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y Degradation of Al...
y Degradation of Alzheimer's Amyloid-beta by a Catalytically Inactive Insulin-Degrading Enzyme
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- Sahoo, Bikash R. (författare)
- Univ Michigan, Dept Chem Macromol Engn & Sci & Biomed Engn, Biophys, Ann Arbor, MI 48109 USA.
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- Panda, Pritam Kumar, PhD Student, 1991- (författare)
- Uppsala universitet,Materialteori
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- Liang, Wenguang (författare)
- Univ Chicago, Ben May Dept Canc Res, Chicago, IL 60637 USA.
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- Tang, Wei-Jen (författare)
- Univ Chicago, Ben May Dept Canc Res, Chicago, IL 60637 USA.
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- Ahuja, Rajeev, 1965- (författare)
- Uppsala universitet,Materialteori,Teoretisk fysik,Uppsala Univ, Dept Phys & Astron, Mat Theory Div, Condensed Matter Theory Grp, Box 516, SE-75120 Uppsala, Sweden.;Royal Inst Technol KTH, Dept Mat Sci & Engn, Appl Mat Phys, SE-10044 Stockholm, Sweden.
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- Ramamoorthy, Ayyalusamy (författare)
- Univ Michigan, Dept Chem Macromol Engn & Sci & Biomed Engn, Biophys, Ann Arbor, MI 48109 USA.
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Univ Michigan, Dept Chem Macromol Engn & Sci & Biomed Engn, Biophys, Ann Arbor, MI 48109 USA Materialteori (creator_code:org_t)
- Elsevier, 2021
- 2021
- Engelska.
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Ingår i: Journal of Molecular Biology. - : Elsevier. - 0022-2836 .- 1089-8638. ; 433:13
- Relaterad länk:
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https://doi.org/10.1...
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https://doi.org/10.1...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- It is known that insulin-degrading-enzyme (IDE) plays a crucial role in the clearance of Alzheimer's amyloid-beta (A beta). The cysteine-free IDE mutant (cf-E111Q-IDE) is catalytically inactive against insulin, but its effect on A beta degradation is unknown that would help in the allosteric modulation of the enzyme activity. Herein, the degradation of A beta(1-40) by cf-E111Q-IDE via a non-chaperone mechanism is demonstrated by NMR and LC-MS, and the aggregation of fragmented peptides is characterized using fluorescence and electron microscopy. cf-E111Q-IDE presented a reduced effect on the aggregation kinetics of A beta(1-40) when compared with the wild-type IDE. Whereas LC-MS and diffusion ordered NMR spectroscopy revealed the generation of A beta fragments by both wild-type and cf-E111Q-IDE. The aggregation propensities and the difference in the morphological phenotype of the full-length A beta(1-40) and its fragments are explained using multi-microseconds molecular dynamics simulations. Notably, our results reveal that zinc binding to A beta(1-40) inactivates cf-E111Q-IDE's catalytic function, whereas zinc removal restores its function as evidenced from high-speed AFM, electron microscopy, chromatography, and NMR results. These findings emphasize the catalytic role of cf-E111Q-IDE on A beta degradation and urge the development of zinc chelators as an alternative therapeutic strategy that switches on/off IDE's function. (C) 2021 Elsevier Ltd. All rights reserved.
Ämnesord
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Nyckelord
- Amyloid-beta
- Insulin degrading enzyme
- Amyloid degradation
- A beta(1-40)
- Alzheimer's disease
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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