Conformational Changes Preceding Amyloid-fibril Formation of Amyloid-beta and Stefin B; Parallels in pH Dependence

Authors: Matsunaga, Y.; Ierovnik, E.; Yamada, T.; Turk, V.

Source: Current Medicinal Chemistry, Volume 9, Number 19, October 2002 , pp. 1717-1724(8)

Publisher: Bentham Science Publishers

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Abstract:

Amyloid beta (Aβ) protein is the key component of amyloid plaques in Alzheimer's disease brain whereas stefin B is an intracellular cysteine proteinase inhibitor, broadly distributed in different tissue and recently reported to form amyloid fibrils in vitro. By reducing the pH to 4.6, the native conformation of both polypeptides are changed into less ordered metastable intermediates that are stabilized by formation of the more stable fibrils. In Aβ, the Glu at position 11 was found to be responsible for the conformational change at pH 4.6. Metal ions, including copper and zinc, could also induce conformational changes of Aβ at neutral pH. The acid modified Aβ conformer exhibited protease K resistance, preferential internalization and accumulation in the human glial cells. In stefin B, reducing the pH to pH 3.3 results in another intermediate of the moltenglobule type which also leads to amyloid fibril formation. Multiple sequence alignment revealed distinct similarities of Aβ (1-42) peptide, stefin B (13 to 61 residues) and prion fragment (90 to 144 residues).

Keywords: Amyloid; amyloidfibrillogenesis; cystatins; metal ions; molten globule; protease resistance; stefin B

Document Type: Review Article

DOI: http://dx.doi.org/10.2174/0929867023369097

Publication date: October 1, 2002

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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