TY - JOUR
T1 - Aβ(1-42) fibril structure illuminates self-recognition and replication of amyloid in Alzheimer's disease
AU - Xiao, Yiling
AU - Ma, Buyong
AU - McElheny, Dan
AU - Parthasarathy, Sudhakar
AU - Long, Fei
AU - Hoshi, Minako
AU - Nussinov, Ruth
AU - Ishii, Yoshitaka
N1 - Publisher Copyright:
© 2015 Nature America, Inc. All rights reserved.
PY - 2015/6/3
Y1 - 2015/6/3
N2 - Increasing evidence has suggested that formation and propagation of misfolded aggregates of 42-residue human amyloid β (Aβ(1-42)), rather than of the more abundant Aβ(1-40), provokes the Alzheimer's disease cascade. However, structural details of misfolded Aβ(1-42) have remained elusive. Here we present the atomic model of an Aβ(1-42) amyloid fibril, from solid-state NMR (ssNMR) data. It displays triple parallel-β-sheet segments that differ from reported structures of Aβ(1-40) fibrils. Remarkably, Aβ(1-40) is incompatible with the triple-β-motif, because seeding with Aβ(1-42) fibrils does not promote conversion of monomeric Aβ(1-40) into fibrils via cross-replication. ssNMR experiments suggest that C-terminal Ala42, absent in Aβ(1-40), forms a salt bridge with Lys28 to create a self-recognition molecular switch that excludes Aβ(1-40). The results provide insight into the Aβ(1-42)-selective self-replicating amyloid-propagation machinery in early-stage Alzheimer's disease.
AB - Increasing evidence has suggested that formation and propagation of misfolded aggregates of 42-residue human amyloid β (Aβ(1-42)), rather than of the more abundant Aβ(1-40), provokes the Alzheimer's disease cascade. However, structural details of misfolded Aβ(1-42) have remained elusive. Here we present the atomic model of an Aβ(1-42) amyloid fibril, from solid-state NMR (ssNMR) data. It displays triple parallel-β-sheet segments that differ from reported structures of Aβ(1-40) fibrils. Remarkably, Aβ(1-40) is incompatible with the triple-β-motif, because seeding with Aβ(1-42) fibrils does not promote conversion of monomeric Aβ(1-40) into fibrils via cross-replication. ssNMR experiments suggest that C-terminal Ala42, absent in Aβ(1-40), forms a salt bridge with Lys28 to create a self-recognition molecular switch that excludes Aβ(1-40). The results provide insight into the Aβ(1-42)-selective self-replicating amyloid-propagation machinery in early-stage Alzheimer's disease.
UR - http://www.scopus.com/inward/record.url?scp=84930413213&partnerID=8YFLogxK
U2 - 10.1038/nsmb.2991
DO - 10.1038/nsmb.2991
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AN - SCOPUS:84930413213
SN - 1545-9993
VL - 22
SP - 499
EP - 505
JO - Nature Structural and Molecular Biology
JF - Nature Structural and Molecular Biology
IS - 6
ER -