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Database: UniProt
Entry: P14735
LinkDB: P14735
Original site: P14735 
ID   IDE_HUMAN               Reviewed;        1019 AA.
AC   P14735; B2R721; B7ZAU2; D3DR35; Q5T5N2;
DT   01-APR-1990, integrated into UniProtKB/Swiss-Prot.
DT   25-NOV-2008, sequence version 4.
DT   07-APR-2021, entry version 212.
DE   RecName: Full=Insulin-degrading enzyme {ECO:0000303|PubMed:20364150};
DE            EC=3.4.24.56 {ECO:0000269|PubMed:10684867, ECO:0000269|PubMed:17051221, ECO:0000269|PubMed:21098034, ECO:0000269|PubMed:2293021};
DE   AltName: Full=Abeta-degrading protease;
DE   AltName: Full=Insulin protease {ECO:0000303|PubMed:20364150};
DE            Short=Insulinase {ECO:0000303|PubMed:20364150};
DE   AltName: Full=Insulysin {ECO:0000303|PubMed:20364150};
GN   Name=IDE {ECO:0000303|PubMed:20364150, ECO:0000312|HGNC:HGNC:5381};
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   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 homologies
RT   with E. coli protease III.";
RL   Science 242:1415-1418(1988).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), SEQUENCE REVISION, FUNCTION, AND
RP   CATALYTIC ACTIVITY.
RX   PubMed=2293021; DOI=10.1210/mend-4-8-1125;
RA   Affholter J.A., Hsieh C.L., Francke U., Roth R.A.;
RT   "Insulin-degrading enzyme: stable expression of the human complementary
RT   DNA, characterization of its protein product, and chromosomal mapping of
RT   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., Sudo H.,
RA   Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA   Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA   Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA   Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA   Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA   Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA   Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA   Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA   Aotsuka S., 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., Fujimori Y.,
RA   Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA   Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA   Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA   Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA   Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA   Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA   Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA   Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA   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., Brown J.Y.,
RA   Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P.,
RA   Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N.,
RA   Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A.,
RA   Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C.,
RA   Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D.,
RA   Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C.,
RA   Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K.,
RA   Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A.,
RA   Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S.,
RA   McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S.,
RA   Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V.,
RA   Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A.,
RA   Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA   Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A.,
RA   Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P.,
RA   Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y.,
RA   Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D.,
RA   Durbin R.M., Hubbard T., 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., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., 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 project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [7]
RP   FUNCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
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   [8]
RP   FUNCTION, SUBCELLULAR LOCATION, CATALYTIC ACTIVITY, MUTAGENESIS OF GLU-111,
RP   AND ACTIVE SITE.
RX   PubMed=10684867; DOI=10.1523/jneurosci.20-05-01657.2000;
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   [9]
RP   SUBCELLULAR LOCATION, FUNCTION (MICROBIAL INFECTION), INTERACTION WITH VZV
RP   GLYCOPROTEIN E, AND ACTIVITY REGULATION.
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-zoster
RT   virus infection and cell-to-cell spread.";
RL   Cell 127:305-316(2006).
RN   [10]
RP   FUNCTION (MICROBIAL INFECTION), AND 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   [11]
RP   FUNCTION, AND SUBCELLULAR LOCATION.
RX   PubMed=20364150; DOI=10.1038/ni.1862;
RA   Parmentier N., Stroobant V., Colau D., de Diesbach P., Morel S.,
RA   Chapiro J., van Endert P., Van den Eynde B.J.;
RT   "Production of an antigenic peptide by insulin-degrading enzyme.";
RL   Nat. Immunol. 11:449-454(2010).
RN   [12]
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., Buerckstuemmer T.,
RA   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   [13]
RP   FUNCTION.
RX   PubMed=26968463; DOI=10.1016/j.bbagen.2016.03.010;
RA   Hubin E., Cioffi F., Rozenski J., van Nuland N.A., Broersen K.;
RT   "Characterization of insulin-degrading enzyme-mediated cleavage of Abeta in
RT   distinct aggregation states.";
RL   Biochim. Biophys. Acta 1860:1281-1290(2016).
RN   [14] {ECO:0007744|PDB:2G47, ECO:0007744|PDB:2G48, ECO:0007744|PDB:2G49, ECO:0007744|PDB:2G54, ECO:0007744|PDB:2G56}
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, MUTAGENESIS
RP   OF GLU-111; SER-132; ASN-184; ASP-426; GLU-817; GLN-828 AND LYS-899,
RP   FUNCTION, CATALYTIC ACTIVITY, COFACTOR, ACTIVE SITE, AND SUBUNIT.
