Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 53, Issue 27, Pages 6888-6892Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201402636
Keywords
amyloid beta-peptides; NMR spectroscopy; protein folding; toxic oligomers; transient structures
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Funding
- SERC of the Department of Science and Technology, India [SR/S1/PC/27/2009]
- Dept. of Biotechnology, India [BT/53/NE/TBP/2010]
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Small oligomers of the amyloid beta (A beta) 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 A beta(40) 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 A beta 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.
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