Conformational changes preceding amyloid-fibril formation of amyloid-beta and stefin B; parallels in pH dependence.

Abstract

Amyloid beta (A beta) 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 A beta, 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 A beta at neutral pH. The acid modified A beta 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 molten-globule type which also leads to amyloid fibril formation. Multiple sequence alignment revealed distinct similarities of A beta (1-42) peptide, stefin B (13 to 61 residues) and prion fragment (90 to 144 residues).