domain of the beta-amyloid precursor protein, which had recently been
found to be degraded by IDE in vitro. Farris et al. (2003) concluded
that, together with emerging genetic evidence, their in vivo findings
suggest that IDE hypofunction may underlie or contribute to some forms
of Alzheimer disease and type II diabetes and provide a mechanism for
the recognized association among hyperinsulinemia, diabetes, and
Alzheimer disease.
Leissring et al. (2003) found that developmentally delayed,
neuron-specific overexpression of Ide or neprilysin (MME; 120520) in
mice significantly reduced brain beta-amyloid levels, retarded or
prevented amyloid plaque formation and its associated cytopathology, and
rescued the premature lethality in APP transgenic mice. They concluded
that chronic upregulation of beta-amyloid-degrading proteases may combat
Alzheimer-type pathology in vivo.
*FIELD* RF
1. Abraham, R.; Myers, A.; Wavrant-DeVrieze, F.; Hamshere, M. L.;
Thomas, H. V.; Marshall, H.; Compton, D.; Spurlock, G.; Turic, D.;
Hoogendoorn, B.; Kwon, J. M.; Petersen, R. C.; and 12 others: Substantial
linkage disequilibrium across the insulin-degrading enzyme locus but
no association with late-onset Alzheimer's disease. Hum. Genet. 109:
646-652, 2001.
2. Affholter, J. A.; Fried, V. A.; Roth, R. A.: Human insulin-degrading
enzyme shares structural and functional homologies with E. coli protease
III. Science 242: 1415-1418, 1988.
3. Affholter, J. A.; Hsieh, C.-L.; Francke, U.; Roth, R. A.: Insulin-degrading
enzyme: stable expression of the human complementary DNA, characterization
of its protein product, and chromosomal mapping of the human and mouse
genes. Molec. Endocr. 4: 1125-1135, 1990.
4. Bian, L.; Yang, J. D.; Guo, T. W.; Sun, Y.; Duan, S. W.; Chen,
W. Y.; Pan, Y. X.; Feng, G. Y.; He, L.: Insulin-degrading enzyme
and Alzheimer disease: a genetic association study in the Han Chinese. Neurology 63:
241-245, 2004.
5. Cook, D. G.; Leverenz, J. B.; McMillan, P. J.; Kulstad, J. J.;
Ericksen, S.; Roth, R. A.; Schellenberg, G. D.; Jin, L.-W.; Kovacina,
K. S.; Craft, S.: Reduced hippocampal insulin-degrading enzyme in
late-onset Alzheimer's disease is associated with the apolipoprotein
E-epsilon-4 allele. Am. J. Path. 162: 313-319, 2003.
6. Edbauer, D.; Willem, M.; Lammich, S.; Steiner, H.; Haass, C.:
Insulin-degrading enzyme rapidly removes the beta-amyloid precursor
protein intracellular domain (AICD). J. Biol. Chem. 277: 13389-13393,
2002.
7. Ertekin-Taner, N.; Allen, M.; Fadale, D.; Scanlin, L.; Younkin,
L.; Petersen, R. C.; Graff-Radford, N.; Younkin, S. G.: Genetic variants
in a haplotype block spanning IDE are significantly associated with
plasma A-beta-42 levels and risk for Alzheimer disease. Hum. Mutat. 23:
334-342, 2004.
8. Espinosa, R., III; Lemons, R. S.; Perlman, R. K.; Kuo, W.-L.; Rosner,
M. R.; Le Beau, M. M.: Localization of the gene encoding insulin-degrading
enzyme to human chromosome 10, bands q23-q25. Cytogenet. Cell Genet. 57:
184-186, 1991.
9. Fakhrai-Rad, H.; Nikoshkov, A.; Kamel, A.; Fernstrom, M.; Zierath,
J. R.; Norgren, S.; Luthman, H.; Galli, J.: Insulin-degrading enzyme
identified as a candidate diabetes susceptibility gene in GK rats. Hum.
Molec. Genet. 9: 2149-2158, 2000.
