Natural regulatory mechanisms of insulin degradation by insulin degrading enzyme

Akiyama, Hiroyuki; Yokono, Koichi; Shii, Kozui; Ogawa, Wataru; Taniguchi, Hiroshi; Baba, Shigeaki; Kasuga, Masato

doi:10.1016/0006-291x(90)90539-y

Cited by 25 publications

(12 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In agreement with prior biochemical and molecular studies (22)(23)(24)(25)(26), this work has shown by in situ hybridization that IDE gene expression is very widespread and is detected in most tissues in both the perinatal and adult rat. Likewise, the expression of either IR or IGFR is virtually universal in rat tissues, consistent with the fundamental role ofthese hormones in cellular metabolism and growth.…”

Section: Discussionsupporting

confidence: 91%

“…To further elucidate the possible functions of this enzyme and to evaluate its anatomical correlation with sites of insulin and IGF action and presumably also hydrolysis, this study was undertaken to localize the mRNAs encoding IDE, insulin, and IGF-I receptors (IGF) in serial sections by in situ hybridization. Prior studies have analyzed the levels of IDE protein by enzyme assays (22), crosslinking with labeled insulin (23), radioimmunoassays (24), and immunocytochemical localization (25). The localization of IDE mRNA has previously been investigated by Northern blot analyses and by ribonuclease protection assay (25,26).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Cellular distribution of insulin-degrading enzyme gene expression. Comparison with insulin and insulin-like growth factor receptors.

Bondy¹,

Zhou²,

Chin³

et al. 1994

J. Clin. Invest.

View full text Add to dashboard Cite

show abstract

Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Cellular distribution of insulin-degrading enzyme gene expression. Comparison with insulin and insulin-like growth factor receptors.

Bondy¹,

Zhou²,

Chin³

et al. 1994

J. Clin. Invest.

View full text Add to dashboard Cite

show abstract

“…; 16 IDE can rapidly degrade insulin with high specificity17; 18, and accumulating evidence supports the notion that IDE is a major enzyme for insulin degradation in vivo and is involved in the development of diabetes. 19; 20; 21; 22; 23 In addition, IDE can effectively degrade amyloid-β (Aβ), a peptide critical for the progression of Alzheimer's disease 24. Consistent with this notion, IDE gene disruption in mice results in elevated cerebral accumulation of Aβ, while the overexpression of IDE leads to reduced brain Aβ levels 22…”

Section: Introductionmentioning

confidence: 91%

Ubiquitin Is a Novel Substrate for Human Insulin-Degrading Enzyme

Ralat

Kalas

Zheng

et al. 2011

Journal of Molecular Biology

View full text Add to dashboard Cite

Insulin-degrading enzyme (IDE) can degrade insulin and amyloid-β (Aβ), peptides involved in diabetes and Alzheimer's disease, respectively. IDE selects its substrates based on size, charge, and flexibility. From these criteria, we predict that IDE can cleave and inactivate ubiquitin (Ub). Here, we show that IDE cleaves Ub in a biphasic manner, first, by rapidly removing the two Cterminal glycines (k cat = 2 sec -1 ) followed by a slow cleavage between residues 72-73 (k cat = 0.07 sec -1 ), thereby producing the inactive Ub1-74 and Ub1-72. IDE is a ubiquitously expressed cytosolic protein, where monomeric Ub is also present. Thus, Ub degradation by IDE should be regulated. IDE is known to bind the cytoplasmic intermediate filament protein nestin with high affinity. We found that nestin potently inhibits the cleavage of Ub by IDE. In addition, Ub1-72 has a markedly increased affinity for IDE (∼90 fold). Thus, the association of IDE with cellular regulators and product inhibition by Ub1-72 can prevent inadvertent proteolysis of cellular Ub by IDE. Ub is a highly stable protein. However, IDE instead prefers to degrade peptides with high intrinsic flexibility. Indeed, we demonstrate that IDE is exquisitely sensitive to Ub stability. Mutations that only mildly destabilize Ub (ΔΔG ‹ 0.6 kcal/mol) render IDE hypersensitive to Ub with rate enhancements greater than 12-fold. The Ub-bound IDE structure and IDE mutants reveal that interaction of the exosite with the N-terminus of Ub guides the unfolding of Ub, allowing its sequential cleavages. Together, our studies link the control of Ub clearance with IDE. Accession Number: The atomic coordinates and structure factors (PDB ID: 3OFI) have been deposited in the Protein Data Bank,

show abstract

“…IDE is concentrated in the cytoplasm—and even more so in the peroxisomes in liver, kidney, muscle, and brain cells—and it plays a key role in degrading many important peptides [6–8]. Therefore, not only DAT but also type 2 diabetes mellitus (DM) are linked to IDE [9, 10], and DM is reported to promote the incidence of DAT [11].…”

Section: Introductionmentioning

confidence: 99%

IDE Gene Polymorphism Influences on BPSD in Mild Dementia of Alzheimer's Type

Sato

Ueki

Ueno

et al. 2008

Current Gerontology and Geriatrics Research

View full text Add to dashboard Cite

Insulin degrading enzyme (IDE) degrades amyloid β (Aβ), which may inhibit the accumulation of Aβ in a brain affected with dementia of Alzheimer's type (DAT). A decrease in the activity of IDE results in changes in glucose utilization in the brain, which could affect the cognitive and psychiatric symptoms of DAT. We investigated a possible association of IDE gene polymorphism and the behavioral and psychological symptoms of dementia (BPSD) in mild DAT. The genotyping for IDE and apolipoprotein E (ApoE) was determined in 207 patients with mild DAT and 215 controls. The occurrence of BPSD was demonstrated using the Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD). IDE gene polymorphism is unlikely to play a substantial role in conferring susceptibility to DAT, but it may be involved in the development of affective disturbance through the course of mild DAT, regardless of the presence of an ApoE ε4 allele. The present data could be the result of a small sample size. Further investigations using larger samples are thus required to clarify the correlation between IDE gene polymorphism, susceptibility to DAT, and emergence of BPSD.

show abstract

Natural regulatory mechanisms of insulin degradation by insulin degrading enzyme

Cited by 25 publications

References 16 publications

Cellular distribution of insulin-degrading enzyme gene expression. Comparison with insulin and insulin-like growth factor receptors.

Cellular distribution of insulin-degrading enzyme gene expression. Comparison with insulin and insulin-like growth factor receptors.

Ubiquitin Is a Novel Substrate for Human Insulin-Degrading Enzyme

IDE Gene Polymorphism Influences on BPSD in Mild Dementia of Alzheimer's Type

Contact Info

Product

Resources

About