Interactive sequences in the molecular chaperone, human αB crystallin modulate the fibrillation of amyloidogenic proteins

Multiple interactive domains are involved in the activity of the stress protein, alpha B crystallin that protects against the unfolding, aggregation, and toxicity of amyloidogenic proteins. Six peptides corresponding to the interactive sequences (41)STSLSPFYLRPPSFLRAP(58), (73)DRFSVNLDVKHFS(85), (101)HGKHEERQDE(110), (113)FISREFHR(120), (131)LTITSSLSSDGV(142), and (156)ERTIPITRE(164) in human alpha B crystallin were synthesized and evaluated in Thioflavin T fluorescence assays for their effects on the modulation of fibrillation of four disease-related amyloidogenric proteins: amyloid-beta, alpha-synuclein, transthyretin, and beta 2- microglobulin. The (73)DRFSVNLDVKHFS(85) and (101)HGKHEERQDE(110) peptides in the conserved alpha crystallin core domain of alpha B crystallin were the most effective fibril inhibitors. (73)DRFSVNLDVKHFS(85) completely inhibited alpha-synuclein fibrillation and reduced the fibrillation of amyloid-beta, transthyretin, and beta 2-microglobulin by >50%. (101)HGKHEERQDE(110) completely inhibited amyloid-beta fibrillation and reduced the fibrillation of alpha-synuclein, transthyretin, and beta 2-microglobulin by >50%. The peptides FSVN, NLDV, HGKH, and HEER, which are synthetic fragments Of (73)DRFSVNLDVKHFS(85) and (101)HGKHEERQDE(110), inhibited fibrillation of all four amyloidogenic proteins by >75%. In contrast, the peptides FISREFHR, ERTIPITRE, DRFS, KHFS, and EERQ were the strongest promoters of fibrillation. Molecular modeling of the interactions between transthyretin and beta 2-microglobulin and the synthetic bioactive peptides determined that residues Phe-75, Ser-76, Val-77, Asn-78, Leu-79, and Asp-80 in (73)DRFSVNLDVKHFS(85) and residues His-101, Lys-103, His-104, Glu-105, and Arg-107 in (101)HGKHEERQDE(110) interact with exposed residues in the beta strands, F and D of transthyretin and beta 2-microglobulin, respectively, to modulate fibrillation. This is the first characterization of specific bioactive peptides synthesized on the basis of interactive domains in the small heat shock protein, alpha beta crystallin that protect against the fibrillation of amyloidogenic proteins. (C) 2007 Elsevier Ltd. All rights reserved.