10. Farris, W.; Mansourian, S.; Chang, Y.; Lindsley, L.; Eckman, E.
A.; Frosch, M. P.; Eckman, C. B.; Tanzi, R. E.; Selkoe, D. J.; Guenette,
S.: Insulin-degrading enzyme regulates the levels of insulin, amyloid
beta-protein, and the beta-amyloid precursor protein intracellular
domain in vivo. Proc. Nat. Acad. Sci. 100: 4162-4167, 2003.
11. Leissring, M. A.; Farris, W.; Chang, A. Y.; Walsh, D. M.; Wu,
X.; Sun, X.; Frosch, M. P.; Selkoe, D. J.: Enhanced proteolysis of
beta-amyloid in APP transgenic mice prevents plaque formation, secondary
pathology, and premature death. Neuron 40: 1087-1093, 2003.
12. Li, Q.; Ali, M. A.; Cohen, J. I.: Insulin degrading enzyme is
a cellular receptor mediating varicella-zoster virus infection and
cell-to-cell spread. Cell 127: 305-316, 2006.
13. Miller, B. C.; Eckman, E. A.; Sambamurti, K.; Dobbs, N.; Chow,
K. M.; Eckman, C. B.; Hersh, L. B.; Thiele, D. L.: Amyloid-beta peptide
levels in brain are inversely correlated with insulysin activity levels
in vivo. Proc. Nat. Acad. Sci. 100: 6221-6226, 2003.
14. Prince, J. A.; Feuk, L.; Gu, H. F.; Johansson, B.; Gatz, M.; Blennow,
K.; Brookes, A. J.: Genetic variation in a haplotype block spanning
IDE influences Alzheimer disease. Hum. Mutat. 22: 363-371, 2003.
15. Qiu, W. Q.; Walsh, D. M.; Ye, Z.; Vekrellis, K.; Zhang, J.; Podlisny,
M. B.; Rosner, M. R.; Safavi, A.; Hersh, L. B.; Selkoe, D. J.: Insulin-degrading
enzyme regulates extracellular levels of amyloid beta-protein by degradation. J.
Biol. Chem. 273: 32730-32738, 1998.
16. Qiu, W. Q.; Ye, Z.; Kholodenko, D.; Seubert, P.; Selkoe, D. J.
: Degradation of amyloid beta-protein by a metalloprotease secreted
by microglia and other neural and non-neural cells. J. Biol. Chem. 272:
6641-6646, 1997.
17. Shen, Y.; Joachimiak, A.; Rosner, M. R.; Tang, W.-J.: Structures
of human insulin-degrading enzyme reveal a new substrate recognition
mechanism. Nature 443: 870-874, 2006.
*FIELD* CN
Stylianos E. Antonarakis - updated: 3/20/2007
Ada Hamosh - updated: 10/31/2006
Cassandra L. Kniffin - updated: 9/7/2005
Patricia A. Hartz - updated: 6/18/2004
Victor A. McKusick - updated: 5/5/2004
Victor A. McKusick - updated: 11/19/2003
Ada Hamosh - updated: 7/24/2003
Victor A. McKusick - updated: 6/19/2003
Patricia A. Hartz - updated: 5/24/2002
Victor A. McKusick - updated: 1/2/2002
George E. Tiller - updated: 11/17/2000
*FIELD* CD
Victor A. McKusick: 1/3/1989
*FIELD* ED
ckniffin: 05/06/2010
mgross: 9/28/2009
mgross: 3/20/2007
alopez: 11/3/2006
terry: 10/31/2006
wwang: 9/29/2005
ckniffin: 9/7/2005
terry: 3/16/2005
mgross: 6/24/2004
terry: 6/18/2004
tkritzer: 5/7/2004
terry: 5/5/2004
tkritzer: 11/21/2003
terry: 11/19/2003
carol: 7/24/2003
terry: 7/24/2003
alopez: 6/27/2003
terry: 6/19/2003
carol: 5/28/2002
terry: 5/24/2002
carol: 1/16/2002
mcapotos: 1/8/2002
terry: 1/2/2002
mcapotos: 12/4/2000
terry: 11/17/2000
supermim: 3/16/1992
carol: 2/5/1992
carol: 10/22/1990
supermim: 3/20/1990
ddp: 10/27/1989
root: 1/3/1989