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- W3101755023 abstract "ABSTRACT Intramembrane cleavage of the β-amyloid precursor protein C99 substrate by γ-secretase is implicated in Alzheimer’s disease pathogenesis. Since conformational flexibility of a di-glycine hinge in the C99 transmembrane domain (TMD) might be critical for γ-secretase cleavage, we mutated one of the glycine residues, G38, to a helix-stabilizing leucine and to a helix-distorting proline. CD, NMR and hydrogen/deuterium exchange measurements as well as MD simulations showed that the mutations distinctly altered the intrinsic structural and dynamical properties of the TMD. However, although helix destabilization/unfolding was not observed at the initial ε-cleavage sites of C99, both mutants impaired γ-secretase cleavage and altered its cleavage specificity. Moreover, helix flexibility enabled by the di-glycine hinge translated to motions of other helix parts. Our data suggest that both local helix stabilization and destabilization in the di-glycine hinge may decrease the occurrence of enzyme-substrate complex conformations required for normal catalysis and that hinge mobility can be conducive for productive substrate-enzyme interactions." @default.
- W3101755023 created "2020-11-23" @default.
- W3101755023 creator A5002196787 @default.
- W3101755023 creator A5016355522 @default.
- W3101755023 creator A5018513639 @default.
- W3101755023 creator A5022068141 @default.
- W3101755023 creator A5022612053 @default.
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- W3101755023 creator A5037870803 @default.
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- W3101755023 creator A5046200708 @default.
- W3101755023 creator A5053831188 @default.
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- W3101755023 creator A5063364599 @default.
- W3101755023 creator A5075992388 @default.
- W3101755023 creator A5079092438 @default.
- W3101755023 date "2018-07-23" @default.
- W3101755023 modified "2023-09-25" @default.
- W3101755023 title "Modulating hinge flexibility in the APP transmembrane domain alters γ-secretase cleavage" @default.
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