Glycoconjugate Journal

, 26:999

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

  • Maho Utsumi
  • Yoshiki Yamaguchi
  • Hiroaki Sasakawa
  • Naoki Yamamoto
  • Katsuhiko Yanagisawa
  • Koichi Kato
Article

DOI: 10.1007/s10719-008-9216-7

Cite this article as:
Utsumi, M., Yamaguchi, Y., Sasakawa, H. et al. Glycoconj J (2009) 26: 999. doi:10.1007/s10719-008-9216-7

Abstract

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.

Keywords

Amyloid β-proteinGangliosideNMRAlzheimer’s disease

Abbreviations

Amyloid β-peptide

AD

Alzheimer’s disease

CD

Circular dichroism

HSQC

Heteronuclear single-quantum correlation

NMR

Nuclear magnetic resonance

PG

Phosphatidylglycerol

TROSY

Transverse relaxation-optimized spectroscopy

Supplementary material

10719_2008_9216_MOESM1_ESM.pdf (143 kb)
Supplementary Table 1Chemical shifts of 2H-, 13C-, and 15N-labeled Ab(1–40) bound to lyso-GM1a. a CaH chemical shifts were assigned for His6 (4.49 ppm), Val12 (4.35 ppm), His13 (4.49 ppm), and His14 (4.50 ppm) by using 13C- and 15N-labeled Ab(1–40) and also used for the TALOS calculation. b not detectable. (PDF 1.20 MB)
10719_2008_9216_MOESM2_ESM.pdf (152 kb)
Supplementary Fig. 1SupplementaryPlot of the molar ellipticity at 222 nm as a function of ganglioside-to-Ab(1–40) ratio. Lyso-GM1 (green), GM1 (blue) and GM1-containing liposomes composed of GM1/cholesterol/SM (40:30:30) (red). The values (mean + SD) were calculated from molar ellipticities at 222 nm in the three independent experiments. (PDF 1.20 MB)
10719_2008_9216_MOESM3_ESM.pdf (225 kb)
Supplementary Fig. 21H–15N HSQC titration of 15N-labeled Ab(1–40) (0.2 mM) with GM1 in which Ab(1–40): GM1 concentration ratio of 1:0 (red), 1:2 (blue) and 1:30 (black). The spectra were recorded at the proton observation frequency of 500 MHz. The insets show close views of trajectories of the Phe4 and Tyr10 peaks boxed (magenta and cyan, respectively). (PDF 1.20 MB)
10719_2008_9216_MOESM4_ESM.pdf (165 kb)
Supplementary Fig. 3Plots of the intensity ratios of the backbone amide peaks of Ab(1–40) with on-resonance and off-resonance irradiation of the acyl (CH2) groups of GM1 (upper) and H2O (lower). Asterisk indicates the amino acid residue that did not exhibit observable peak in the spectrum due to severe broadening. Intensity ratios are the mean + SD of three independent experiments. (PDF 1.20 MB)

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Maho Utsumi
    • 1
    • 2
    • 3
  • Yoshiki Yamaguchi
    • 1
    • 3
    • 4
  • Hiroaki Sasakawa
    • 1
    • 2
  • Naoki Yamamoto
    • 5
    • 9
  • Katsuhiko Yanagisawa
    • 5
  • Koichi Kato
    • 1
    • 2
    • 3
    • 6
    • 7
    • 8
  1. 1.Graduate School of Pharmaceutical SciencesNagoya City UniversityNagoyaJapan
  2. 2.Institute for Molecular ScienceNational Institutes of Natural SciencesOkazakiJapan
  3. 3.CREST, Japan Science and Technology AgencyKawaguchiJapan
  4. 4.Advanced Science Institute, Chemical Biology Department, Systems Glycobiology Research Group, Structural Glycobiology TeamRIKENSaitamaJapan
  5. 5.Department of Alzheimer’s Disease Research, National Institute for Longevity SciencesNational Center for Geriatrics and GerontologyObuJapan
  6. 6.Okazaki Institute for Integrative BioscienceNational Institutes of Natural SciencesOkazakiJapan
  7. 7.The Glycoscience InstituteOchanomizu UniversityTokyoJapan
  8. 8.GLYENCE Co., Ltd.NagoyaJapan
  9. 9.Department of Pharmacy, College of Pharmaceutical SciencesRitsumeikan UniversityKusatsuJapan