PMID:25938662

Citation	Xiao, Y, Ma, B, McElheny, D, Parthasarathy, S, Long, F, Hoshi, M, Nussinov, R and Ishii, Y (2015) Aβ(1-42) fibril structure illuminates self-recognition and replication of amyloid in Alzheimer's disease. Nat. Struct. Mol. Biol. 22:499-505
Abstract	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.
Links	PubMed PMC4476499 Online version:10.1038/nsmb.2991
Keywords	Alzheimer Disease/physiopathology; Amyloid beta-Peptides/chemistry; Amyloid beta-Peptides/metabolism; Humans; Magnetic Resonance Spectroscopy; Models, Molecular; Peptide Fragments/chemistry; Peptide Fragments/metabolism; Protein Binding; Protein Conformation; Protein Folding; Protein Multimerization
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:A4	enables	GO:0042802: identical protein binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:P05067:PRO_0000000092	F		Seeded From UniProt	complete

References

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