Up-and-down topological mode of amyloid β-peptide lying on hydrophilic/hydrophobic interface of ganglioside clusters

摘要

Growing evidence has indicated that GM1 ganglioside specifically interacts with Amyloid β-peptide (Aβ) and thereby promotes Alzheimer’s disease-associated Aβ assembly. To characterize the conformation of Aβ bound to the ganglioside, we performed 920 MHz ultra-high field NMR analyses using isotopically labeled Aβ(1–40) in association with GM1 and lyso-GM1 micelles. Our NMR data revealed that (1) Aβ(1–40) forms discontinuous α-helices at the segments His14-Val24 and Ile31-Val36 upon binding to the gangliosidic micelles, leaving the remaining regions disordered, and (2) Aβ(1–40) lies on hydrophobic/hydrophilic interface of the ganglioside cluster exhibiting an up-and-down topological mode in which the two α-helices and the C-terminal dipeptide segment are in contact with the hydrophobic interior, whereas the remaining regions are exposed to the aqueous environment. These findings suggest that the ganglioside clusters serve as a unique platform for binding coupled with conformational transition of Aβ molecules, rendering their spatial rearrangements restricted to promote specific intermolecular interactions.