Aβ(1-42) fibril structure illuminates self-recognition and replication of amyloid in Alzheimer's disease.
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.
Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois, USA.
Yiling
Y
Xiao
Cancer and Inflammation Program, Leidos Biomedical Research, National Cancer Institute at Frederick, Frederick, Maryland, USA.
Buyong
000000027383719X
B
Ma
Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois, USA.
Dan
D
McElheny
Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois, USA.
Sudhakar
S
Parthasarathy
Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois, USA.
Fei
F
Long
1] Institute of Biomedical Research and Innovation, Kobe, Japan. [2] Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Minako
M
Hoshi
1] Cancer and Inflammation Program, Leidos Biomedical Research, National Cancer Institute at Frederick, Frederick, Maryland, USA. [2] Sackler Institute of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Ruth
R
Nussinov
1] Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois, USA. [2] Center for Structural Biology, University of Illinois at Chicago, Chicago, Illinois, USA.
Yoshitaka
Y
Ishii
D000544:Alzheimer Disease / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D055503:Protein Multimerization
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)