The Amyloid Precursor Protein Has a Flexible Transmembrane Domain and Binds Cholesterol

Abstract

Insights into Amyloidogenesis The amyloid-β (Aβ) peptides associated with Alzheimer's disease are generated by cleavage of the transmembrane C-terminal domain (C99) of the amyloid precursor protein by the enzyme γ-secretase. Barrett et al. (p. 1168 ) used nuclear magnetic resonance (NMR) and electron paramagnetic resonance spectroscopy to show that C99 contains surface-associated N- and C-terminal helices and a flexibly curved transmembrane helix that is well suited to processive cleavage by γ-secretase. Elevated cholesterol levels have been found to increase Aβ generation. NMR titration together with mutagenesis revealed a binding site for cholesterol within C99 that included a motif previously implicated in protein oligomerization.