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Conformational changes induced by the A21G Flemish mutation in the amyloid precursor protein lead to increased A? production.

ABSTRACT: Proteolysis of the ? C-terminal fragment (?-CTF) of the amyloid precursor protein generates the A? peptides associated with Alzheimer's disease. Familial mutations in the ?-CTF, such as the A21G Flemish mutation, can increase A? secretion. We establish how the Flemish mutation alters the structure of C55, the first 55 residues of the ?-CTF, using FTIR and solid-state NMR spectroscopy. We show that the A21G mutation reduces ? sheet structure of C55 from Leu17 to Ala21, an inhibitory region near the site of the mutation, and increases ?-helical structure from Gly25 to Gly29, in a region near the membrane surface and thought to interact with cholesterol. Cholesterol also increases A? peptide secretion, and we show that the incorporation of cholesterol into model membranes enhances the structural changes induced by the Flemish mutant, suggesting a common link between familial mutations and the cellular environment.

SUBMITTER: Tang TC 

PROVIDER: S-EPMC3952111 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Conformational changes induced by the A21G Flemish mutation in the amyloid precursor protein lead to increased Aβ production.

Tang Tzu-Chun TC   Hu Yi Y   Kienlen-Campard Pascal P   El Haylani Laetitia L   Decock Marie M   Van Hees Joanne J   Fu Ziao Z   Octave Jean-Noel JN   Constantinescu Stefan N SN   Smith Steven O SO  

Structure (London, England : 1993) 20140123 3

Proteolysis of the β C-terminal fragment (β-CTF) of the amyloid precursor protein generates the Aβ peptides associated with Alzheimer's disease. Familial mutations in the β-CTF, such as the A21G Flemish mutation, can increase Aβ secretion. We establish how the Flemish mutation alters the structure of C55, the first 55 residues of the β-CTF, using FTIR and solid-state NMR spectroscopy. We show that the A21G mutation reduces β sheet structure of C55 from Leu17 to Ala21, an inhibitory region near t  ...[more]

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