L17A/F19A Substitutions Augment the α-Helicity of β-Amyloid Peptide Discordant Segment.
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.
Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan, R.O.C.|Basic Research Division, Medical Research Department, Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C.
Chu-Ting
CT
Liang
Department of Life Science and the Institute of Molecular Biology, National Chung Cheng University, Chiayi, Taiwan, R.O.C.
Hsien-Bin
HB
Huang
Structural Biology Program, National Yang-Ming University, Taipei, Taiwan, R.O.C.|Institute of Biochemistry & Molecular Biology, National Yang-Ming University, Taipei, Taiwan, R.O.C.
Chih-Ching
CC
Wang
Structural Biology Program, National Yang-Ming University, Taipei, Taiwan, R.O.C.|Department and Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan, R.O.C.
Yi-Ru
YR
Chen
Genomics Research Center, Academia Sinica, Taipei, Taiwan, R.O.C.
Chi-Fon
CF
Chang
Department of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan, R.O.C.
Ming-Shi
MS
Shiao
Department of Medicine, Mackay Medical College, Taipei, Taiwan, R.O.C.
Yi-Cheng
YC
Chen
Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan, R.O.C.|Basic Research Division, Medical Research Department, Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C.|Structural Biology Program, National Yang-Ming University, Taipei, Taiwan, R.O.C.|Institute of Biochemistry & Molecular Biology, National Yang-Ming University, Taipei, Taiwan, R.O.C.
Ta-Hsien
TH
Lin
D000409:Alanine / Q000737:chemistry; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D002942:Circular Dichroism; D006801:Humans; D007554:Isotopes / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D009154:Mutation; D017433:Protein Structure, Secondary
D016229:Amyloid beta-Peptides; D007554:Isotopes; D000409:Alanine