This section gathers key publications on IDE

First catalytic site inhibitor of IDE in vivo***

Deprez-Poulain, R., Nathalie, H., Bosc, D., Liang, W. G., Enee, E., Marechal, X., Julie, C., Totobenazara, J., Berte, G., Jahklal, J., Verdelet, T., Dumont, J., Dassonneville, S., Woitrain, E., Gauriot, M., Paquet, C., Duplan, I., Hermant, P., Cantrelle, F.-X., Sevin, E., Culot, M., Landry, V., Herledan, A., Piveteau, C., Lippens, G., Florence, L., Tang, W. J., Van Endert, P., Staels, B., & Deprez, B. Catalytic site inhibition of insulin-degrading enzyme by a small molecule induces glucose intolerance in mice. Nature Comm.,2015, 6.
doi:10.1038/ncomms9250 OPEN ACCESS

Dual binders of IDE full SAR***

Charton, J., Gauriot, M., Totobenazara, J., Hennuyer, N., Dumont, J., Bosc, D., Marechal, X., Elbakali, J., Herledan, A., Wen, X., Ronco, C., Gras-Masse, H., Heninot, A., Pottiez, V., Landry, V., Staels, B., Liang, W. G., Leroux, F., Tang, W. J., Deprez, B., & Deprez-Poulain, R. Structure-activity relationships of Imidazole-derived 2-[N-carbamoylmethyl-alkylamino]acetic acids, dual binders of human Insulin-Degrading Enzyme. Eur J Med Chem. 90: 547-567 doi:10.1016/j.ejmech.2014.12.005

Dual binders of IDE inhibit amyloid beta catabolism in vitro and in cells***

Charton, J., Gauriot, M., Guo, Q., Hennuyer, N., Marechal, X., Dumont, J., Hamdane, M., Pottiez, V., Landry, V., Sperandio, O., Flipo, M., Buee, L., Staels, B., Leroux, F., Tang, W.-J., Deprez, B., & Deprez-Poulain, R. Imidazole-derived 2-[N-carbamoylmethyl-alkylamino]acetic acids, substrate-dependent modulators of insulin-degrading enzyme in amyloid-beta hydrolysis. European Journal of Medicinal Chemistry,2014, 79, 184-193. 10.1016/j.ejmech.2014.04.009

Exosite inhibitors acting on several hormones

Maianti, J. P., McFedries, A., Foda, Z. H., Kleiner, R. E., Du, X. Q., Leissring, M. A., Tang, W.-J., Charron, M. J., Seeliger, M. A., Saghatelian, A., & Liu, D. R. Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones. Nature,2014, advance online publication: in press. 10.1038/nature13297

IDE and the PI3K pathway***

Galagovsky, D., Katz, M. J., Acevedo, J. M., Sorianello, E., Glavic, A., & Wappner, P. The Drosophila insulin-degrading enzyme restricts growth by modulating the PI3K pathway in a cell-autonomous manner. Mol Biol Cell,2014, 25(6): 916-924.10.1091/mbc.E13-04-0213

IDE and antigenic presentation

Culina, S., Mauvais, F. X., Hsu, H. T., Burgevin, A., Guenette, S., Moser, A., & van Endert, P. No major role for insulin-degrading enzyme in antigen presentation by MHC molecules. PLoS One,2014, 9(2): e88365.10.1371/journal.pone.0088365

Inhibition of IDE by ATP

Seabra, G. D., & da Cruz, C. H. Molecular Dynamics Simulations Reveal a Novel Mechanism for ATP Inhibition of Insulin Degrading Enzyme. PLoS One,2014, 9(2): e88365.10.1021/ci400695m

Amyloid beta catabolism by IDE in the mitochondria

Leal, M. C., Magnani, N., Villordo, S., Buslje, C. M., Evelson, P., Castano, E. M., & Morelli, L. Transcriptional regulation of insulin-degrading enzyme modulates mitochondrial amyloid beta (Abeta) peptide catabolism and functionality. J Biol Chem,2013, 288(18): 12920-12931.10.1074/jbc.M112.424820

