title: Is aggregation of beta-amyloid peptides a mis-functioning of a current interaction process?
abstract: In a previous study, Hughes et al. [Proc. Natl. Acad. Sci. USA 93 (1996) 2065-2070] demonstrated that the amyloid peptide is able to interact with itself in a two-hybrid system and that interaction is specific. They further supported that the method could be used to define the sequences that might be important in nucleation-dependent aggregation. The sequence of the amyloid 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 and tested by the two-hybrid approach, series of mutations spread all over the sequence and changing the distribution of hydrophobicity and/or the spatial hindrance. In the two-hybrid assay, interaction of native Abeta is reproduced. 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 all 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 are important for the native interaction. We support that the folded three-dimensional (3D) structure is the Abeta-Abeta interacting species, that the whole sequence is involved in that 3D fold which has a low secondary structure propensity and a high susceptibility to mutations and thus should have a low stability. The native fold of Abeta could be stabilized in Abeta-Abeta complexes which could in other circumstances facilitate the nucleation event of aggregation that leads to the formation of stable senile plaques.
authors: INSERM U410, Faculté X. Bichat, 75870 Paris Cedex 18, France.
authors: F
authors: F
authors: Festy
authors: L
authors: L
authors: Lins
authors: G
authors: G
authors: Péranzi
authors: J N
authors: JN
authors: Octave
authors: R
authors: R
authors: Brasseur
authors: A
authors: A
authors: Thomas
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D015686:Gene Products, env / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary / Q000502:physiology; D015682:Retroviridae Proteins, Oncogenic / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D020798:Two-Hybrid System Techniques; D014760:Viral Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015003:Yeasts / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D016229:Amyloid beta-Peptides; D015686:Gene Products, env; D010446:Peptide Fragments; D015682:Retroviridae Proteins, Oncogenic; D014760:Viral Fusion Proteins; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C059580:transmembrane protein, Simian immunodeficiency virus