A structural motif of acetylcholinesterase that promotes amyloid β-peptide fibril formation

G. V. De Ferrari, M. A. Canales, I. Shin, L. M. Weiner, I. Silman, N. C. Inestrosa

Resultado de la investigación: Contribución a una revistaArtículorevisión exhaustiva

367 Citas (Scopus)


Acetylcholinesterase (AChE) has been found to be associated with the core of senile plaques. We have shown that AChE interacts with the amyloid β-peptide (Aβ) and promotes amyloid fibril formation by a hydrophobic environment close to the peripheral anionic binding site (PAS) of the enzyme. Here we present evidence for the structural motif of AChE involved in this interaction. First, we modeled the docking of Aβ onto the structure of Torpedo californica AChE, and identified four potential sites for AChE-Aβ complex formation. One of these, Site L spans a major hydrophobic sequence exposed on the surface of AChE, which had been previously shown to interact with liposomes [Shin et al. (1996) Protein Sci. 5, 42-51]. Second, we examined several AChE-derived peptides and found that a synthetic 35-residue peptide corresponding to the above hydrophobic sequence was able to promote amyloid formation. We also studied the ability to promote amyloid formation of two synthetic 24-residue peptides derived from the sequence of a Ω-loop, which has been suggested as anAChE - Aβ interacting motif. Kinetic analyses indicate that only the 35-residue hydrophobic peptide mimics the effect of intact AChE on amyloid formation. Moreover, RP-HPLC analysis revealed that the 35-residue peptide was incorporated into the growing Aβ-fibrils. Finally, fluorescence binding studies showed that this peptide binds Aβ with a Kd = 184 μM, independent of salt concentration, indicating that the interaction is primarily hydrophobic. Our results indicate that the homologous human AChE motif is capable of accelerating Aβ fibrillogenesis.

Idioma originalInglés
Páginas (desde-hasta)10447-10457
Número de páginas11
EstadoPublicada - 4 sept. 2001

Áreas temáticas de ASJC Scopus

  • Bioquímica


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