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 24-JAN-2024, entry version 225. 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}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; 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 PDB; 7RZE; EM; 3.30 A; A/B=1-1011. DR PDB; 7RZF; EM; 3.40 A; A/B=1-1011. DR PDB; 7RZG; EM; 4.10 A; A/B=1-1011. DR PDB; 7RZH; EM; 3.80 A; A/B=1-1011. DR PDB; 7RZI; EM; 3.00 A; A/B=1-1011. 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 PDBsum; 7RZE; -. DR PDBsum; 7RZF; -. DR PDBsum; 7RZG; -. DR PDBsum; 7RZH; -. DR PDBsum; 7RZI; -. DR AlphaFoldDB; P14735; -. DR EMDB; EMD-24757; -. DR EMDB; EMD-24758; -. DR EMDB; EMD-24759; -. DR EMDB; EMD-24760; -. DR EMDB; EMD-24761; -. DR EMDB; EMD-7041; -. DR EMDB; EMD-7062; -. DR EMDB; EMD-7065; -. DR EMDB; EMD-7066; -. DR EMDB; EMD-7090; -. DR EMDB; EMD-7091; -. DR EMDB; EMD-7092; -. DR EMDB; EMD-7093; -. DR SMR; P14735; -. DR BioGRID; 109642; 211. DR DIP; DIP-55771N; -. DR IntAct; P14735; 77. DR MINT; P14735; -. DR STRING; 9606.ENSP00000265986; -. DR BindingDB; P14735; -. DR ChEMBL; CHEMBL1293287; -. DR DrugBank; DB00626; Bacitracin. DR DrugBank; DB09456; Insulin beef. DR DrugBank; DB09564; Insulin degludec. DR DrugBank; DB01307; Insulin detemir. 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; 9606-ENSP00000265986; -. DR PeptideAtlas; P14735; -. DR ProteomicsDB; 53079; -. [P14735-1] DR ProteomicsDB; 7086; -. DR Pumba; P14735; -. DR ABCD; P14735; 3 sequenced antibodies. DR Antibodypedia; 3227; 615 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 AGR; HGNC:5381; -. 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; 129328at2759; -. 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-77387; Insulin receptor recycling. DR Reactome; R-HSA-9033241; Peroxisomal protein import. DR SignaLink; P14735; -. DR SIGNOR; P14735; -. DR BioGRID-ORCS; 3416; 16 hits in 1175 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 204 other cell types or tissues. DR ExpressionAtlas; P14735; baseline and differential. 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: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 Gene3D; 3.30.830.10; Metalloenzyme, LuxS/M16 peptidase-like; 4. DR InterPro; IPR011249; Metalloenz_LuxS/M16. DR InterPro; IPR011765; Pept_M16_N. DR InterPro; IPR001431; Pept_M16_Zn_BS. DR InterPro; IPR007863; Peptidase_M16_C. DR InterPro; IPR032632; Peptidase_M16_M. DR PANTHER; PTHR43690:SF18; INSULIN-DEGRADING ENZYME-RELATED; 1. DR PANTHER; PTHR43690; NARDILYSIN; 1. DR Pfam; PF00675; Peptidase_M16; 1. DR Pfam; PF05193; Peptidase_M16_C; 2. DR Pfam; PF16187; Peptidase_M16_M; 1. DR SUPFAM; SSF63411; LuxS/MPP-like metallohydrolase; 4. DR PROSITE; PS00143; INSULINASE; 1. DR Genevisible; P14735; HS. 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..104 FT /evidence="ECO:0007829|PDB:7RZI" 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 STRAND 123..125 FT /evidence="ECO:0007829|PDB:7RZI" 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 945..947 FT /evidence="ECO:0007829|PDB:7RZF" FT STRAND 949..951 FT /evidence="ECO:0007829|PDB:7RZE" 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 //