IDE and proteotoxic stress**

Beuzelin, C., Evnouchidou, I., Rigolet, P., Cauvet-Burgevin, A., Girard, P. M., Dardalhon, D., Culina, S., Gdoura, A., van Endert, P., & Francesconi, S. Deletion of the fission yeast homologue of human insulinase reveals a TORC1-dependent pathway mediating resistance to proteotoxic stress. PLoS One,2013, 8(6): e67705.10.1371/journal.pone.0067705

Swining door in IDE***

McCord, L. A., Liang, W. G., Dowdell, E., Kalas, V., Hoey, R. J., Koide, A., Koide, S., & Tang, W. J. Conformational states and recognition of amyloidogenic peptides of human insulin-degrading enzyme. Proc Natl Acad Sci U S A,2013, 110(34): 13827-13832.10.1073/pnas.1304575110

Alzheimer's disease and Diabetes Type 2 molecular links

Haque, R., & Nazir, A. Insulin-Degrading Enzyme: A Link between Alzheimer's and Type 2 Diabetes Mellitus. CNS Neurol Disord Drug Targets,2013,

IDE polymorphisms

Gutierrez-Hermosillo, H., Diaz De Leon-Gonzalez, E., Palacios-Corona, R., Cedillo-Rodriguez, J. A., Camacho-Luis, A., Reyes-Romero, M. A., Medina-Chavez, J. H., & Blandon, P. A. C allele of the rs2209972 single nucleotide polymorphism of the insulin degrading enzyme gene and Alzheimer's disease in type 2 diabetes, a case control study. Med Clin (Barc),2013.10.1016/j.medcli.2013.09.03

Meta-analysis of IDE polymorphisms and susceptibility to Alzheimer's disease**

Zhang, Y., Wang, B., Wan, H., Zhou, Q., & Li, T. Meta-analysis of the insulin degrading enzyme polymorphisms and susceptibility to Alzheimer's disease. Neurosci. Lett., 2013, 541: 132-137. doi:10.1016/j.neulet.2013.01.051

IDE as a Heat Shock-like protein

Tundo, G. R., Sbardella, D., Ciaccio, C., Bianculli, A., Orlandi, A., Desimio, M. G., Arcuri, G., Coletta, M., & Marini, S. Insulin-degrading enzyme (IDE): A novel heat shock-like protein. J. Biol. Chem., 2013, 288(4): 2281-2289. doi:10.1074/jbc.M112.393108

IDE polymorphisms and Diabetes in older adults

McFall, G. P., Wiebe, S. A., Vergote, D., Westaway, D., Jhamandas, J., & Dixon, R. A. IDE (rs6583817) polymorphism and type 2 diabetes differentially modify executive function in older adults. Neurobiol. Aging, 2013, 34(9): 2208. doi:10.1016/j.neurobiolaging.2013.03.010

IDE-deficient rat and Aβ peptide aggregates

de Tullio, M. B., Castelletto, V., Hamley, I. W., Martino Adami, P. V., Morelli, L., & Castano, E. M. Proteolytically inactive insulin-degrading enzyme inhibits amyloid formation yielding non-neurotoxic Aβ peptide aggregates. PLoS ONE, 2013, 8(4): e59113. doi:10.1371/journal.pone.0059113

IDE deficiency and atherosclerosis in mice model

Caravaggio, J. W., Hasu, M., MacLaren, R., Thabet, M., Raizman, J. E., Veinot, J. P., Marcel, Y. L., Milne, R. W., & Whitman, S. C. Insulin-degrading enzyme deficiency in bone marrow cells increases atherosclerosis in LDL receptor-deficient mice. Cardiovasc. Pathol., 2013, in press. doi:10.1016/j.carpath.2013.03.006

