Is aggregation of beta-amyloid peptides a mis-functioning of a current interaction process?

In a previous study, Hughes ct al. [Proc. Natl. Acad. Sci. USA 93 (1996) 20 65-2070] demonstrated that the amyloid peptide is able to interact with its elf in a two-hybrid system and that interaction is specific. They further s upported that the method could be used to define the sequences that might b e important in nucleation-dependent aggregation. The sequence of the amyloi d peptide can be split into four clusters, two hydrophilic (1-16 and 22-28) and two hydrophobic (17-21 and 29-42). We designed by molecular modeling a nd tested by the two-hybrid approach, series of mutations spread all over t he sequence and changing the distribution of hydrophobicity and/or the spat ial hindrance. In the two-hybrid assay, interaction of native A beta is rep roduced. Screening of mutations demonstrates that the C-domain (residues 29 -40 (42)), the median domain (residues 17-22) and the N-domain (1-16) are a ll crucial for interaction. This demonstrates that almost all fragments of the amyloid peptide but a loop (residues 23-28) and the C-term amino acid a re important for the native interaction. We support that the folded three-d imensional (3D) structure is the A beta -A beta interacting species, that t he whole sequence is involved in that 3D fold which has a row secondary str ucture propensity and a high susceptibility to mutations and thus should ha ve a low stability. The native fold of A beta could be stabilized in A beta -A beta complexes which could in other circumstances facilitate the nuclea tion event of aggregation that leads to the formation of stable senile plaq ues. (C) 2001 Elsevier Science B.V. All rights reserved.