L17A/F19A Substitutions Augment the α-Helicity of β-Amyloid Peptide Discordant Segment

Chu-Ting Liang; Hsien-Bin Huang; Chih-Ching Wang; Yi-Ru Chen; Chi-Fon Chang; Ming-Shi Shiao; Yi-Cheng Chen; Ta-Hsien Lin

doi:10.1371/journal.pone.0154327

L17A/F19A Substitutions Augment the α-Helicity of β-Amyloid Peptide Discordant Segment

PLoS One. 2016 Apr 22;11(4):e0154327. doi: 10.1371/journal.pone.0154327. eCollection 2016.

Authors

Chu-Ting Liang^{1

2}, Hsien-Bin Huang³, Chih-Ching Wang^{4

5}, Yi-Ru Chen^{4

6}, Chi-Fon Chang⁷, Ming-Shi Shiao⁸, Yi-Cheng Chen⁹, Ta-Hsien Lin^{1

2

4

5}

Affiliations

¹ Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan, R.O.C.
² Basic Research Division, Medical Research Department, Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C.
³ Department of Life Science and the Institute of Molecular Biology, National Chung Cheng University, Chiayi, Taiwan, R.O.C.
⁴ Structural Biology Program, National Yang-Ming University, Taipei, Taiwan, R.O.C.
⁵ Institute of Biochemistry & Molecular Biology, National Yang-Ming University, Taipei, Taiwan, R.O.C.
⁶ Department and Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan, R.O.C.
⁷ Genomics Research Center, Academia Sinica, Taipei, Taiwan, R.O.C.
⁸ Department of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan, R.O.C.
⁹ Department of Medicine, Mackay Medical College, Taipei, Taiwan, R.O.C.

Abstract

β-amyloid peptide (Aβ) aggregation has been thought to be associated with the pathogenesis of Alzheimer's disease. Recently, we showed that L17A/F19A substitutions may increase the structural stability of wild-type and Arctic-type Aβ40 and decrease the rates of structural conversion and fibril formation. However, the underlying mechanism for the increase of structural stability as a result of the alanine substitutions remained elusive. In this study, we apply nuclear magnetic resonance and circular dichroism spectroscopies to characterize the Aβ40 structure, demonstrating that L17A/F19A substitutions can augment the α-helicity of the residues located in the α/β-discordant segment (resides 15 to 23) of both wild-type and Arctic-type Aβ40. These results provide a structural basis to link the α-helicity of the α/β-discordant segment with the conformational conversion propensity of Aβ.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alanine / chemistry
Alzheimer Disease / metabolism*
Amyloid beta-Peptides / chemistry*
Circular Dichroism
Humans
Isotopes / chemistry
Magnetic Resonance Spectroscopy
Mutation
Protein Structure, Secondary

Substances

Amyloid beta-Peptides
Isotopes
Alanine

Grants and funding

This work was supported by grants from the National Science Council of the Republic of China (NSC99-2320-B-194-003-MY3, NSC101-2113-M-010-003-MY2 and MOST103-2113-M-010-002), Taipei Veterans General Hospital, Taiwan, ROC (V100C-180, V101C-003 and V102C-037) and a grant from Ministry of Education, Aiming for the Top University Plan.