Chapter 22 Structure, Function, and Regulation of Insulin‐Degrading Enzyme

Hulse, Raymond E.; Ralat, Luis A.; Tang, Wei-Jen

doi:10.1016/s0083-6729(08)00622-5

Cited by 54 publications

(45 citation statements)

References 46 publications

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“…IDE is a zinc metalloendoprotease that is ubiquitously expressed in mammals and plays a crucial role in the turnover of peptide hormones such as insulin and glucagon, and of aggregation prone proteins like amyloid-β [44]. We analyzed the impact of the competitive IDE-substrate insulin on in vitro degradation of s p6.…”

Section: Resultsmentioning

confidence: 99%

Proteolysis of mature HIV-1 p6 Gag protein by the insulin-degrading enzyme (IDE) regulates virus replication in an Env-dependent manner

et al. 2017

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There is a significantly higher risk for type II diabetes in HIV-1 carriers, albeit the molecular mechanism for this HIV-related pathology remains enigmatic. The 52 amino acid HIV-1 p6 Gag protein is synthesized as the C-terminal part of the Gag polyprotein Pr55. In this context, p6 promotes virus release by its two late (L-) domains, and facilitates the incorporation of the viral accessory protein Vpr. However, the function of p6 in its mature form, after proteolytic release from Gag, has not been investigated yet. We found that the mature p6 represents the first known viral substrate of the ubiquitously expressed cytosolic metalloendopeptidase insulin-degrading enzyme (IDE). IDE is sufficient and required for degradation of p6, and p6 is approximately 100-fold more efficiently degraded by IDE than its eponymous substrate insulin. This observation appears to be specific for HIV-1, as p6 proteins from HIV-2 and simian immunodeficiency virus, as well as the 51 amino acid p9 from equine infectious anaemia virus were insensitive to IDE degradation. The amount of virus-associated p6, as well as the efficiency of release and maturation of progeny viruses does not depend on the presence of IDE in the host cells, as it was shown by CRISPR/Cas9 edited IDE KO cells. However, HIV-1 mutants harboring IDE-insensitive p6 variants exhibit reduced virus replication capacity, a phenomenon that seems to depend on the presence of an X4-tropic Env. Furthermore, competing for IDE by exogenous insulin or inhibiting IDE by the highly specific inhibitor 6bK, also reduced virus replication. This effect could be specifically attributed to IDE since replication of HIV-1 variants coding for an IDE-insensitive p6 were inert towards IDE-inhibition. Our cumulative data support a model in which removal of p6 during viral entry is important for virus replication, at least in the case of X4 tropic HIV-1.

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Section: Resultsmentioning

confidence: 99%

Proteolysis of mature HIV-1 p6 Gag protein by the insulin-degrading enzyme (IDE) regulates virus replication in an Env-dependent manner

et al. 2017

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“…; 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.…”

Section: Introductionmentioning

confidence: 92%

Ubiquitin Is a Novel Substrate for Human Insulin-Degrading Enzyme

Ralat

Kalas

Zheng

et al. 2011

Journal of Molecular Biology

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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,

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“…Because of IDE’s ability to degrade insulin, amylin, and Aβ42, it is thought to be a link connecting hyperinsulemia, IR and AD [140, 141]. IDE’s unique structure with two half-dome subunits connected by a linker limits its ability to cleave large Aβ subunits[142]. Therefore, IDE is thought to only cleave monomeric Aβ [138, 142].…”

Section: Brain Ir and Aβ Pathologymentioning

confidence: 99%

“…IDE’s unique structure with two half-dome subunits connected by a linker limits its ability to cleave large Aβ subunits[142]. Therefore, IDE is thought to only cleave monomeric Aβ [138, 142]. In mice, insulin resistance leads to increased brain amyloidosis through an increase in gamma-secretase activity, as well as decreased IDE [143, 144].…”

Section: Brain Ir and Aβ Pathologymentioning

confidence: 99%

Insulin resistance in Alzheimer's disease

Diehl

Mullins

Kapogiannis

2017

Translational Research

104

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The links between systemic insulin resistance (IR), brain-specific IR and Alzheimer’s disease (AD) has been an extremely productive area of current research. This review will cover the fundamentals and pathways leading to IR; its connection to AD via cellular mechanisms, the most prominent methods and models used to examine it, an introduction to the role of extracellular vesicles (EVs) as a source of biomarkers for IR and AD, and an overview of modern clinical studies on the subject. To provide additional context, we also present a novel analysis of the spatial correlation of gene expression in the brain with the aid of Allen Human Brain Atlas data. Ultimately, examining the relation between IR and AD can be seen as a means of advancing the understanding of both disease states, with IR being a promising target for therapeutic strategies in AD treatment. In conclusion, we highlight the therapeutic potential of targeting brain IR in AD and the main strategies to pursue this goal.

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Chapter 22 Structure, Function, and Regulation of Insulin‐Degrading Enzyme

Cited by 54 publications

References 46 publications

Proteolysis of mature HIV-1 p6 Gag protein by the insulin-degrading enzyme (IDE) regulates virus replication in an Env-dependent manner

Proteolysis of mature HIV-1 p6 Gag protein by the insulin-degrading enzyme (IDE) regulates virus replication in an Env-dependent manner

Ubiquitin Is a Novel Substrate for Human Insulin-Degrading Enzyme

Insulin resistance in Alzheimer's disease

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