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   [15] {ECO:0007744|PDB:2JBU, ECO:0007744|PDB:2JG4}
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, ACTIVITY
RP   REGULATION, ATP-BINDING, SUBUNIT, MUTAGENESIS OF ASP-426 AND LYS-899, AND
RP   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   [16] {ECO:0007744|PDB:3CWW}
RP   X-RAY CRYSTALLOGRAPHY (1.96 ANGSTROMS) OF 42-1019 OF MUTANT GLN-111 IN
RP   COMPLEX WITH BRADYKININ AND ZINC IONS, FUNCTION, CATALYTIC ACTIVITY, AND
RP   ACTIVITY 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).
RN   [17] {ECO:0007744|PDB:2WBY, ECO:0007744|PDB:2WC0}
RP   X-RAY CRYSTALLOGRAPHY (2.60 ANGSTROMS) OF 42-1019 IN COMPLEX WITH INSULIN
RP   AND ZINC, FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, COFACTOR, MUTAGENESIS OF
RP   GLU-111, AND ACTIVE SITE.
RX   PubMed=19321446; DOI=10.1074/jbc.m900068200;
RA   Manolopoulou M., Guo Q., Malito E., Schilling A.B., Tang W.J.;
RT   "Molecular basis of catalytic chamber-assisted unfolding and cleavage of
RT   human insulin by human insulin-degrading enzyme.";
RL   J. Biol. Chem. 284:14177-14188(2009).
RN   [18] {ECO:0007744|PDB:3N56, ECO:0007744|PDB:3N57}
RP   X-RAY CRYSTALLOGRAPHY (3.03 ANGSTROMS) OF 42-1019 IN COMPLEX WITH ZINC,
RP   FUNCTION, CATALYTIC ACTIVITY, COFACTOR, AND MUTAGENESIS OF ARG-767.
RX   PubMed=21098034; DOI=10.1074/jbc.m110.173252;
RA   Ralat L.A., Guo Q., Ren M., Funke T., Dickey D.M., Potter L.R., Tang W.J.;
RT   "Insulin-degrading enzyme modulates the natriuretic peptide-mediated
RT   signaling response.";
RL   J. Biol. Chem. 286:4670-4679(2011).
RN   [19] {ECO:0007744|PDB:4IOF}
RP   X-RAY CRYSTALLOGRAPHY (3.35 ANGSTROMS) OF 42-1019 IN COMPLEX WITH ZINC,
RP   FUNCTION, CATALYTIC ACTIVITY, COFACTOR, SUBUNIT, MUTAGENESIS OF PRO-286;
RP   366-GLY--GLY-369; TYR-496; PHE-530 AND ARG-767, AND ACTIVE SITE.
RX   PubMed=23922390; DOI=10.1073/pnas.1304575110;
RA   McCord L.A., Liang W.G., Dowdell E., Kalas V., Hoey R.J., Koide A.,
RA   Koide S., Tang W.J.;
RT   "Conformational states and recognition of amyloidogenic peptides of human
RT   insulin-degrading enzyme.";
RL   Proc. Natl. Acad. Sci. U.S.A. 110:13827-13832(2013).
RN   [20] {ECO:0007744|PDB:4LTE}
RP   X-RAY CRYSTALLOGRAPHY (2.71 ANGSTROMS) OF 42-1019 IN COMPLEX WITH ZINC,
RP   CATALYTIC ACTIVITY, AND FUNCTION.
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   [21] {ECO:0007744|PDB:4IFH, ECO:0007744|PDB:4NXO, ECO:0007744|PDB:4RE9}
RP   X-RAY CRYSTALLOGRAPHY (2.73 ANGSTROMS) OF 42-1019 IN COMPLEX WITH ZINC AND
RP   SYNTHETIC INHIBITOR, FUNCTION, CATALYTIC ACTIVITY, COFACTOR, AND SUBUNIT.
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).
RN   [22] {ECO:0007744|PDB:6B3Q, ECO:0007744|PDB:6B70, ECO:0007744|PDB:6B7Y, ECO:0007744|PDB:6B7Z, ECO:0007744|PDB:6BF6, ECO:0007744|PDB:6BF7, ECO:0007744|PDB:6BF8, ECO:0007744|PDB:6BF9, ECO:0007744|PDB:6BFC}
RP   STRUCTURE BY ELECTRON MICROSCOPY (3.70 ANGSTROMS) OF 42-1019 IN COMPLEX
RP   WITH INSULIN, FUNCTION, SUBUNIT, AND CATALYTIC ACTIVITY.
RX   PubMed=29596046; DOI=10.7554/elife.33572;
RA   Zhang Z., Liang W.G., Bailey L.J., Tan Y.Z., Wei H., Wang A., Farcasanu M.,
RA   Woods V.A., McCord L.A., Lee D., Shang W., Deprez-Poulain R., Deprez B.,
RA   Liu D.R., Koide A., Koide S., Kossiakoff A.A., Li S., Carragher B.,
RA   Potter C.S., Tang W.J.;
RT   "Ensemble cryoEM elucidates the mechanism of insulin capture and
RT   degradation by human insulin degrading enzyme.";
RL   Elife 7:0-0(2018).
