A Neatly Pleated Sheet

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Science  10 Sep 2004:
Vol. 305, Issue 5690, pp. 1535
DOI: 10.1126/science.305.5690.1535b

Amyloid diseases such as Alzheimer's disease are characterized by a buildup of insoluble protein aggregates in tissues. These aggregates are formed by the conversion of normal soluble proteins into insoluble self-assembling fibrils via a soluble oligomeric intermediate that may be toxic to cells. An antibody that binds specifically to the oligomeric intermediates of several different amyloid proteins blocks toxicity, suggesting that the intermediates may share a common structure.

To identify what this structure might be, Armen et al. have modeled the conformational changes of four amyloid proteins under the low pH conditions that favor amyloid fibril formation. From their molecular dynamics simulations, they conclude that a key step in oligomeric intermediate formation is the acquisition of an α-pleated sheet that could be the target of the toxicity-blocking antibody. The α-pleated sheet, a secondary structural motif proposed more than 50 years ago by Pauling and Corey, has garnered little attention because it is rarely found in proteins. The α-pleated sheet has a residue length of 3.0 Å compared to 3.3 Å for the more common β-sheet conformation found in many proteins. The hunt is on to find this α-pleated sheet structure in the test tube; if it exists, such an unusual structure would be a valuable target for designing therapeutics. — OMS

Proc. Natl. Acad. Sci. U.S.A. 101, 11622 (2004).

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