Interactive sequences in the molecular chaperone, human αB crystallin modulate the fibrillation of amyloidogenic proteins
- 作者：Joy G. Ghosh ; Scott A. Houck ; John I. Clark
- 关键词：Crystallin ; Chaperone ; Fibril ; Amyloid ; Synuclein ; Transthyretin ; Microglobulin ; Alzheimer's disease ; Parkinson's disease
- 刊名：The International Journal of Biochemistry and Cell Biology
- 出版年：2008
- 期刊代码：127_13572725
- 类别：med
- 出版时间：2008
- 卷：40
- 期：5
- 页码：954-967
- 文件大小：1415 K
摘要
Multiple interactive domains are involved in the activity of the stress protein, 
B 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 B 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, -synuclein, transthyretin, and β2-microglobulin. The 73DRFSVNLDVKHFS85 and 101HGKHEERQDE110 peptides in the conserved crystallin core domain of B crystallin were the most effective fibril inhibitors. 73DRFSVNLDVKHFS85 completely inhibited -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 -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, B crystallin that protect against the fibrillation of amyloidogenic proteins.
B 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 B 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, -synuclein, transthyretin, and β2-microglobulin. The 73DRFSVNLDVKHFS85 and 101HGKHEERQDE110 peptides in the conserved crystallin core domain of B crystallin were the most effective fibril inhibitors. 73DRFSVNLDVKHFS85 completely inhibited -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 -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, B crystallin that protect against the fibrillation of amyloidogenic proteins.