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:2293021, PubMed:10684867, PubMed:26968463,
CC       PubMed:17051221, PubMed:17613531, PubMed:18986166, PubMed:19321446,
CC       PubMed:23922390, PubMed:24847884, PubMed:26394692, PubMed:29596046,
CC       PubMed:21098034). Substrate binding induces important conformation
CC       changes, making it possible to bind and degrade larger substrates, such
CC       as insulin (PubMed:23922390, PubMed:26394692, PubMed:29596046).
CC       Contributes to the regulation of peptide hormone signaling cascades and
CC       regulation of blood glucose homeostasis via its role in the degradation
CC       of insulin, glucagon and IAPP (By similarity). Plays a role in the
CC       degradation and clearance of APP-derived amyloidogenic peptides that
CC       are secreted by neurons and microglia (PubMed:9830016, PubMed:26394692)
CC       (Probable). Degrades the natriuretic peptides ANP, BNP and CNP,
CC       inactivating their ability to raise intracellular cGMP
CC       (PubMed:21098034). Also degrades an aberrant frameshifted 40-residue
CC       form of NPPA (fsNPPA) which is associated with familial atrial
CC       fibrillation in heterozygous patients (PubMed:21098034). Involved in
CC       antigen processing. Produces both the N terminus and the C terminus of
CC       MAGEA3-derived antigenic peptide (EVDPIGHLY) that is presented to
CC       cytotoxic T lymphocytes by MHC class I. {ECO:0000250|UniProtKB:Q9JHR7,
CC       ECO:0000269|PubMed:10684867, ECO:0000269|PubMed:17051221,
CC       ECO:0000269|PubMed:17613531, ECO:0000269|PubMed:18986166,
CC       ECO:0000269|PubMed:19321446, ECO:0000269|PubMed:20364150,
CC       ECO:0000269|PubMed:21098034, ECO:0000269|PubMed:2293021,
CC       ECO:0000269|PubMed:23922390, ECO:0000269|PubMed:24847884,
CC       ECO:0000269|PubMed:26394692, ECO:0000269|PubMed:26968463,
CC       ECO:0000269|PubMed:29596046, ECO:0000269|PubMed:9830016,
CC       ECO:0000305|PubMed:23922390}.
CC   -!- FUNCTION: (Microbial infection) The membrane-associated isoform acts as
CC       an entry receptor for varicella-zoster virus (VZV).
CC       {ECO:0000269|PubMed:17055432, ECO:0000269|PubMed:17553876}.
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:10684867, ECO:0000269|PubMed:17051221,
CC         ECO:0000269|PubMed:17613531, ECO:0000269|PubMed:18986166,
CC         ECO:0000269|PubMed:19321446, ECO:0000269|PubMed:21098034,
CC         ECO:0000269|PubMed:2293021, ECO:0000269|PubMed:23922390,
CC         ECO:0000269|PubMed:24847884, ECO:0000269|PubMed:26394692,
CC         ECO:0000269|PubMed:29596046};
CC   -!- COFACTOR:
CC       Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC         Evidence={ECO:0000269|PubMed:17051221, ECO:0000269|PubMed:18986166,
CC         ECO:0000269|PubMed:19321446, ECO:0000269|PubMed:21098034,
CC         ECO:0000269|PubMed:23922390, ECO:0000269|PubMed:26394692};
CC       Note=Binds 1 zinc ion per subunit. {ECO:0000269|PubMed:17051221,
CC       ECO:0000269|PubMed:18986166, ECO:0000269|PubMed:19321446,
CC       ECO:0000269|PubMed:21098034, ECO:0000269|PubMed:23922390,
CC       ECO:0000269|PubMed:26394692};
CC   -!- ACTIVITY REGULATION: Activated by small peptides (By similarity).
CC       Activated by ATP and GTP, and to a lesser extent by CTP, TTP and PPPi
CC       (PubMed:17613531). Inhibited by bacitracin (PubMed:17055432,
CC       PubMed:17613531). In vitro modification of Cys residues impairs enzyme
CC       activity (PubMed:18986166). {ECO:0000250, ECO:0000269|PubMed:17055432,
CC       ECO:0000269|PubMed:17613531, ECO:0000269|PubMed:18986166}.
CC   -!- SUBUNIT: Homodimer (PubMed:17051221, PubMed:19321446, PubMed:23922390,
CC       PubMed:26394692, PubMed:29596046) (Probable). Can also form
CC       homotetramers (By similarity). {ECO:0000250|UniProtKB:P35559,
CC       ECO:0000269|PubMed:17051221, ECO:0000269|PubMed:19321446,
CC       ECO:0000269|PubMed:23922390, ECO:0000269|PubMed:26394692,
CC       ECO:0000269|PubMed:29596046, ECO:0000305|PubMed:17613531}.
