Interactive sequences in the molecular chaperone, human alphaB crystallin modulate the fibrillation of amyloidogenic proteins.
Multiple interactive domains are involved in the activity of the stress protein, alphaB 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 alphaB 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-beta, alpha-synuclein, transthyretin, and beta2-microglobulin. The 73DRFSVNLDVKHFS85 and 101HGKHEERQDE110 peptides in the conserved alpha crystallin core domain of alphaB crystallin were the most effective fibril inhibitors. 73DRFSVNLDVKHFS85 completely inhibited alpha-synuclein fibrillation and reduced the fibrillation of amyloid-beta, transthyretin, and beta2-microglobulin by >50%. 101HGKHEERQDE110 completely inhibited amyloid-beta fibrillation and reduced the fibrillation of alpha-synuclein, transthyretin, and beta2-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 beta2-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 beta strands, F and D of transthyretin and beta2-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, alphaB crystallin that protect against the fibrillation of amyloidogenic proteins.
Ghosh
Joy G
JG
Department of Biological Structure, University of Washington, Seattle, WA 98195, USA. jghosh@rics.bwh.harvard.edu
Houck
Scott A
SA
Clark
John I
JI
D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry* / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D011228:Prealbumin / Q000737:chemistry; D038203:alpha-Crystallin B Chain / Q000737:chemistry*; D001613:beta 2-Microglobulin / Q000737:chemistry
D000682:Amyloid; C059215:CRYAB protein, human; D010455:Peptides; D011228:Prealbumin; D038203:alpha-Crystallin B Chain; D001613:beta 2-Microglobulin