Significant structural differences between transient amyloid-β oligomers and less-toxic fibrils in regions known to harbor familial Alzheimer's mutations.
Small oligomers of the amyloid β (Aβ) peptide, rather than the monomers or the fibrils, are suspected to initiate Alzheimer's disease (AD). However, their low concentration and transient nature under physiological conditions have made structural investigations difficult. A method for addressing such problems has been developed by combining rapid fluorescence techniques with slower two-dimensional solid-state NMR methods. The smallest Aβ40 oligomers that demonstrate a potential sign of toxicity, namely, an enhanced affinity for cell membranes, were thus probed. The two hydrophobic regions (residues 10-21 and 30-40) have already attained the conformation that is observed in the fibrils. However, the turn region (residues 22-29) and the N-terminal tail (residues 1-9) are strikingly different. Notably, ten of eleven known Aβ mutants that are linked to familial AD map to these two regions. Our results provide potential structural cues for AD therapeutics and also suggest a general method for determining transient protein structures.
Department of Chemical Sciences, Tata Institute of Fundamental Research, Homi Bhabha Road, Colaba, Mumbai 400005 (India).
Bidyut
B
Sarkar
Venus Singh
VS
Mithu
Bappaditya
B
Chandra
Arghya
A
Mandal
Muralidharan
M
Chandrakesan
Debanjan
D
Bhowmik
Perunthiruthy K
PK
Madhu
Sudipta
S
Maiti
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000235:genetics* / Q000378:metabolism / Q000633:toxicity; D002462:Cell Membrane / Q000187:drug effects; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D009682:Magnetic Resonance Spectroscopy; D009154:Mutation; D010446:Peptide Fragments / Q000235:genetics* / Q000378:metabolism / Q000633:toxicity; D017510:Protein Folding; D017434:Protein Structure, Tertiary
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)
NMR spectroscopy; amyloid β-peptides; protein folding; toxic oligomers; transient structures