CC   -!- SUBUNIT: (Microbial infection) Interacts (via N-terminus) with
CC       varicella-zoster virus (VZV) envelope glycoprotein E (via N-terminus);
CC       the membrane-associated isoform may function as an entry receptor for
CC       this virus (PubMed:17055432, PubMed:17553876).
CC       {ECO:0000269|PubMed:17055432, ECO:0000269|PubMed:17553876}.
CC   -!- INTERACTION:
CC       P14735; P05067: APP; NbExp=3; IntAct=EBI-2556886, EBI-77613;
CC       P14735; P10147: CCL3; NbExp=3; IntAct=EBI-2556886, EBI-8459634;
CC       P14735-1; PRO_0000000093 [P05067]: APP; NbExp=3; IntAct=EBI-15607031, EBI-2431589;
CC       P14735-1; P01275: GCG; NbExp=3; IntAct=EBI-15607031, EBI-7629173;
CC       P14735-1; P10997: IAPP; NbExp=3; IntAct=EBI-15607031, EBI-8526679;
CC       P14735-1; P14735-1: IDE; NbExp=2; IntAct=EBI-15607031, EBI-15607031;
CC       P14735-1; P01308: INS; NbExp=3; IntAct=EBI-15607031, EBI-7090529;
CC       P14735-1; Q9J3M8: gE; Xeno; NbExp=2; IntAct=EBI-15607031, EBI-2532305;
CC   -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:20364150,
CC       ECO:0000269|PubMed:9830016}. Cell membrane
CC       {ECO:0000250|UniProtKB:P35559}. Secreted {ECO:0000269|PubMed:9830016}.
CC       Note=Present at the cell surface of neuron cells. The membrane-
CC       associated isoform is approximately 5 kDa larger than the known
CC       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   -!- TISSUE SPECIFICITY: Detected in brain and in cerebrospinal fluid (at
CC       protein level). {ECO:0000269|PubMed:9830016}.
CC   -!- DOMAIN: The SlyX motif may be involved in the non-conventional
CC       secretion of the protein. {ECO:0000250|UniProtKB:Q9JHR7}.
CC   -!- PTM: The N-terminus is blocked.
CC   -!- MISCELLANEOUS: ATP-binding induces a conformation change.
CC       {ECO:0000269|PubMed:17613531}.
CC   -!- SIMILARITY: Belongs to the peptidase M16 family. {ECO:0000305}.
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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; -; NOT_ANNOTATED_CDS; 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   CCDS; CCDS53554.1; -. [P14735-2]
DR   CCDS; CCDS7421.1; -. [P14735-1]
DR   PIR; A40119; SNHUIN.
DR   RefSeq; NP_001159418.1; NM_001165946.1. [P14735-2]
DR   RefSeq; NP_004960.2; NM_004969.3. [P14735-1]
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=43-1019.
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; 4GSF; X-ray; 2.70 A; A/B=42-1019.
DR   PDB; 4IFH; X-ray; 3.29 A; A/B=42-1019.
DR   PDB; 4IOF; X-ray; 3.35 A; A/B=42-1019.
DR   PDB; 4LTE; X-ray; 2.70 A; A/B=42-1019.
DR   PDB; 4M1C; X-ray; 3.50 A; A/B=42-1019.
DR   PDB; 4NXO; X-ray; 2.73 A; A/B=42-1019.
DR   PDB; 4PES; X-ray; 2.21 A; A/B=42-1019.
DR   PDB; 4PF7; X-ray; 2.33 A; A/B=42-1019.
DR   PDB; 4PF9; X-ray; 2.50 A; A/B=42-1019.
DR   PDB; 4PFC; X-ray; 2.21 A; A/B=42-1019.
DR   PDB; 4QIA; X-ray; 3.20 A; A/B=42-1019.
DR   PDB; 4RAL; X-ray; 3.15 A; A/B=42-1019.
DR   PDB; 4RE9; X-ray; 2.91 A; A/B=42-1019.
DR   PDB; 5CJO; X-ray; 3.29 A; A=42-1019.
DR   PDB; 5UOE; X-ray; 3.80 A; A/B/C/D/E=42-1019.
DR   PDB; 5WOB; X-ray; 3.95 A; A/B/C/D/E/F/G/H=42-1019.
DR   PDB; 6B3Q; EM; 3.70 A; A/B=42-1019.
DR   PDB; 6B70; EM; 3.70 A; A/B=46-1011.
DR   PDB; 6B7Y; EM; 6.50 A; A/B=46-1011.