IDE deficiency and cerebrovascular amyloidosis in rat model

Lifshitz, V., Benromano, T., Weiss, R., Blanga-Kanfi, S., & Frenkel, D. Insulin-degrading enzyme deficiency accelerates cerebrovascular amyloidosis in an animal model. Brain Behav. Immun.,2013, 30: 143-149. doi:10.1016/j.bbi.2012.12.003

Dipeptide inhibitor of insulin degradation

Abdul-Hay, S. O., Lane, A. L., Caulfield, T. R., Claussin, C., Bertrand, J., Masson, A., Choudhry, S., Fauq, A. H., Maharvi, G. M., & Leissring, M. A. Optimization of peptide hydroxamate inhibitors of Insulin-Degrading Enzyme reveals marked substrate-selectivity. J. Med. Chem., 2013, 56(6): 2246-2255. doi:10.1021/jm301280p

ATP-binding site***

Noinaj, N., Song, E. S., Bhasin, S., Alper, B. J., Schmidt, W. K., Hersh, L. B., & Rodgers, D. W. Anion Activation Site of Insulin-degrading Enzyme. J. Biol. Chem., 2012, 287(1): 48-57. doi:10.1074/jbc.M111.264614

Statin-induced secretion**

Glebov, K., & Walter, J. Statins in unconventional secretion of insulin-degrading enzyme and degradation of the amyloid-beta peptide. Neurodegenerative Dis., 2012, 10(1-4): 309-312. doi:10.1159/000332595

In cellulo insulin degradation inhibitor

Cakir, B., Dagliyan, O., Dagyildiz, E., Baris, I., Kavakli, I. H., Kizilel, S., & Turkay, M. Structure based discovery of small molecules to regulate the activity of human Insulin-Degrading Enzyme. PLoS ONE, 2012, 7(2): e31787. doi:10.1371/journal.pone.0031787

Transcription initiation by NRF-1

Zhang, L., Ding, Q., & Wang, Z. Nuclear Respiratory Factor 1 mediates the transcription initiation of Insulin-Degrading Enzyme in a TATA box-binding protein-independent manner. PLoS ONE, 2012, 7(8): e42035. doi:10.1371/journal.pone.0042035

Activation by somatostatine

Tundo, G., Ciaccio, C., Sbardella, D., Boraso, M., Viviani, B., Coletta, M., & Marini, S. Somatostatin modulates insulin-degrading-enzyme metabolism: implications for the regulation of microglia activity in AD. PLoS ONE, 2012, 7(4): e34376. doi:10.1371/journal.pone.0034376

a-factor based reporters rat-IDE mediated degradation inhibitor

Kukday, S. S., Manandhar, S. P., Ludley, M. C., Burriss, M. E., Alper, B. J., & Schmidt, W. K. Cell-permeable, small-molecule activators of the insulin-degrading enzyme. J. Biomol. Screening, 2012, 17(10): 1348-1361. doi:10.1177/1087057112451921

2-6 months-old IDE KO mice description***

Abdul-Hay, S. O., Kang, D., McBride, M., Li, L., Zhao, J., & Leissring, M. A. Deletion of insulin-degrading enzyme elicits antipodal, age-dependent effects on glucose and insulin tolerance. PLoS ONE, 2011, 6(6): e20818. doi:10.1371/journal.pone.0020818

SlyX sequence for secretory pathway

Glebov, K., Schutze, S., & Walter, J. Functional relevance of a novel SlyX motif in non-conventional secretion of insulin-degrading enzyme. J. Biol. Chem., 2011, 286(26): 22711-22715. doi:10.1074/jbc.C110.217893

