TY - JOUR
T1 - Polymorphism of Alzheimer's Aβ17-42 (p3) oligomers
T2 - The importance of the turn location and its conformation
AU - Miller, Yifat
AU - Ma, Buyong
AU - Nussinov, Ruth
PY - 2009/8/19
Y1 - 2009/8/19
N2 - Aβ17-42 (so-called p3) amyloid is detected in vivo in the brains of individuals with Alzheimer's disease or Down's syndrome. We investigated the polymorphism of Aβ17-42 oligomers based on experimental data from steady-state NMR measurements, electron microscopy, two-dimensional hydrogen exchange, and mutational studies, using all-atom moleculardynamics simulation with explicit solvent. We assessed the structural stability and the populations. Our results suggest that conformational differences in the U-turn of Aβ17-42 lead to polymorphism in β-sheet registration and retention of an ordered β-strand organization at the termini. Further, although the parallel Aβ17-42 oligomer organization is the most stable of the conformers investigated here, different antiparallel Aβ17-42 organizations are also stable and compete with the parallel architectures, presenting a polymorphic population. In this study we propose that 1), the U-turn conformation is the primary factor leading to polymorphism in the assembly of Aβ17-42 oligomers, and is also coupled to oligomer growth; and 2), both parallel Aβ17-42 oligomers and an assembly of Aβ17-42 oligomers that includes both parallel and antiparallel organizations contribute to amyloid fibril formation. Finally, since a U-turn motif generally appears in amyloids formed by full proteins or long fragments, and since to date these have been shown to exist only in parallel architectures, our results apply to a broad range of oligomers and fibrils.
AB - Aβ17-42 (so-called p3) amyloid is detected in vivo in the brains of individuals with Alzheimer's disease or Down's syndrome. We investigated the polymorphism of Aβ17-42 oligomers based on experimental data from steady-state NMR measurements, electron microscopy, two-dimensional hydrogen exchange, and mutational studies, using all-atom moleculardynamics simulation with explicit solvent. We assessed the structural stability and the populations. Our results suggest that conformational differences in the U-turn of Aβ17-42 lead to polymorphism in β-sheet registration and retention of an ordered β-strand organization at the termini. Further, although the parallel Aβ17-42 oligomer organization is the most stable of the conformers investigated here, different antiparallel Aβ17-42 organizations are also stable and compete with the parallel architectures, presenting a polymorphic population. In this study we propose that 1), the U-turn conformation is the primary factor leading to polymorphism in the assembly of Aβ17-42 oligomers, and is also coupled to oligomer growth; and 2), both parallel Aβ17-42 oligomers and an assembly of Aβ17-42 oligomers that includes both parallel and antiparallel organizations contribute to amyloid fibril formation. Finally, since a U-turn motif generally appears in amyloids formed by full proteins or long fragments, and since to date these have been shown to exist only in parallel architectures, our results apply to a broad range of oligomers and fibrils.
UR - http://www.scopus.com/inward/record.url?scp=69449099387&partnerID=8YFLogxK
U2 - 10.1016/j.bpj.2009.05.042
DO - 10.1016/j.bpj.2009.05.042
M3 - Article
AN - SCOPUS:69449099387
SN - 0006-3495
VL - 97
SP - 1168
EP - 1177
JO - Biophysical Journal
JF - Biophysical Journal
IS - 4
ER -