DR   PDB; 6B7Z; EM; 6.50 A; A/B=46-1011.
DR   PDB; 6BF6; EM; 6.50 A; A/B=46-1011.
DR   PDB; 6BF7; EM; 6.50 A; A/B=46-1011.
DR   PDB; 6BF8; EM; 4.20 A; A/B=46-1011.
DR   PDB; 6BF9; EM; 7.20 A; A/B=46-1011.
DR   PDB; 6BFC; EM; 3.70 A; A/B=46-1011.
DR   PDB; 6BYZ; X-ray; 2.96 A; A/B=1-1019.
DR   PDB; 6EDS; X-ray; 3.18 A; A/B=42-1019.
DR   PDB; 6MQ3; X-ray; 3.57 A; A/B=42-1019.
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; 4GSF; -.
DR   PDBsum; 4IFH; -.
DR   PDBsum; 4IOF; -.
DR   PDBsum; 4LTE; -.
DR   PDBsum; 4M1C; -.
DR   PDBsum; 4NXO; -.
DR   PDBsum; 4PES; -.
DR   PDBsum; 4PF7; -.
DR   PDBsum; 4PF9; -.
DR   PDBsum; 4PFC; -.
DR   PDBsum; 4QIA; -.
DR   PDBsum; 4RAL; -.
DR   PDBsum; 4RE9; -.
DR   PDBsum; 5CJO; -.
DR   PDBsum; 5UOE; -.
DR   PDBsum; 5WOB; -.
DR   PDBsum; 6B3Q; -.
DR   PDBsum; 6B70; -.
DR   PDBsum; 6B7Y; -.
DR   PDBsum; 6B7Z; -.
DR   PDBsum; 6BF6; -.
DR   PDBsum; 6BF7; -.
DR   PDBsum; 6BF8; -.
DR   PDBsum; 6BF9; -.
DR   PDBsum; 6BFC; -.
DR   PDBsum; 6BYZ; -.
DR   PDBsum; 6EDS; -.
DR   PDBsum; 6MQ3; -.
DR   SMR; P14735; -.
DR   BioGRID; 109642; 111.
DR   DIP; DIP-55771N; -.
DR   IntAct; P14735; 68.
DR   MINT; P14735; -.
DR   STRING; 9606.ENSP00000265986; -.
DR   BindingDB; P14735; -.
DR   ChEMBL; CHEMBL1293287; -.
DR   DrugBank; DB00626; Bacitracin.
DR   DrugBank; DB00030; Insulin human.
DR   DrugBank; DB00071; Insulin pork.
DR   DrugBank; DB14487; Zinc acetate.
DR   DrugBank; DB14533; Zinc chloride.
DR   DrugBank; DB14548; Zinc sulfate, unspecified form.
DR   DrugCentral; P14735; -.
DR   GuidetoPHARMACOLOGY; 2371; -.
DR   MEROPS; M16.002; -.
DR   iPTMnet; P14735; -.
DR   MetOSite; P14735; -.
DR   PhosphoSitePlus; P14735; -.
DR   BioMuta; IDE; -.
DR   DMDM; 215274252; -.
DR   EPD; P14735; -.
DR   jPOST; P14735; -.
DR   MassIVE; P14735; -.
DR   MaxQB; P14735; -.
DR   PaxDb; P14735; -.
DR   PeptideAtlas; P14735; -.
DR   PRIDE; P14735; -.
DR   ProteomicsDB; 53079; -. [P14735-1]
DR   ProteomicsDB; 7086; -.
DR   ABCD; P14735; 3 sequenced antibodies.
DR   Antibodypedia; 3227; 505 antibodies.
DR   Ensembl; ENST00000265986; ENSP00000265986; ENSG00000119912. [P14735-1]
DR   Ensembl; ENST00000371581; ENSP00000360637; ENSG00000119912. [P14735-2]
DR   GeneID; 3416; -.
DR   KEGG; hsa:3416; -.
DR   UCSC; uc001kia.4; human. [P14735-1]
DR   CTD; 3416; -.
DR   DisGeNET; 3416; -.
DR   GeneCards; IDE; -.
DR   HGNC; HGNC:5381; IDE.
DR   HPA; ENSG00000119912; Low tissue specificity.
DR   MIM; 146680; gene.
DR   neXtProt; NX_P14735; -.
DR   OpenTargets; ENSG00000119912; -.
DR   PharmGKB; PA29629; -.
DR   VEuPathDB; HostDB:ENSG00000119912.15; -.
DR   eggNOG; KOG0959; Eukaryota.
DR   GeneTree; ENSGT00940000155780; -.
DR   HOGENOM; CLU_004639_1_1_1; -.
DR   InParanoid; P14735; -.
DR   OMA; HGNLYKE; -.
