IDE_HUMAN
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 03-AUG-2022, entry version 217.
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 PDB; 7K1D; X-ray; 3.00 A; A/B=42-1019.
DR PDB; 7K1E; X-ray; 2.80 A; A/B=42-1019.
DR PDB; 7K1F; X-ray; 2.60 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 PDBsum; 7K1D; -.
DR PDBsum; 7K1E; -.
DR PDBsum; 7K1F; -.
DR AlphaFoldDB; P14735; -.
DR SMR; P14735; -.
DR BioGRID; 109642; 175.
DR DIP; DIP-55771N; -.
DR IntAct; P14735; 74.
DR MINT; P14735; -.
DR STRING; 9606.ENSP00000265986; -.
DR BindingDB; P14735; -.
DR ChEMBL; CHEMBL1293287; -.
DR DrugBank; DB00626; Bacitracin.
DR DrugBank; DB09456; Insulin beef.
DR DrugBank; DB00030; Insulin human.
DR DrugBank; DB00046; Insulin lispro.
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 MEROPS; M16.982; -.
DR MEROPS; M16.984; -.
DR GlyGen; P14735; 1 site, 1 O-linked glycan (1 site).
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; 522 antibodies from 46 providers.
DR DNASU; 3416; -.
DR Ensembl; ENST00000265986.11; ENSP00000265986.6; ENSG00000119912.18. [P14735-1]
DR Ensembl; ENST00000371581.9; ENSP00000360637.5; ENSG00000119912.18. [P14735-2]
DR GeneID; 3416; -.
DR KEGG; hsa:3416; -.
DR MANE-Select; ENST00000265986.11; ENSP00000265986.6; NM_004969.4; NP_004960.2.
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; -.
DR eggNOG; KOG0959; Eukaryota.
DR GeneTree; ENSGT00940000155780; -.
DR HOGENOM; CLU_004639_1_1_1; -.
DR InParanoid; P14735; -.
DR OMA; WIFDEMK; -.
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; 13 hits in 1090 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 upper leg skin and 202 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: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:0005524; F:ATP binding; IDA:UniProtKB.
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: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: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: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; IMP:UniProtKB.
DR GO; GO:0006508; P:proteolysis; IDA:UniProtKB.
DR GO; GO:0051603; P:proteolysis involved in 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 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 BINDING 108
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
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 112
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
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 189
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
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 336..342
FT /ligand="substrate"
FT /note="in the exosite"
FT BINDING 359..363
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:18986166"
FT BINDING 429
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P35559"
FT BINDING 895..901
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P35559"
FT MOD_RES 192
FT /note="N6-succinyllysine"
FT /evidence="ECO: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:0007829|PDB:3CWW"
FT STRAND 63..69
FT /evidence="ECO:0007829|PDB:3CWW"
FT STRAND 74..79
FT /evidence="ECO:0007829|PDB:3CWW"
FT STRAND 84..93
FT /evidence="ECO:0007829|PDB:3CWW"
FT HELIX 96..98
FT /evidence="ECO:0007829|PDB:3CWW"
FT STRAND 101..103
FT /evidence="ECO:0007829|PDB:4IFH"
FT HELIX 106..113
FT /evidence="ECO:0007829|PDB:3CWW"
FT HELIX 114..116
FT /evidence="ECO:0007829|PDB:3CWW"
FT STRAND 118..121
FT /evidence="ECO:0007829|PDB:3CWW"
FT HELIX 126..132
FT /evidence="ECO:0007829|PDB:3CWW"
FT TURN 133..135
FT /evidence="ECO:0007829|PDB:3CWW"
FT STRAND 137..142
FT /evidence="ECO:0007829|PDB:3CWW"
FT STRAND 147..154
FT /evidence="ECO:0007829|PDB:3CWW"
FT HELIX 155..157
FT /evidence="ECO:0007829|PDB:3CWW"
FT HELIX 158..166
FT /evidence="ECO:0007829|PDB:3CWW"
FT HELIX 167..169
