Effects of Familial Alzheimer's Disease Mutations on the Folding Nucleation of the Amyloid β-Protein
作者： Mary Griffin Krone , Andrij Baumketner , Summer L. Bernstein , Thomas Wyttenbach , Noel D. Lazo
DOI: 10.1016/J.JMB.2008.05.069
关键词:
摘要: The effect of single amino acid substitutions associated with the Italian (E22K), Arctic (E22G), Dutch (E22Q) and Iowa (D23N) familial forms Alzheimer's disease cerebral amyloid angiopathy on structure 21-30 fragment Alzheimer beta-protein (Abeta) is investigated by replica-exchange molecular dynamics simulations. segment has been shown in our earlier work to adopt a bend solution that may serve as folding nucleation site for Abeta. Our simulations reveal 24-28 motif retained all E22 mutants, suggesting mutations involving residue not affect Enhanced aggregation Abeta result from depletion E22-K28 salt bridge, which destabilizes structure. Alternately, longer-range interactions outside can impact Substituting at D23, other hand, leads formation turn rather than motif, implying contrast D23N mutant monomer subsequent aggregation. suggest mechanisms D23 are fundamentally different.
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