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, αB crystallin that protects against the unfolding, aggregation, and toxicity of amyloidogenic proteins. Six peptides corresponding to the interactive sequences 41STSLSPFYLRPPSFLRAP58, 73DRFSVNLDVKHFS85, 101HGKHEERQDE110, 113FISREFHR120, 131LTITSSLSSDGV142, and 156ERTIPITRE164 in human αB crystallin were synthesized and evaluated in Thioflavin T fluorescence assays for their effects on the modulation of fibrillation of four disease-related amyloidogenic proteins: amyloid-β, α-synuclein, transthyretin, and β2-microglobulin. The 73DRFSVNLDVKHFS85 and 101HGKHEERQDE110 peptides in the conserved α crystallin core domain of αB crystallin were the most effective fibril inhibitors. 73DRFSVNLDVKHFS85 completely inhibited α-synuclein fibrillation and reduced the fibrillation of amyloid-β, transthyretin, and β2-microglobulin by >50%. 101HGKHEERQDE110 completely inhibited amyloid-β fibrillation and reduced the fibrillation of α-synuclein, transthyretin, and β2-microglobulin by >50%. The peptides FSVN, NLDV, HGKH, and HEER, which are synthetic fragments of 73DRFSVNLDVKHFS85 and 101HGKHEERQDE110, 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 β2-microglobulin and the synthetic bioactive peptides determined that residues Phe-75, Ser-76, Val-77, Asn-78, Leu-79, and Asp-80 in 73DRFSVNLDVKHFS85 and residues His-101, Lys-103, His-104, Glu-105, and Arg-107 in 101HGKHEERQDE110 interact with exposed residues in the β strands, F and D of transthyretin and β2-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, αB crystallin that protect against the fibrillation of amyloidogenic proteins.