DR   OrthoDB; 1008844at2759; -.
DR   PhylomeDB; P14735; -.
DR   TreeFam; TF106275; -.
DR   BRENDA; 3.4.24.56; 2681.
DR   PathwayCommons; P14735; -.
DR   Reactome; R-HSA-5689880; Ub-specific processing proteases.
DR   Reactome; R-HSA-9033241; Peroxisomal protein import.
DR   SignaLink; P14735; -.
DR   SIGNOR; P14735; -.
DR   BioGRID-ORCS; 3416; 6 hits in 1005 CRISPR screens.
DR   ChiTaRS; IDE; human.
DR   EvolutionaryTrace; P14735; -.
DR   GeneWiki; Insulin-degrading_enzyme; -.
DR   GenomeRNAi; 3416; -.
DR   Pharos; P14735; Tchem.
DR   PRO; PR:P14735; -.
DR   Proteomes; UP000005640; Chromosome 10.
DR   RNAct; P14735; protein.
DR   Bgee; ENSG00000119912; Expressed in hair follicle and 231 other tissues.
DR   ExpressionAtlas; P14735; baseline and differential.
DR   Genevisible; P14735; HS.
DR   GO; GO:0016323; C:basolateral plasma membrane; IMP:ARUK-UCL.
DR   GO; GO:0009986; C:cell surface; IDA:UniProtKB.
DR   GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR   GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR   GO; GO:0031597; C:cytosolic proteasome complex; IEA:Ensembl.
DR   GO; GO:0009897; C:external side of plasma membrane; IDA:ARUK-UCL.
DR   GO; GO:0070062; C:extracellular exosome; ISS:ARUK-UCL.
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; IBA:GO_Central.
DR   GO; GO:0005777; C:peroxisome; IDA:UniProtKB.
DR   GO; GO:0001540; F:amyloid-beta binding; IEA:Ensembl.
DR   GO; GO:0005524; F:ATP binding; IDA:UniProtKB.
DR   GO; GO:0016887; F:ATPase activity; IEA:Ensembl.
DR   GO; GO:0031626; F:beta-endorphin binding; IEA:Ensembl.
DR   GO; GO:0004175; F:endopeptidase activity; IDA:UniProtKB.
DR   GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR   GO; GO:0043559; F:insulin binding; IDA:UniProtKB.
DR   GO; GO:0004222; F:metalloendopeptidase activity; IDA:UniProtKB.
DR   GO; GO:0042277; F:peptide binding; IPI:UniProtKB.
DR   GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR   GO; GO:0044877; F:protein-containing complex binding; IEA:Ensembl.
DR   GO; GO:0140036; F:ubiquitin-dependent protein binding; IPI:UniProtKB.
DR   GO; GO:0001618; F:virus receptor activity; IEA:UniProtKB-KW.
DR   GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB.
DR   GO; GO:0097242; P:amyloid-beta clearance; IMP:ARUK-UCL.
DR   GO; GO:0150094; P:amyloid-beta clearance by cellular catabolic process; IMP:ARUK-UCL.
DR   GO; GO:0050435; P:amyloid-beta metabolic process; IDA:UniProtKB.
DR   GO; GO:0019885; P:antigen processing and presentation of endogenous peptide antigen via MHC class I; IMP:UniProtKB.
DR   GO; GO:0010815; P:bradykinin catabolic process; IDA:UniProtKB.
DR   GO; GO:0044257; P:cellular protein catabolic process; IMP:UniProtKB.
DR   GO; GO:0008340; P:determination of adult lifespan; IDA:UniProtKB.
DR   GO; GO:0042447; P:hormone catabolic process; IDA:UniProtKB.
DR   GO; GO:1901143; P:insulin catabolic process; IDA:UniProtKB.
DR   GO; GO:1901142; P:insulin metabolic process; IDA:UniProtKB.
DR   GO; GO:0008286; P:insulin receptor signaling pathway; NAS:UniProtKB.
DR   GO; GO:0045861; P:negative regulation of proteolysis; IEA:Ensembl.
DR   GO; GO:0043171; P:peptide catabolic process; IDA:UniProtKB.
DR   GO; GO:0032092; P:positive regulation of protein binding; IDA:UniProtKB.
DR   GO; GO:0045732; P:positive regulation of protein catabolic process; TAS:ARUK-UCL.
DR   GO; GO:0030163; P:protein catabolic process; ISS:ARUK-UCL.
DR   GO; GO:0008104; P:protein localization; TAS:Reactome.
DR   GO; GO:0006508; P:proteolysis; IDA:UniProtKB.
DR   GO; GO:0051603; P:proteolysis involved in cellular protein catabolic process; IDA:UniProtKB.
DR   GO; GO:1903715; P:regulation of aerobic respiration; IGI:ARUK-UCL.