Insulin degradation peptide inhibitor**

Leissring, M. A., Malito, E., Hedouin, S., Reinstatler, L., Sahara, T., Abdul-Hay, S. O., Choudhry, S., Maharvi, G. M., Fauq, A. H., Huzarska, M., May, P. S., Choi, S., Logan, T. P., Turk, B. E., Cantley, L. C., Manolopoulou, M., Tang, W.-J., Stein, R. L., Cuny, G. D., & Selkoe, D. J. Designed inhibitors of insulin-degrading enzyme regulate the catabolism and activity of insulin. PLoS ONE, 2010, 5(5): e10504. doi:10.1371/journal.pone.0010504

Monomeric variant*

Song, E. S., Rodgers, D. W., & Hersh, L. B. A monomeric variant of insulin degrading enzyme (IDE) loses its regulatory properties. PLoS ONE, 2010, 5(3): e9719. doi:10.1371/journal.pone.0009719

Aβ kinetics in the CNS of 12 AD patients*

Mawuenyega, K. G., Sigurdson, W., Ovod, V., Munsell, L., Kasten, T., Morris, J. C., Yarasheski, K. E., & Bateman, R. J. Decreased clearance of CNS beta-amyloid in Alzheimer's disease. Science, 2010, 330(6012): 1774-1774. doi:10.1126/science.1197623

Statins promote IDE secretion

Tamboli, I. Y., Barth, E., Christian, L., Siepmann, M., Kumar, S., Singh, S., Tolksdorf, K., Heneka, M. T., Lutjohann, D., Wunderlich, P., & Walter, J. Statins promote the degradation of extracellular amyloid beta-peptide by microglia via stimulation of exosome-associated insulin-degrading enzyme (IDE) secretion. J. Biol. Chem., 2010, 285(48): 37405-37414. doi:10.1074/jbc.M110.149468

Recognition of IGF-II, TGF-alpha and amylin**

Guo, Q., Manolopoulou, M., Bian, Y., Schilling, A. B., & Tang, W.-J. Molecular basis for the recognition and cleavages of IGF-II, TGF-alpha, and amylin by human insulin-degrading enzyme. J. Mol. Biol., 2010, 395(2): 430-443. doi:10.1016/j.jmb.2009.10.072

Fluorogenic peptide substrates degradation activators*

Cabrol, C., Huzarska, M. A., Dinolfo, C., Rodriguez, M. C., Reinstatler, L., Ni, J., Yeh, L.-A., Cuny, G. D., Stein, R. L., Selkoe, D. J., & Leissring, M. A. Small-molecule activators of insulin-degrading enzyme discovered through high-throughput compound screening. PLoS ONE, 2009, 4(4): e5274. doi:10.1371/journal.pone.0005274

Glucose and insulin-mediated regulation*

Pivovarova, O., Gogebakan, O., Pfeiffer, A. F. H., & Rudovich, N. Glucose inhibits the insulin-induced activation of the insulin-degrading enzyme in HepG2 cells. Diabetologia, 2009, 52(8): 1656-1664. doi:10.1007/s00125-009-1350-7

Unconventional protein secretion pathway

Zhao, J., Li, L., & Leissring, M. Insulin-degrading enzyme is exported via an unconventional protein secretion pathway. Mol. Neurodegener., 2009, 4(1): 4-9. doi:10.1186/1750-1326-4-4

Link between hyperglycaemia and hyperinsulinaemia

Fawcett, J., & Duckworth, W. Hyperglycaemia and hyperinsulinaemia: is insulin-degrading enzyme the missing link? Diabetologia, 2009, 52(8): 1457-1460. doi:10.1007/s00125-009-1414-8

Recognition of short substrates**

Malito, E., Ralat, L. A., Manolopoulou, M., Tsay, J. L., Wadlington, N. L., & Tang, W.-J. Molecular bases for the recognition of short peptide substrates and cysteine-directed modifications of human insulin-degrading enzyme. Biochemistry, 2008, 47(48): 12822-12834. doi:10.1021/bi801192h

