scholarly journals The Catalytic Domain of Insulin-degrading Enzyme Forms a Denaturant-resistant Complex with Amyloid β Peptide

2008 ◽  
Vol 283 (25) ◽  
pp. 17039-17048 ◽  
Author(s):  
Ramiro E. Llovera ◽  
Matías de Tullio ◽  
Leonardo G. Alonso ◽  
Malcolm A. Leissring ◽  
Sergio B. Kaufman ◽  
...  
Keyword(s):  
Catalytic Domain ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Insulin Degrading Enzyme ◽  
Degrading Enzyme

scholarly journals Alternative translation initiation generates a novel isoform of insulin-degrading enzyme targeted to mitochondria

2004 ◽  
Vol 383 (3) ◽  
pp. 439-446 ◽  
Author(s):  
Malcolm A. LEISSRING ◽  
Wesley FARRIS ◽  
Xining WU ◽  
Danos C. CHRISTODOULOU ◽  
Marcia C. HAIGIS ◽  
...  
Keyword(s):  
Fluorescent Protein ◽  
Late Onset ◽  
Amyloid Β ◽  
Type Ii Diabetes Mellitus ◽  
Allelic Association ◽  
Amyloid Β Peptide ◽  
Mitochondrial Targeting ◽  
Insulin Degrading Enzyme ◽  
Degrading Enzyme

IDE (insulin-degrading enzyme) is a widely expressed zinc-metallopeptidase that has been shown to regulate both cerebral amyloid β-peptide and plasma insulin levels in vivo. Genetic linkage and allelic association have been reported between the IDE gene locus and both late-onset Alzheimer's disease and Type II diabetes mellitus, suggesting that altered IDE function may contribute to some cases of these highly prevalent disorders. Despite the potentially great importance of this peptidase to health and disease, many fundamental aspects of IDE biology remain unresolved. Here we identify a previously undescribed mitochondrial isoform of IDE generated by translation at an in-frame initiation codon 123 nucleotides upstream of the canonical translation start site, which results in the addition of a 41-amino-acid N-terminal mitochondrial targeting sequence. Fusion of this sequence to the N-terminus of green fluorescent protein directed this normally cytosolic protein to mitochondria, and full-length IDE constructs containing this sequence were also directed to mitochondria, as revealed by immuno-electron microscopy. Endogenous IDE protein was detected in purified mitochondria, where it was protected from digestion by trypsin and migrated at a size consistent with the predicted removal of the N-terminal targeting sequence upon transport into the mitochondrion. Functionally, we provide evidence that IDE can degrade cleaved mitochondrial targeting sequences. Our results identify new mechanisms regulating the subcellular localization of IDE and suggest previously unrecognized roles for IDE within mitochondria.

scholarly journals Statins Promote the Degradation of Extracellular Amyloid β-Peptide by Microglia via Stimulation of Exosome-associated Insulin-degrading Enzyme (IDE) Secretion

2010 ◽  
Vol 285 (48) ◽  
pp. 37405-37414 ◽  
Author(s):  
Irfan Y. Tamboli ◽  
Esther Barth ◽  
Leonie Christian ◽  
Martin Siepmann ◽  
Sathish Kumar ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Insulin Degrading Enzyme ◽  
Degrading Enzyme ◽  
Stimulation Of

scholarly journals The Amino Terminus of Varicella-Zoster Virus (VZV) Glycoprotein E Is Required for Binding to Insulin-Degrading Enzyme, a VZV Receptor

2007 ◽  
Vol 81 (16) ◽  
pp. 8525-8532 ◽  
Author(s):  
Qingxue Li ◽  
Tammy Krogmann ◽  
Mir A. Ali ◽  
Wei-Jen Tang ◽  
Jeffrey I. Cohen
Keyword(s):  
Amino Acids ◽  
Varicella Zoster Virus ◽  
Catalytic Domain ◽  
Amino Terminus ◽  
Dependent Manner ◽  
Insulin Degrading Enzyme ◽  
Concentration Dependent Manner ◽  
Glycoprotein E ◽  
Degrading Enzyme ◽  
Varicella Zoster

ABSTRACT Varicella-zoster virus (VZV) glycoprotein E (gE) is required for VZV infection. Although gE is well conserved among alphaherpesviruses, the amino terminus of VZV gE is unique. Previously, we showed that gE interacts with insulin-degrading enzyme (IDE) and facilitates VZV infection and cell-to-cell spread of the virus. Here we define the region of VZV gE required to bind IDE. Deletion of amino acids 32 to 71 of gE, located immediately after the predicted signal peptide, resulted in loss of the ability of gE to bind IDE. A synthetic peptide corresponding to amino acids 24 to 50 of gE blocked its interaction with IDE in a concentration-dependent manner. However, a chimeric gE in which amino acids 1 to 71 of VZV gE were fused to amino acids 30 to 545 of herpes simplex virus type 2 gE did not show an increased level of binding to IDE compared with that of full-length HSV gE. Thus, amino acids 24 to 71 of gE are required for IDE binding, and the secondary structure of gE is critical for the interaction. VZV gE also forms a heterodimer with glycoprotein gI. Deletion of amino acids 163 to 208 of gE severely reduced its ability to form a complex with gI. The amino portion of IDE, as well an IDE mutant in the catalytic domain of the protein, bound to gE. Therefore, distinct motifs of VZV gE are important for binding to IDE or to gI.

Alternative Splicing of Human Insulin-Degrading Enzyme Yields a Novel Isoform with a Decreased Ability To Degrade Insulin and Amyloid β-Protein†

Biochemistry ◽  
2005 ◽  
Vol 44 (17) ◽  
pp. 6513-6525 ◽  
Author(s):  
Wesley Farris ◽  
Malcolm A. Leissring ◽  
Matthew L. Hemming ◽  
Alice Y. Chang ◽  
Dennis J. Selkoe
Keyword(s):  
Alternative Splicing ◽  
Human Insulin ◽  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Insulin Degrading Enzyme ◽  
Degrading Enzyme ◽  
Β Protein

scholarly journals Purified recombinant insulin-degrading enzyme degrades amyloid β-protein but does not promote its oligomerization

2000 ◽  
Vol 351 (2) ◽  
pp. 509 ◽  
Author(s):  
Valérie CHESNEAU ◽  
Konstantinos VEKRELLIS ◽  
Marsha Rich ROSNER ◽  
Dennis J. SELKOE
Keyword(s):  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Insulin Degrading Enzyme ◽  
Degrading Enzyme ◽  
Β Protein ◽  
Recombinant Insulin
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