Up-and-down topological mode of amyloid beta-peptide lying on hydrophilic/hydrophobic interface of ganglioside clusters.
Growing evidence has indicated that GM1 ganglioside specifically interacts with Amyloid beta-peptide (Abeta) and thereby promotes Alzheimer's disease-associated Abeta assembly. To characterize the conformation of Abeta bound to the ganglioside, we performed 920 MHz ultra-high field NMR analyses using isotopically labeled Abeta(1-40) in association with GM1 and lyso-GM1 micelles. Our NMR data revealed that (1) Abeta(1-40) forms discontinuous alpha-helices at the segments His(14)-Val(24) and Ile(31)-Val(36) upon binding to the gangliosidic micelles, leaving the remaining regions disordered, and (2) Abeta(1-40) lies on hydrophobic/hydrophilic interface of the ganglioside cluster exhibiting an up-and-down topological mode in which the two alpha-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 Abeta molecules, rendering their spatial rearrangements restricted to promote specific intermolecular interactions.
Utsumi
Maho
M
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan.
Yamaguchi
Yoshiki
Y
Sasakawa
Hiroaki
H
Yamamoto
Naoki
N
Yanagisawa
Katsuhiko
K
Kato
Koichi
K
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000818:Animals; D002417:Cattle; D002942:Circular Dichroism; D005732:Gangliosides / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D009682:Magnetic Resonance Spectroscopy; D008823:Micelles; D008969:Molecular Sequence Data; D011485:Protein Binding
D016229:Amyloid beta-Peptides; D005732:Gangliosides; D008823:Micelles