DR   GO; GO:0010992; P:ubiquitin recycling; IDA:UniProtKB.
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   3D-structure; Allosteric enzyme; Alternative splicing; ATP-binding;
KW   Cell membrane; Cytoplasm; Direct protein sequencing;
KW   Host cell receptor for virus entry; Host-virus interaction; Hydrolase;
KW   Membrane; Metal-binding; Metalloprotease; Nucleotide-binding; Protease;
KW   Receptor; Reference proteome; Secreted; Zinc.
FT   CHAIN           1..1019
FT                   /note="Insulin-degrading enzyme"
FT                   /id="PRO_0000074404"
FT   NP_BIND         895..901
FT                   /note="ATP"
FT                   /evidence="ECO:0000250|UniProtKB:P35559"
FT   REGION          336..342
FT                   /note="Substrate binding exosite"
FT   REGION          359..363
FT                   /note="Substrate binding"
FT                   /evidence="ECO:0000269|PubMed:18986166"
FT   MOTIF           853..858
FT                   /note="SlyX motif"
FT                   /evidence="ECO:0000250|UniProtKB:Q9JHR7"
FT   ACT_SITE        111
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10096,
FT                   ECO:0000305|PubMed:10684867, ECO:0000305|PubMed:17051221,
FT                   ECO:0000305|PubMed:19321446, ECO:0000305|PubMed:23922390"
FT   METAL           108
FT                   /note="Zinc"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10096,
FT                   ECO:0000269|PubMed:17051221, ECO:0000269|PubMed:17613531,
FT                   ECO:0000269|PubMed:18986166, ECO:0000269|PubMed:19321446,
FT                   ECO:0007744|PDB:2G54, ECO:0007744|PDB:2JG4,
FT                   ECO:0007744|PDB:3CWW, ECO:0007744|PDB:3N56,
FT                   ECO:0007744|PDB:3N57"
FT   METAL           112
FT                   /note="Zinc"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10096,
FT                   ECO:0000269|PubMed:17051221, ECO:0000269|PubMed:17613531,
FT                   ECO:0000269|PubMed:18986166, ECO:0000269|PubMed:19321446,
FT                   ECO:0007744|PDB:2G54, ECO:0007744|PDB:2JG4,
FT                   ECO:0007744|PDB:3CWW, ECO:0007744|PDB:3N56,
FT                   ECO:0007744|PDB:3N57"
FT   METAL           189
FT                   /note="Zinc"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10096,
FT                   ECO:0000269|PubMed:17051221, ECO:0000269|PubMed:17613531,
FT                   ECO:0000269|PubMed:18986166, ECO:0000269|PubMed:19321446,
FT                   ECO:0007744|PDB:2G54, ECO:0007744|PDB:2JG4,
FT                   ECO:0007744|PDB:3CWW, ECO:0007744|PDB:3N56,
FT                   ECO:0007744|PDB:3N57"
FT   BINDING         429
FT                   /note="ATP"
FT                   /evidence="ECO:0000250|UniProtKB:P35559"
FT   MOD_RES         192
FT                   /note="N6-succinyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9JHR7"
FT   MOD_RES         697
FT                   /note="N6-succinyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9JHR7"
FT   VAR_SEQ         1..555
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:14702039"
FT                   /id="VSP_044303"
FT   MUTAGEN         111
FT                   /note="E->Q: Loss of catalytic activity."
FT                   /evidence="ECO:0000269|PubMed:10684867,
FT                   ECO:0000269|PubMed:17051221, ECO:0000269|PubMed:18986166,
FT                   ECO:0000269|PubMed:19321446"
FT   MUTAGEN         132
FT                   /note="S->C: Increases catalytic rate towards INS and
FT                   amyloid; when associated with C-817."
FT                   /evidence="ECO:0000269|PubMed:17051221"
FT   MUTAGEN         184
FT                   /note="N->C: Increases catalytic rate towards INS and
FT                   amyloid; when associated with C-828."
FT                   /evidence="ECO:0000269|PubMed:17051221"
FT   MUTAGEN         286
FT                   /note="P->G: Reduced enzyme activity."
FT                   /evidence="ECO:0000269|PubMed:23922390"
FT   MUTAGEN         366..369
FT                   /note="GARG->AARA: Reduced enzyme activity."
FT                   /evidence="ECO:0000269|PubMed:23922390"
FT   MUTAGEN         426
FT                   /note="D->C: Increases catalytic rate towards INS and
FT                   amyloid; when associated with C-899."
FT                   /evidence="ECO:0000269|PubMed:17051221,
FT                   ECO:0000269|PubMed:17613531"
FT   MUTAGEN         496
FT                   /note="Y->A: Strongly reduced enzyme activity."