Regulation by ubiquitin

Grasso, G., Rizzarelli, E., & Spoto, G. How the binding and degrading capabilities of insulin degrading enzyme are affected by ubiquitin. Biochim. Biophy. Acta, 2008, 1784: 1122-1126. doi:10.1016/j.bbapap.2008.04.011

Substrate-free X-ray structure***

Im, H., Manolopoulou, M., Malito, E., Shen, Y., Zhao, J., Neant-Fery, M., Sun, C.-Y., Meredith, S. C., Sisodia, S. S., Leissring, M. A., & Tang, W.-J. Structure of substrate-free human insulin-degrading enzyme (IDE) and biophysical analysis of ATP-induced conformational switch of IDE. J. Biol. Chem., 2007, 282(35): 25453-25463. doi:10.1074/jbc.M701590200

Regulation of cellular proteins degradation*

Fawcett, J., Permana, P. A., Levy, J. L., & Duckworth, W. C. Regulation of protein degradation by insulin-degrading enzyme: Analysis by small interfering RNA-mediated gene silencing. Arch. Biochem. Biophy., 2007, 468(1): 128-133. doi:10.1016/j.abb.2007.09.019

X-ray structure of IDE ***

Shen, Y., Joachimiak, A., Rich Rosner, M., & Tang, W.-J. Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism. Nature, 2006, 443(7113): 870-874. doi:10.1038/nature05143

Aβ deposit-associated overexpression of IDE in Tg2576 mice**

Leal, M. C., Dorfman, V. B., Gamba, A. F., Frangione, B., Wisniewski, T., Castano, E. M., Sigurdsson, E. M., & Morelli, L. Plaque-associated overexpression of insulin-degrading enzyme in the cerebral cortex of aged transgenic Tg2576 mice with Alzheimer pathology. J. Neuropathol. Exp. Neurol., 2006, 65(10): 976-987. doi:10.1097/01.jnen.0000235853.70092.ba

Dimerization of IDE

Li, P., Kuo, W.-L., Yousef, M., Rosner, M. R., & Tang, W.-J. The C-terminal domain of human insulin degrading enzyme is required for dimerization and substrate recognition. Biochem. Biophy. Res. Com., 2006, 343(4): 1032-1037. doi:10.1016/j.bbrc.2006.03.083

IDE as a receptor mediating VZV infection

Li, Q., Ali, M. A., & Cohen, J. I. Insulin degrading enzyme is a cellular receptor mediating varicella-zoster virus infection and cell-to-cell spread. Cell, 2006, 127(2): 305-316 doi:10.1016/j.cell.2006.08.046

Alternative splicing of IDE**

Farris, W., Leissring, M. A., Hemming, M. L., Chang, A. Y., & Selkoe, D. J. Alternative splicing of human insulin-degrading enzyme yields a novel isoform with a decreased ability to degrade insulin and amyloid beta-protein. Biochemistry, 2005, 44(17): 6513-6525. doi:10.1021/bi0476578

Natural partial loss-of-function of IDE in GK rats*

Farris, W., Mansourian, S., Leissring, M. A., Eckman, E. A., Bertram, L., Eckman, C. B., Tanzi, R. E., & Selkoe, D. J. Partial loss-of-function mutations in insulin-degrading enzyme that induce diabetes also impair degradation of amyloid beta-protein. Am. J. Pathol., 2004, 164(4): 1425-1434. doi:10.1016/S0002-9440(10)63229-4

Polymorphisms in IDE gene and Alzheimer’s disease

Ertekin-Taner, N., Allen, M., Fadale, D., Scanlin, L., Younkin, L., Petersen, R. C., Graff-Radford, N., & Younkin, S. G. Genetic variants in a haplotype block spanning IDE are significantly associated with plasma Aβ42 levels and risk for Alzheimer disease. Hum. Mutat., 2004, 23(4): 334-342. doi:10.1002/humu.20016

