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Title:

Optimum Amyloid Fibril Formation of a Peptide Fragment Suggests the Amyloidogenic Preference of {beta}2-Microglobulin under Physiological Conditions

Date:

3/2004

Link to Journal Abstract

Abstract:

{beta}2-Microglobulin ({beta}2m) is a major component of amyloid fibrils deposited in patients with dialysis-related amyloidosis. Although full-length {beta}2m readily forms amyloid fibrils in vitro by seed-dependent extension with a maximum at pH 2.5, fibril formation under physiological conditions as detected in patients has been difficult to reproduce. A 22-residue K3 peptide of {beta}2m, Ser20–Lys41, obtained by digestion with Acromobacter protease I, forms amyloid fibrils without seeding. To obtain further insight into the mechanism of fibril formation, we studied the pH dependence of fibril formation of the K3 peptide and its morphology using a ThT fluorescence assay and electron microscopy, respectively. K3 peptide formed amyloid fibrils over a wide range of pH values with an optimum around pH 7 and contrasted with the pH profile of the seed-dependent extension reaction of full-length {beta}2m. This suggests that once the rigid native-fold of {beta}2m is unfolded and additional factors triggering the nucleation process are provided, full-length {beta}2m discloses an intrinsic potential to form amyloid fibrils at neutral pH. The fibril formation was strongly promoted by dimerization of K3 through Cys25. The morphology of the fibrils varied depending on the fibril formation conditions and the presence or absence of a disulfide bond. Various fibrils had the potential to seed fibril formation of full-length {beta}2m accompanied with a characteristic lag phase, suggesting that the internal structures are similar.

Content Emphasis

Peer Reviewed Journal Article

Target Audience

Technical Research

Citation:

J. Biol. Chem., Vol. 279, Issue 11, 10814-10821, March 12, 2004

Publication:

Journal of Biological Chemistry

Author:

Y. Ohhashi, K. Hasegawa, H. Naiki, and Y. Goto

Volume:

279