The β-amyloid (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. 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.
P. J. Barrett, Y. Song, W. D. Van Horn, E. J. Hustedt, J. M. Schafer, A. Hadziselimovic, A. J. Beel, C. R. Sanders, The amyloid precursor protein has a flexible transmembrane domain and binds cholesterol. Science 336, 1168–1171 (2012). [Abstract] [Full Text]