JOURNAL ARTICLE

Effects of familial Alzheimer's disease mutations on the folding nucleation of the amyloid beta-protein

Mary Griffin Krone, Andrij Baumketner, Summer L Bernstein, Thomas Wyttenbach, Noel D Lazo, David B Teplow, Michael T Bowers, Joan-Emma Shea
Journal of Molecular Biology 2008 August 1, 381 (1): 221-8
18597778
The effect of single amino acid substitutions associated with the Italian (E22K), Arctic (E22G), Dutch (E22Q) and Iowa (D23N) familial forms of Alzheimer's disease and cerebral amyloid angiopathy on the structure of the 21-30 fragment of the Alzheimer amyloid beta-protein (Abeta) is investigated by replica-exchange molecular dynamics simulations. The 21-30 segment has been shown in our earlier work to adopt a bend structure in solution that may serve as the folding nucleation site for Abeta. Our simulations reveal that the 24-28 bend motif is retained in all E22 mutants, suggesting that mutations involving residue E22 may not affect the structure of the folding nucleation site of Abeta. Enhanced aggregation in Abeta with familial Alzheimer's disease substitutions may result from the depletion of the E22-K28 salt bridge, which destabilizes the bend structure. Alternately, the E22 mutations may affect longer-range interactions outside the 21-30 segment that can impact the aggregation of Abeta. Substituting at residue D23, on the other hand, leads to the formation of a turn rather than a bend motif, implying that in contrast to E22 mutants, the D23N mutant may affect monomer Abeta folding and subsequent aggregation. Our simulations suggest that the mechanisms by which E22 and D23 mutations affect the folding and aggregation of Abeta are fundamentally different.

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