IDE activation by ATP

Song, E. S., Juliano, M. A., Juliano, L., Fried, M. G., Wagner, S. L., & Hersh, L. B. ATP effects on insulin-degrading enzyme are mediated primarily through its triphosphate moiety. J. Biol. Chem., 2004, 279(52): 54216-54220. doi:10.1074/jbc.M411177200

IDE KO mice caracterization***

Farris, W., Mansourian, S., Chang, Y., Lindsley, L., Eckman, E. A., Frosch, M. P., Eckman, C. B., Tanzi, R. E., Selkoe, D. J., & Guenette, S. Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. P. Nat. Acad. Sci., 2003, 100(7): 4162-4167. doi:10.1073/pnas.0230450100

Aβ deposit monitoring in IDE and APP double transgenic mice**

Leissring, M. A., Farris, W., Chang, A. Y., Walsh, D. M., Wu, X., Sun, X., Frosch, M. P., & Selkoe, D. J. Enhanced proteolysis of beta-Amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death. Neuron, 2003, 40(6): 1087-1093. doi:10.1016/S0896-6273(03)00787-6

Aβ monitoring in IDE transgenic mice**

Miller, B. C., Eckman, E. A., Sambamurti, K., Dobbs, N., Chow, K. M., Eckman, C. B., Hersh, L. B., & Thiele, D. L. Amyloid-beta peptide levels in brain are inversely correlated with insulysin activity levels in vivo. P. Nat. Acad. Sci.,2003, 100(10): 6221-6226. doi:10.1073/pnas.1031520100

Enhancement of proteasomal activity*

Bennett, R. G., Fawcett, J., Kruer, M. C., Duckworth, W. C., & Hamel, F. G. Insulin inhibition of the proteasome is dependent on degradation of insulin by insulin-degrading enzyme. J. Endocrinol.,2003, 177(3): 399-405. doi: 10.1677/joe.0.1770399

IDE activation by its own substrates

Song, E.-S., Juliano, M. A., Juliano, L., & Hersh, L. B. Substrate Activation of Insulin-degrading Enzyme (Insulysin). J. Biol. Chem.,2003, 278(50): 49789-49794. doi:10.1074/jbc.M308983200

Link between polymorphisms of IDE gene and Diabetes

Karamohamed, S., Demissie, S., Volcjak, J., Liu, C., Heard-Costa, N., Liu, J., Shoemaker, C. M., Panhuysen, C. I., Meigs, J. B., Wilson, P., Atwood, L. D., Cupples, L. A., & Herbert, A. Polymorphisms in the insulin-degrading enzyme gene are associated with type 2 diabetes in men from the NHLBI Framingham Heart Study. Diabetes,2003, 52(6): 1562-1567. doi:10.2337/diabetes.52.6.1562

Enhancement of peroxisomal activity

Hamel, F. G., Bennett, R. G., Upward, J. L., & Duckworth, W. C. Insulin inhibits peroxisomal fatty acid oxidation in isolated rat hepatocytes. Endocrinology, 2001, 142(6): 2702-2706. doi:10.1210/en.142.6.2702

Substrate recognition motif

Kurochkin, I. V. Amyloidogenic determinant as a substrate recognition motif of insulin-degrading enzyme. FEBS Lett., 1998,  427(2): 153-156. doi:10.1016/S0014-5793(98)00422-0

Enhancement of androgen and glucocorticoid receptors signaling

Kupfer, S. R., Wilson, E. M., & French, F. S. Androgen and glucocorticoid receptors interact with insulin degrading enzyme. J. Biol. Chem., 1994, 269(32): 20622-20628.

Rat IDE sequence

Baumeister, H., Muller, D., Rehbein, M., & Richter, D. The rat insulin-degrading enzyme: Molecular cloning and characterization of tissue-specific transcripts. FEBS Lett, 1993, 317(3): 250-254. doi:10.1016/0014-5793(93)81286-9