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

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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.

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Abbreviations

Aβ:

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

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Acknowledgements

This work was supported in part by Nanotechnology Network Project and Grants in Aid for Scientific Research (18023032, 20023033) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by the Joint Studies Program of the Institute for Molecular Science, Japan. We thank Michiko Nakano for her help in the ultra-high field NMR measurements.

Author information

Author notes

  1. Naoki Yamamoto

    Present address: Department of Pharmacy, College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, 525-8577, Japan

Authors and Affiliations

  1. Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, 467-8603, Japan

    Maho Utsumi, Yoshiki Yamaguchi, Hiroaki Sasakawa & Koichi Kato

  2. Institute for Molecular Science, National Institutes of Natural Sciences, 5-1 Higashiyama Myodaiji, Okazaki, 444-8787, Japan

    Maho Utsumi, Hiroaki Sasakawa & Koichi Kato

  3. CREST, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, 332-0012, Japan

    Maho Utsumi, Yoshiki Yamaguchi & Koichi Kato

  4. Advanced Science Institute, Chemical Biology Department, Systems Glycobiology Research Group, Structural Glycobiology Team, RIKEN, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan

    Yoshiki Yamaguchi

  5. Department of Alzheimer’s Disease Research, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, 36–3 Gengo, Morioka, Obu, 474-8522, Japan

    Naoki Yamamoto & Katsuhiko Yanagisawa

  6. Okazaki Institute for Integrative Bioscience, National Institutes of Natural Sciences, 5-1 Higashiyama Myodaiji, Okazaki, 444-8787, Japan

    Koichi Kato

  7. The Glycoscience Institute, Ochanomizu University, 2-1-1 Ohtsuka, Bunkyo-ku, Tokyo, 112-8610, Japan

    Koichi Kato

  8. GLYENCE Co., Ltd., 2-22-8 Chikusa, Chikusa-ku, Nagoya, 474-0858, Japan

    Koichi Kato

Authors
  1. Maho Utsumi
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  5. Katsuhiko Yanagisawa
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Corresponding author

Correspondence to Koichi Kato.

Electronic supplementary material

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Supplementary Table 1

Chemical 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)

Supplementary Fig. 1

SupplementaryPlot 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)

Supplementary Fig. 2

1H–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)

Supplementary Fig. 3

Plots 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)

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Utsumi, M., Yamaguchi, Y., Sasakawa, H. et al. Up-and-down topological mode of amyloid β-peptide lying on hydrophilic/hydrophobic interface of ganglioside clusters. Glycoconj J 26, 999–1006 (2009). https://doi.org/10.1007/s10719-008-9216-7

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