FT                   /evidence="ECO:0000269|PubMed:23922390"
FT   MUTAGEN         530
FT                   /note="F->A: Strongly increased enzyme activity."
FT                   /evidence="ECO:0000269|PubMed:23922390"
FT   MUTAGEN         767
FT                   /note="R->A: Decreases dimerization. No effect on
FT                   degradation of ANP. Retains the ability to degrade an
FT                   aberrant form of ANP, when in the presence of both ANP and
FT                   the aberrant ANP."
FT                   /evidence="ECO:0000269|PubMed:23922390"
FT   MUTAGEN         817
FT                   /note="E->C: Increases catalytic rate towards INS and
FT                   amyloid; when associated with C-132."
FT                   /evidence="ECO:0000269|PubMed:17051221"
FT   MUTAGEN         828
FT                   /note="Q->C: Increases catalytic rate towards INS and
FT                   amyloid; when associated with C-184."
FT                   /evidence="ECO:0000269|PubMed:17051221"
FT   MUTAGEN         831
FT                   /note="Y->F: No effect on catalytic activity."
FT   MUTAGEN         899
FT                   /note="K->C: Increases catalytic rate towards INS and
FT                   amyloid; when associated with C-426."
FT                   /evidence="ECO:0000269|PubMed:17051221,
FT                   ECO:0000269|PubMed:17613531"
FT   CONFLICT        78
FT                   /note="I -> M (in Ref. 2; AAA52712)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        472
FT                   /note="R -> G (in Ref. 3; BAG35668)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        555
FT                   /note="A -> V (in Ref. 2; AAA52712)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        567..569
FT                   /note="FFL -> KKK (in Ref. 2; AAA52712)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        586
FT                   /note="D -> G (in Ref. 3; BAG35668)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        845
FT                   /note="G -> S (in Ref. 2; AAA52712)"
FT                   /evidence="ECO:0000305"
FT   STRAND          47..50
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   STRAND          63..69
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   STRAND          74..79
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   STRAND          84..93
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   HELIX           96..98
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   STRAND          101..103
FT                   /evidence="ECO:0007744|PDB:4IFH"
FT   HELIX           106..113
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   HELIX           114..116
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   STRAND          118..121
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   HELIX           126..132
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   TURN            133..135
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   STRAND          137..142
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   STRAND          147..154
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   HELIX           155..157
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   HELIX           158..166
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   HELIX           167..169
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   HELIX           176..194
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   HELIX           197..207
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   HELIX           214..216
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   HELIX           223..226
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   HELIX           228..232
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   HELIX           237..248
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   HELIX           251..253
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   STRAND          254..262
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   HELIX           264..275
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   STRAND          276..278
FT                   /evidence="ECO:0007744|PDB:4PF9"
FT   HELIX           295..297
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   STRAND          298..304
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   STRAND          307..309
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   STRAND          312..319
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   HELIX           323..325
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   TURN            326..328
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   HELIX           330..338
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   HELIX           346..352
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   STRAND          359..367
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   STRAND          370..378
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   HELIX           381..385
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   HELIX           387..404
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   HELIX           408..423
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   HELIX           430..440
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   TURN            441..443
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   HELIX           446..448
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   TURN            449..454
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   HELIX           461..468
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   HELIX           473..475
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   STRAND          477..481
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   HELIX           483..485
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   TURN            486..488
FT                   /evidence="ECO:0007744|PDB:2G48"
FT   TURN            494..496
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   STRAND          499..504
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   HELIX           507..514
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   STRAND          549..553
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   STRAND          555..563
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   STRAND          565..567
FT                   /evidence="ECO:0007744|PDB:2G54"
FT   STRAND          570..579
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   HELIX           581..583
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   STRAND          584..586
FT                   /evidence="ECO:0007744|PDB:4PES"
FT   HELIX           587..613
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   STRAND          616..623
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   STRAND          626..635
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   HELIX           638..650
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   HELIX           656..672
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   HELIX           673..675
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   HELIX           678..690
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   STRAND          691..693
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   HELIX           697..704
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   HELIX           709..721
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   STRAND          722..732
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   HELIX           735..753
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   HELIX           760..762
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   STRAND          775..782
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   STRAND          787..799
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   HELIX           802..823
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   TURN            824..827
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   STRAND          831..840
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   STRAND          843..854
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   HELIX           856..876
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   HELIX           879..894
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   HELIX           900..912
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   HELIX           920..928
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   HELIX           933..943
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   STRAND          952..959
FT                   /evidence="ECO:0007744|PDB:3CWW"
FT   STRAND          990..992
FT                   /evidence="ECO:0007744|PDB:4PF9"
FT   HELIX           995..1000
FT                   /evidence="ECO:0007744|PDB:3CWW"
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
//
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