Is amyloid deposition in Alzheimer's disease preceded by an environment-induced double conformational transition?
Fragments of amyloid polypeptide (A4 or beta-protein) were synthesized on solid phase. Circular dichroism (CD) measurements showed that the N-terminal 1-12 fragment assumes an unordered conformation in water, but probably adopts a type I(III) beta-turn in trifluoroethanol (TFE). The central 11-25 fragment has a beta-sheet conformation in aqueous solution, while the full-length N-terminal 1-28 peptide shows helical features in TFE as well as in TFE-water mixtures. Based on secondary structural predictions, molecular mechanical calculations, and the differing and size-dependent conformational propensities of the smaller fragments in aqueous solution, the amyloid peptide is likely to undergo a double conformational transition that is characterized by a pleating process of its central segment. This conformational transition may start spontaneously above a critical peptide concentration, or it may be triggered by age-related or pathological changes ("watering") of the extracellular environment.
Hollosi
M
M
Institute of Organic Chemistry, L. Eotvos University, Budapest, Hungary.
Otvos
L
L
Kajtar
J
J
Percel
A
A
Lee
V M
VM
D000544:Alzheimer Disease / Q000378:metabolism*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D002942:Circular Dichroism; D006801:Humans; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D011487:Protein Conformation
D016229:Amyloid beta-Peptides; D010455:Peptides