Identification of the metal associated with the insulin degrading enzyme

Ebrahim, Alireza; Hamel, Frederick G.; Bennett, Robert G.; Duckworth, William C.

doi:10.1016/0006-291x(91)92094-z

Cited by 30 publications

(12 citation statements)

References 24 publications

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“…1,7-Phenanthroline, a non-zinc-chelating isomer, had no effect on insulin degradation. These results indicated insulin-degrading activity required zinc, which is consistent with reports by other investigators (Ebrahim et al, 1991;Becker and Roth, 1992;Ding et al, 1992). As shown by the solid lines in Fig.…”

Section: Resultssupporting

confidence: 94%

1,10-Phenanthroline Increases Nuclear Accumulation of Insulin in Response to Inhibiting Insulin Degradation but Has a Biphasic Effect on Insulin's Ability to Increase mRNA Levels

Harada

Smith²,

Jarett³

1994

DNA and Cell Biology

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Previous reports demonstrated that insulin is translocated through the cytoplasm to the nucleus of H35 hepatoma cells and suggested that nuclear insulin may be involved in stimulating transcription of immediate-early genes. In a recent study, inhibition of insulin-degrading enzyme with 1,10-phenanthroline, a Zn2+ chelator, caused a significant increase in the nuclear accumulation of insulin. The present study characterized the effects of 1,10-phenanthroline and its nonchelating isomer, 1,7-phenanthroline, on insulin degradation, nuclear accumulation, and stimulation of immediate-early gene expression. 1,10- but not 1,7-phenanthroline inhibited insulin degradation and increased nuclear accumulation of insulin in a dose-dependent manner. 1,7-phenanthroline caused a dose-dependent decrease in the expression of insulin-stimulated immediate-early genes, but had no significant effect on alpha-tubulin mRNA levels. In the presence of insulin, Northern analysis revealed that 1,10-phenanthroline at all concentrations tested increased alpha-tubulin mRNA levels, but had a biphasic effect on insulin-stimulated immediate-early gene expression. At low concentrations (5-200 microM), 1,10-phenanthroline increased the expression of insulin-stimulated g33, c-fos, and Egr-1 mRNA. At concentrations greater than 1 mM, insulin-stimulated immediate-early gene expression was decreased similar to the effect seen with 1,7-phenanthroline. Nuclear run-on analysis demonstrated that high concentrations of 1,10-phenanthroline decreased insulin-stimulated immediate-early gene transcription but had no effect on transcription of alpha-tubulin. However, low concentrations of 1,10-phenanthroline did not increase transcription of any genes.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Resultssupporting

confidence: 94%

1,10-Phenanthroline Increases Nuclear Accumulation of Insulin in Response to Inhibiting Insulin Degradation but Has a Biphasic Effect on Insulin's Ability to Increase mRNA Levels

Harada

Smith²,

Jarett³

1994

DNA and Cell Biology

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“…Insulin-degrading enzyme (IDE), a Zn2+-metalloprotease involved in the clearance of insulin [69], can also degrade IAPP [70]. IDE has been identified as a T2D susceptibility gene and a 40% reduction of IDE levels in β-cells from T2D patients has been reported [71–73].…”

Section: Iapp Synthesis Processing and Clearancementioning

confidence: 99%

Type 2 diabetes as a protein misfolding disease

Mukherjee¹,

Morales-Scheihing²,

Butler³

et al. 2015

Trends in Molecular Medicine

279

202

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Type 2 diabetes is a highly prevalent and chronic metabolic disorder. Recent evidence suggests that formation of toxic aggregates of the islet amyloid polypeptide (IAPP) might contribute to β-cell dysfunction and disease. However, the mechanism of protein aggregation and associated toxicity is still unclear. Misfolding, aggregation and accumulation of diverse proteins in different organs is the hallmark in the group of protein misfolding disorders (PMDs), including highly prevalent illnesses affecting the central nervous system such as Alzheimer’s and Parkinson’s diseases. In this review we will discuss the current understanding of the mechanisms implicated in the formation of protein aggregates in pancreas and associated toxicity in the light of the longstanding knowledge from neurodegenerative disorders associated with protein misfolding.

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“…All three mutants lost their processing activity, indicating that this motif is involved in the formation of the active site of fl-MPP [47]. Pitrilysin and the insulindegrading enzymes have been shown to have an absolute requirement for metal cofactors [48][49][50]. Published methods for the purification of MPP from fungi and…”

Section: Functional Cooperation Of the Mpp Subunitsmentioning

confidence: 99%

The mitochondrial processing peptidase: Function and specificity

Luciano

Géli

1996

Experientia

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Targeting signals of mitochondrial precursors are cleaved in the matrix during or after import by the mitochondrial processing peptidase (MPP). This enzyme consists of two nonidentical alpha- and beta-subunits each of molecular weight of about 50 kDa. In mammals and fungi, MPP is soluble in the matrix, whereas in plants the enzyme is part of the cytochrome bc1 complex. MPP is a metalloendopeptidase which has been classified as a member of the pitrilysin family on the basis of the HXXEHX76E zinc-binding motif present in beta-MPP. Both subunits of MPP are required for processing activity. The alpha-subunit of MPP, which probably recognizes a three-dimensional motif adopted by the presequence, presents the presequence to beta-MPP, which carries the catalytic active site. MPP acts as an endoprotease on chemically synthesized peptides corresponding to mitochondrial presequences. Matrix-targeting signals and MPP cleavage signals seem to be distinct, although the two signals may overlap within a given presequence. The structural element helix-turn-helix, that cleavable presequences adopt in a membrane mimetic environment, may be required for processing but is not sufficient for proteolysis. Binding of the presequence by alpha-MPP tolerates a high degree of mutations of the presequence. alpha-MPP may present a degenerated cleavage site motif to beta-MPP in an accessible conformation for processing. The conformation of mitochondrial presequences bound to MPP remains largely unknown.

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Identification of the metal associated with the insulin degrading enzyme

Cited by 30 publications

References 24 publications

1,10-Phenanthroline Increases Nuclear Accumulation of Insulin in Response to Inhibiting Insulin Degradation but Has a Biphasic Effect on Insulin's Ability to Increase mRNA Levels

1,10-Phenanthroline Increases Nuclear Accumulation of Insulin in Response to Inhibiting Insulin Degradation but Has a Biphasic Effect on Insulin's Ability to Increase mRNA Levels

Type 2 diabetes as a protein misfolding disease

The mitochondrial processing peptidase: Function and specificity

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