FT /evidence="ECO:0007829|PDB:3CWW"
FT HELIX 176..194
FT /evidence="ECO:0007829|PDB:3CWW"
FT HELIX 197..207
FT /evidence="ECO:0007829|PDB:3CWW"
FT HELIX 214..216
FT /evidence="ECO:0007829|PDB:3CWW"
FT HELIX 223..226
FT /evidence="ECO:0007829|PDB:3CWW"
FT HELIX 228..232
FT /evidence="ECO:0007829|PDB:3CWW"
FT HELIX 237..248
FT /evidence="ECO:0007829|PDB:3CWW"
FT HELIX 251..253
FT /evidence="ECO:0007829|PDB:3CWW"
FT STRAND 254..262
FT /evidence="ECO:0007829|PDB:3CWW"
FT HELIX 264..275
FT /evidence="ECO:0007829|PDB:3CWW"
FT STRAND 276..278
FT /evidence="ECO:0007829|PDB:4PF9"
FT HELIX 295..297
FT /evidence="ECO:0007829|PDB:3CWW"
FT STRAND 298..304
FT /evidence="ECO:0007829|PDB:3CWW"
FT STRAND 307..309
FT /evidence="ECO:0007829|PDB:3CWW"
FT STRAND 312..319
FT /evidence="ECO:0007829|PDB:3CWW"
FT HELIX 323..325
FT /evidence="ECO:0007829|PDB:3CWW"
FT TURN 326..328
FT /evidence="ECO:0007829|PDB:3CWW"
FT HELIX 330..338
FT /evidence="ECO:0007829|PDB:3CWW"
FT HELIX 346..352
FT /evidence="ECO:0007829|PDB:3CWW"
FT STRAND 359..367
FT /evidence="ECO:0007829|PDB:3CWW"
FT STRAND 370..378
FT /evidence="ECO:0007829|PDB:3CWW"
FT HELIX 381..385
FT /evidence="ECO:0007829|PDB:3CWW"
FT HELIX 387..404
FT /evidence="ECO:0007829|PDB:3CWW"
FT HELIX 408..423
FT /evidence="ECO:0007829|PDB:3CWW"
FT HELIX 430..440
FT /evidence="ECO:0007829|PDB:3CWW"
FT TURN 441..443
FT /evidence="ECO:0007829|PDB:3CWW"
FT HELIX 446..448
FT /evidence="ECO:0007829|PDB:3CWW"
FT TURN 449..454
FT /evidence="ECO:0007829|PDB:3CWW"
FT HELIX 461..468
FT /evidence="ECO:0007829|PDB:3CWW"
FT HELIX 473..475
FT /evidence="ECO:0007829|PDB:3CWW"
FT STRAND 477..481
FT /evidence="ECO:0007829|PDB:3CWW"
FT HELIX 483..485
FT /evidence="ECO:0007829|PDB:3CWW"
FT TURN 486..488
FT /evidence="ECO:0007829|PDB:2G48"
FT TURN 494..496
FT /evidence="ECO:0007829|PDB:3CWW"
FT STRAND 499..504
FT /evidence="ECO:0007829|PDB:3CWW"
FT HELIX 507..514
FT /evidence="ECO:0007829|PDB:3CWW"
FT STRAND 549..553
FT /evidence="ECO:0007829|PDB:3CWW"
FT STRAND 555..563
FT /evidence="ECO:0007829|PDB:3CWW"
FT STRAND 565..567
FT /evidence="ECO:0007829|PDB:2G54"
FT STRAND 570..579
FT /evidence="ECO:0007829|PDB:3CWW"
FT HELIX 581..583
FT /evidence="ECO:0007829|PDB:3CWW"
FT STRAND 584..586
FT /evidence="ECO:0007829|PDB:4PES"
FT HELIX 587..613
FT /evidence="ECO:0007829|PDB:3CWW"
FT STRAND 616..623
FT /evidence="ECO:0007829|PDB:3CWW"
FT STRAND 626..635
FT /evidence="ECO:0007829|PDB:3CWW"
FT HELIX 638..650
FT /evidence="ECO:0007829|PDB:3CWW"
FT HELIX 656..672
FT /evidence="ECO:0007829|PDB:3CWW"
FT HELIX 673..675
FT /evidence="ECO:0007829|PDB:3CWW"
FT HELIX 678..690
FT /evidence="ECO:0007829|PDB:3CWW"
FT STRAND 691..693
FT /evidence="ECO:0007829|PDB:3CWW"
FT HELIX 697..704
FT /evidence="ECO:0007829|PDB:3CWW"
FT HELIX 709..721
FT /evidence="ECO:0007829|PDB:3CWW"
FT STRAND 722..732
FT /evidence="ECO:0007829|PDB:3CWW"
FT HELIX 735..753
FT /evidence="ECO:0007829|PDB:3CWW"
FT HELIX 760..762
FT /evidence="ECO:0007829|PDB:3CWW"
FT STRAND 775..782
FT /evidence="ECO:0007829|PDB:3CWW"
FT STRAND 787..799
FT /evidence="ECO:0007829|PDB:3CWW"
FT HELIX 802..823
FT /evidence="ECO:0007829|PDB:3CWW"
FT TURN 824..827
FT /evidence="ECO:0007829|PDB:3CWW"
FT STRAND 831..840
FT /evidence="ECO:0007829|PDB:3CWW"
FT STRAND 843..854
FT /evidence="ECO:0007829|PDB:3CWW"
FT HELIX 856..876
FT /evidence="ECO:0007829|PDB:3CWW"
FT HELIX 879..894
FT /evidence="ECO:0007829|PDB:3CWW"
FT HELIX 900..912
FT /evidence="ECO:0007829|PDB:3CWW"
FT HELIX 920..928
FT /evidence="ECO:0007829|PDB:3CWW"
FT HELIX 933..943
FT /evidence="ECO:0007829|PDB:3CWW"
FT STRAND 952..959
FT /evidence="ECO:0007829|PDB:3CWW"
FT STRAND 990..992
FT /evidence="ECO:0007829|PDB:4PF9"
FT HELIX 995..1000
FT /evidence="ECO:0007829|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
